The skin is the largest organ of the body, and skin disease is unique in often being immediately visible to others. This is one reason why dermatologic disease is accompanied by significant psychological distress and psychiatric morbidity.^1,2

Many dermatologic disorders are associated with negative quality of life, and psychiatric disturbances are reported in at least 30% of these patients.^2,3 There are many reasons for the elevated frequency of psychiatric disturbance in dermatologic patients, including disfigurement, perceived social stigma, and unforeseen changes in lifestyle. Although less common, the dermatologist may also encounter primary psychiatric disorders, including obsessive-compulsive disorder, trichotillomania, dysmorphophobia, delusions of parasitosis, and factitious disorder. Skin conditions and psychiatric symptoms may be present concomitantly in some illnesses, such as systemic lupus erythematosus or porphyria. And medications utilized in dermatologic practice, such as corticosteroids, may precipitate psychiatric symptoms.

The connection between brain and skin begins in the embryo, when the nervous system and epidermis originate from the same tissue layer (ectoderm). They then maintain close neural, endocrine, and immunologic connections throughout life, including being targets of the same immunologic processes, neurotransmitters, neuropeptides, and second messengers.^4,5 It is hypothesized that chemical messengers released by epidermal keratinocytes influence the brain, and this may account for an association between the severity of certain skin diseases (e.g., atopic dermatitis, psoriasis) and depression or anxiety.⁵ When a large area of skin is involved, cytokine levels may be of sufficient concentration to affect mental state.⁶

This chapter focuses on the most common dermatologic illnesses associated with depression: acne vulgaris, herpes zoster (HZ) (shingles), psoriasis, vitiligo, and atopic dermatitis (Fig. 12-1).

INTRODUCTION

Acne is very common in adolescence and is strongly associated with depressive symptoms. Acne has an adverse effect on quality of life comparable to that of epilepsy, asthma, diabetes, and arthritis. Although the disorder is self-limited for many, even patients with mild to moderate acne may have significant psychosocial difficulties. Acne can also be severe and disfiguring, with profound and lifelong consequences for a significant number of patients. Sequelae include hypertrophic or pitted scarring, poor body image, interpersonal problems, social withdrawal, higher unemployment rates, lower self-esteem, depression, anxiety, suicidal ideation, and suicide. Further complicating care, acne is exacerbated by emotional and psychosocial stress and associated with major depression.^7,8

EPIDEMIOLOGY

Facial acne has an overall prevalence of 54%, though most is mild, and clinically significant facial acne is present in 3% of men and 12% of women (Box 12-1).⁹ It typically begins early in puberty, triggered by hormonal changes. It may precede menarche in girls by one or more years.¹⁰ Acne may become chronic and persist into adulthood and a small percentage of cases develop after age 25. Acne is found in 85% of the population between 12 and 24 years of age and is moderate to severe in 15% to 20% of those affected. Fifty percent of boys aged 10 and 11 and 78% of girls between ages 8 and 12 have some degree of acne. Visible acne is present in up to 64% of people ages 20 to 29, 43% in ages 30 to 39 years, and 24.3% in ages 40 to 49.¹¹

PATHOPHYSIOLOGY

Acne is a disorder of the pilosebaceous unit that involves obstructive desquamation of keratinocytes lining the hair follicle, excess sebum production, development of noninflammatory lesions (open and closed comedones), inflammatory lesions (papules, pustules, nodules), and the presence of Propionibacterium acnes (Box 12-2).¹⁰ Acne has a significant genetic component, occurring in up to 78% of first-degree relatives and 75% of second-degree relatives.¹² In patients with positive family history, acne begins at a younger age and tends to be more severe.^13,14

Epidermal cells have androgen and interleukin (IL)-1 receptors. In acne IL-1 is upregulated, triggering an immune response of IL-1.¹⁵ Before microcomedone formation, there is follicular inflammatory infiltration with memory and effector T-cells of the immune system, thought to be a response to an antigen produced by the bacteria P. acnes.

P. acnes binds to receptors on sebocytes, dendritic cells, and keratinocytes. That receptor in turn triggers multiple chemokines, including tumor necrosis factor (TNF)-α, IL-8, and IL-6, which causes infiltration of lymphocytes, monocytes, neutrophils, and macrophages that also produce these cytokines. The keratinocytes lining the follicle infundibulum thus proliferate, delay desquamation, and obstruct the outflow of sebum resulting in comedone formation (Fig. 12-2).¹⁵

Sebaceous glands also contain multiple receptors for hormones, cytokines, and neurotransmitters and increase production of sebum in response to these. Substance P is released during stress and potentiates sebaceous gland response to cytokines and TNF-α. Progression of this process can lead to follicular membrane disruption and fatty acid egress into the dermis with dissolution of extracellular matrix. This results in papules, pustules, and nodules.

