Relevant issues in pharmacotherapy of psycho-cutaneous disorders.

Psychiatric disorders frequently co-occur with dermatological conditions and psychotropic agents may be indicated in treating the underlying psychiatric symptoms. Use of psychotropics can be associated with significant cutaneous adverse effects as well as drug interactions with pharmacological agents used in treatment of the dermatological conditions. Knowledge of indication, contraindication, side effects, and interactions of psycho-tropics is essential for the practicing dermatologist in managing psycho-dermatological conditions. This review aims at discussing relevant issues in pharmacological management of psycho-cutaneous disorders.

Introduction

The psychotropic medications most commonly prescribed in patients with psycho-cutaneous disorders are those that target anxiety, depression, psychosis, compulsive disorders and impulse control disorders. Psychiatric side effects of dermatologic drugs can be significant but are less commonly seen than the cutaneous side effects of psychotropic medications. This review focuses on the salient points to be kept in mind during pharmacotherapeutic management of psychodermatological disorders and also some of the frequent drug interactions and side effects that clinicians may encounter in day to day practice.

Overview of Psychotropic Drugs

Drugs frequently used by psychiatrists that may also be required in a psychodermatological setting are antipsychotics, anti-depressants, anxiolytics and mood-stabilizers. Anti-psychotics maybe be first generation or second generation depending on the receptors on which they act and side effect profile. A number of randomized, controlled trials (RCTs) suggest that Second Generation Antipsychotics (SGAs) may offer some advantages over First generation Antipsychotics (FGAs), such as lesser incidence of Extra-pyramidal symptoms (EPS) and tardive dyskinesia (TD).[1] However SGAs are associated with higher incidence of metabolic adverse effects like weight gain, diabetes mellitus, and dyslipidemia.[2] Among anti-depressants, use of Selective Serotonin Re-Uptake Inhibitors (SSRIs) and tricyclic antidepressants (such as amitriptyline, doxepin) is currently the treatment of choice. Newer antidepressants include Serotonin Norepinephrine Re-uptake Inhibitors (SNRI's) like venlafaxine and duloxetine as well as Noradrenergic and Specific Serotonergic Antidepressants (NaSSAs) like mirtazapine. Anxiolytics include medications for immediate, short term relief of anxiety like benzodiazepines and drugs for prolonged treatment for which purpose buspirone and SSRI's have been found to be effective. Mood stabilizers which are used primarily for the treatment of bipolar disorders include drugs like lithium, sodium valproate, carbamazepine and lamotrigine.

The important classes of medications that may be required in psycho-dermatology are summarized in Table 1.

Table 1

Psychotropics and important cutaneous adverse effects

Treatment of psychiatric disorders associated with dermatological conditions

The indication for psychopharmacology is generally directed at the predominant psychiatric symptoms underlying the skin disorder.

Treatment of Delusional Disorders

The treatment of choice for monosymptomatic hypochondriacal psychosis like delusional parasitosis is a first generation antipsychotic drug called Pimozide. Pimozide is similar to haloperidol in chemical structure and potency, and has been shown to be uniquely effective in the treatment of this condition, especially in decreasing formication.[3] The effective dose range is 4-6 mg/day which is gradually titrated.[4] Among the SGA's, risperidone has some demonstrated efficacy in delusional disorders.[5] The challenge in pharmacological management of patients with delusional disorders; who do not have insight into their symptoms, lies in introducing the antipsychotic without offending the patient in a tactful and diplomatic manner.

Treatment of Depressive Disorders

Patients with neurotic excoriations usually may have underlying depression or anxiety. A commonly used antidepressant with potential benefit in dermatological conditions is Doxepin. This is a tricyclic antidepressant with anti-pruritic, anti-histaminic effects as well as sedative/tranquilizing effects. As many people with depression who excoriate their lesions are agitated, the sedative effect of this drug provides a valuable therapeutic benefit. These patients create their own skin lesions as they continue to pick at their skin, not allowing it to heal, thus the ‘itch-scratch-cycle’ may create intensely itchy patches that can benefit from the antipruritic effect of doxepin.[6] The dose should begin with 25-50 mg in the evening and then be titrated at 5-7/day intervals to a higher dose up to the target dose of 100-200 mg/day. The antidepressant effect is not usually evident until after two weeks, and the therapeutic effect can only then be assessed. However, the onset of antipruritic effect is immediate. Sedation, malaise, orthostatic hypotension, weight gain, and anticholinergic side effects such as dry mouth may occur and sometimes lead to discontinuation of the drug by the patient.[7] Other conditions where tricyclic antidepressants have been successfully used are in chronic urticaria, nocturnal pruritus in atopic dermatitis, post-herpetic neuralgia, psoriasis, acne, hyperhidrosis, alopecia areata and psychogenic pruritus.[8]