Androgens must be present for sebum production in both normal and acne-affected skin. Hyperkeratinized sebaceous gland development and production of adult sebum is mediated by androgen receptors on sebocytes and keratinocytes. Skin cells themselves also manufacture androgen hormones from cholesterol.

Sebaceous glands have numerous receptors for androgen and estrogen hormones, TSH, histamine, prostaglandins, corticotropin-releasing hormone, neurotransmitters, neuropeptides, and other chemical messengers. There are changes in the quantity and composition of sebum produced at the onset of puberty, which is thought to support increased proliferation of P. acnes. Although the mechanism of the coordination of onset between puberty and acne is unclear, it is hypothesized that this is due to the hypothalamic–pituitary–adrenal axis.¹⁵

CLINICAL PRESENTATION AND ASSESSMENT OF DEPRESSION IN ACNE

The relationships among depression, psychological stress, and acne are complex. Acne occurs predominantly in adolescence, and adolescents are at high risk for suicidal behavior (Box 12-3). The prevalence of suicidal ideation is greater in adolescents with subthreshold anxiety or subthreshold depression and greater still in patients who meet criteria for depression or anxiety disorder.¹⁶

Most studies that consider the psychological effects of acne find decreased quality of life and increased psychiatric comorbidity. Most are uncontrolled and collect data with self-report questionnaires to measure the severity of acne and psychiatric symptoms. A summary of 16 studies published between 1981 and 2007¹⁷ demonstrated an increased risk of psychiatric comorbidity in patients with acne, though methods and populations in the studies varied and two of the studies do not show increased risk of depression or anxiety.^18,19 In the most significant of these studies²⁰ patients with acne were at higher risk than a non-acne comparison group for depression (29.5% vs. 0%) and anxiety (26.2% vs. 0%); there was no significant difference in age or gender between the groups. No correlations were found between acne severity and depression or anxiety, or quality of life.

The effect of acne on emotional status has been examined and compared to a random sample of the general population and to patients with other chronic medical illnesses. Although quality of life measures do not correlate with acne severity, self-esteem scores in acne patients are significantly lower, particularly for women. Acne patients are at higher risk for nonpsychotic psychiatric disorders (41% vs. 31%).²¹ When compared to patients with asthma, epilepsy, diabetes, arthritis, and coronary heart disease, those with acne had significant impairments in mental health, social functioning, energy/vitality, and role limitations due to emotional problems.²¹ Although acne patients did not view themselves as ill on the perceived health dimension (community subjects with these chronic illnesses did), the mental health scores for acne patients were worse than for these other chronic illnesses. Role limitations for emotional reasons were worse for the other medical conditions, except for diabetes and coronary heart disease.²¹

The risk of suicidality is elevated in acne patients.²² A large study of patients with chronic and potentially disfiguring dermatologic disorders, specifically noncystic facial acne, alopecia areata, atopic dermatitis, and psoriasis,²³ found that acne patients had significantly higher risk of depression and of active suicidal ideation than all other groups except for inpatients with psoriasis. Patients with acne were younger, and this may have contributed to the higher rate of active suicidality.

Community-based studies show variable associations between acne, psychological distress, psychiatric disorders, and suicidality.²² A large New Zealand survey of adolescents revealed an association between greater subjective acne severity (“having really bad or terrible problem with acne”) and severity of depressive and anxiety symptoms, and an increased risk of suicide attempts.²⁴ The association between acne and suicide attempts persisted after controlling for depressive and anxiety.²⁴

Patients with depression and anxiety may perceive their acne as more severe due to the cognitive-emotional effects of their mood symptoms.²⁴ It is also possible that depression and/or anxiety physiologically affect the actual severity of acne. Alternatively, hormonal changes of puberty may independently affect both the rates of acne and of mood/anxiety disorders. In addition, acne may contribute to depression and anxiety via negative cutaneous body image, lower self-esteem, and impaired social functioning.

In sum, although study findings are inconsistent, undiagnosed mood and anxiety disorders clearly carry significant risk in this population. These include developmental, psychosocial, and functional impairment and increased rates of suicidality in patients with acne. These risks are not clearly associated with the objective severity of acne. Suicidal thoughts and behaviors may not correlate with the presence of psychiatric syndromes. It is strongly recommended that clinicians treating patients with acne assess mood and anxiety symptoms and specifically inquire about suicidal ideation and behaviors.

TREATMENT

ACNE MEDICATIONS AND DEPRESSION

Important issues to consider when treating comorbid depression and acne are the effects of acne medications on mood, the dermatological side effects of psychotropics, and drug–drug interactions.

There are numerous topical acne treatments, prescription and over-the-counter.¹⁰ These do not have known adverse psychiatric effects, with the possible exception of dapsone,²⁵ and there are no known drug–drug interactions between psychiatric medications and these topical agents (Table 12-1).

Systemic acne therapies include antibiotics, hormone therapy, glucocorticoids, gonadotropin-releasing hormone agonists, anti-androgens, and isotretinoin (Box 12-4).¹⁰ Isotretinoin has a controversial association with depression and suicidality, and from its release in 1982 until 2000 the FDA received reports of depression, suicidal ideation, suicide attempts, and completed suicide. Sixty-two percent of these patients had past psychiatric history or other risk factors for suicidality.²⁶ One-hundred ten patients with a median age of 17 years were hospitalized for depression, suicidal ideation, and suicide attempts while using or after stopping isotretinoin. Sixty-nine percent had a previous psychiatric history or other potentially contributing factors.

However, determining the role that isotretinoin may play in suicidality is challenging. As noted above, since adolescents and individuals with acne have increased prevalence of mood symptoms and suicidal ideation. A review of 12 controlled studies²⁶ found no increased risk for depression, anxiety, or suicide attempts, and on the contrary suggested that isotretinoin improved depression in comparison to the control population or the baseline patient’s status. This improvement in depressive symptoms was associated with improvement of severe acne in these studies. Although other studies show no increased risk of depression or suicide in patients taking isotretinoin, a retrospective cohort study and a case–control study both showed a slight increase in the relative risk of suicide attempts in patients taking isotretinoin.^27,28 There may be a small subpopulation of patients who are at increased risk for depression or suicide attempts when exposed to isotretinoin²⁶ and depression in these patients apparently improved after drug cessation.

Clinicians should consider patients’ past psychiatric histories, assess for depressive symptomatology and suicidal ideation, and maximize communication with patients who experience depression on isotretinoin. Discussing likely outcomes of isotretinoin treatment may help patients to have more realistic expectations of therapy, which may reduce the occurrence of “lost hope.” In some cases, it may be beneficial to obtain a psychiatric consultation before initiating this agent.

PSYCHOTROPIC MEDICATIONS AND ACNE

Dermatologic adverse drug reactions often occur with psychotropic medications; 2% to 5% of patients taking psychiatric medications experience adverse skin reactions (Box 12-5).²⁹ Acne-type adverse skin reactions are common with lithium.³⁰ The literature reveals no established increased incidence of specifically acne with all classes of antidepressants (TCA, SSRI, SNRI, MAOI, bupropion).³¹ With the exception of isolated case reports, there is no known association of increased frequency of acne with anticonvulsants commonly prescribed for psychiatric disorders (valproic acid/divalproex, lamotrigine, gabapentin, oxcarbazepine, carbamazepine) or antipsychotic medications. However, acne may occur secondarily as part of psychotropic-associated endocrine syndromes, such as hyperprolactinemia or polycystic ovarian syndrome.^32,33

Other dermatologic reactions, both mild (e.g., rash, pruritus) and serious (erythema multiforme, Steven Johnson syndrome, toxic epidermal necrolysis), may occur with many psychotropics.

DRUG–DRUG INTERACTIONS

There are numerous potential drug–drug interactions between systemic treatments for acne and psychotropic medications, especially as many different classes of medication are prescribed for acne (Box 12-6 and Table 12-2). Potential effects include cytochrome P450–mediated interactions, additive QT prolongation, cumulative lowering of seizure threshold, electrolyte imbalances increasing risk of QT prolongation, decreased renal clearance of lithium or unpredictable effects on lithium levels, synergistic hyperprolactinemia, increased risks of hyponatremia and SIADH, and increased risk of orthostatic hypotension.³⁴ Specific interactions of selected medications are summarized in Table 12-2.

SUMMARY

There appears to be a synergistic, bidirectional relationship between acne vulgaris and depression. Clinical research has shown increased risks of depression and suicidality in patients with acne, although confounding factors (e.g., developmental stage of onset of acne) are difficult to exclude. Laboratory research has elucidated pathophysiologic relationships between depression and acne, potentially linking cutaneous disease with neuroendocrine, neurotransmitter, and neuroimmunologic processes of depression. In view of the high prevalence of acne and its association with depressive symptoms, including suicidality, increased awareness of this comorbidity, and recognition and active treatment of both these conditions, could have enduring beneficial effects.

INTRODUCTION

HZ (“shingles”) is a neurocutaneous infection caused by reactivation of endogenous varicella zoster virus (VZV) in the dorsal sensory ganglia after initial infection with varicella (“chickenpox”). Upon initial infection, VZV passes from cutaneous and mucosal lesions into sensory nerve endings and is transported up the sensory nerves to the sensory ganglia.³⁵ Infected T-cells may also transport VZV via sensory ganglia. There the virus becomes dormant and resides until reactivation.