Selective serotonin reuptake inhibitors (SSRIs) are among the newer antidepressants with similar efficacy as the tricyclic antidepressants but have fewer side effects and are emerging as drug of choice for treatment of depressive disorders. Use of antidepressants may be associated with a small increased risk of suicide; especially in adolescents, if somatic symptoms like energy levels and drive improves before the mood change occurs. If there is no adequate improvement in symptoms after four to six weeks, a different anti-depressant should be selected as an alternative.[7]

SSRIs are generally much better tolerated than tricyclic antidepressants. States of restlessness, nervousness, and insomnia may occur as side effects. Some patients complain of nausea, diarrhea, and an increase in anxiety symptoms. Cutaneous reactions to SSRI's are rare but toxic epidermal necrolysis, Steven-Johnson's Syndrome, leukocytoclastic vasculitis and palpable purpuric erythema on sun-exposed areas have been reported with paroxetine, fluvoxamine and fluoxetine.[8-12] SSRIs can also lead to erectile dysfunction.[13] in this case, the antidepressant group should be changed, for example to non-SSRIs like venlafaxine, duloxetine, bupropion or mirtazapine, or to supplementary therapy with peripherally active substances such as the phosphodiesterase inhibitors sildenafil and vardenafil.[1415]

Occasionally, depressive episodes may occur as a part of Bipolar Disorder in which case mood stabilizers like lithium, sodium valproate, carbamazepine and lamotrigine are used which have certain relevant dermatological adverse effects and drug interactions that have been discussed subsequently.

Treatment of disorders of the obsessive compulsive spectrum

When the underlying psychopathology is obsessive-compulsive in nature, as is usually the case in disorders like dermatitis para-artefacta with impaired impulse control (acne excoriee, trichotillomania, and onychophagia), SSRI's like sertraline, fluoxetine, paroxetine, fluvoxamine and clomipramine can be helpful in the pharmacological management. A higher dose of SSRI than what is conventionally prescribed in treatment of depressive disorders is necessary. The treatment trial should last at least 8-12 weeks until improvement in symptoms can be rated, and a different preparation should be selected only after this period. SSRI's are also effective in the treatment of Body-Dysmorphic disorders.[7]

Treatment of anxiety disorders

Psychophysiologic disorders are conditions that are frequently precipitated or exacerbated by emotional stress like alopecia areata, atopic dermatitis, psoriasis, seborrhoeic dermatitis and urticaria.[16] When the patients stress or tension is intense enough to warrant consideration of an anxiolytic, two different classes of medications are generally opted for. Benzodiazepines like lorazepam and clonazepam provide rapid immediate relief from anxiety.[17] However these drugs should not be continued for a long time because of habituation potential. Long term use of benzodiazepines may also lead to the development of tolerance to the medication with reduced efficacy at the same dose. When benzodiazepines are withdrawn, withdrawal symptoms may occur, which must be distinguished from the rebound phenomenon (restlessness, anxiety, insomnia).[18] Other side effects are impaired concentration, inability to drive, and paradoxical excitation, especially in the elderly with organic brain diseases. When drug therapy is required to continue for more than 4-6 weeks, non-benzodiazepines should be used, for which buspirone is a good choice. This is a partial serotonin receptor agonist and D2 blocker and is safe for long term therapy with sufficient anxiolytic effect and little sedation. Adverse effects are usually mild and may occur in the form of headache or nausea. As an alternative to buspirone, SSRI's like paroxetine can be used to treat anxiety.[7]

Other psychiatric drugs used in dermatology include gabapentin (post herpetic neuralgia), topiramate and lamotrigine (skin picking) and naltrexone (pruritus).[819] Recently mirtazapine, a noradrenergic and serotonergic drug has been reported as useful in chronic pruritus and several itchy dermatoses.[20]

Psychiatric Side Effects of Dermatologic Drugs

Corticosteroids are among the dermatologic agents most often associated with psychiatric symptoms, which include cognitive impairment, mood disorders, depression, delirium and psychosis.[21] Isotretinoin has been implicated in depression, suicidal ideation and mood swings.[22] Other drugs associated with depression include dapsone, acyclovir, metronidazole and sulfonamides.[2324]

Cutaneous Side Effects of Psychotropic Drugs

Lithium, a drug that is used widely by psychiatrists in the treatment of mood disorders is associated with a variety of cutaneous side effects.[25] It has been associated with both the onset and exacerbation of psoriasis, triggering localized or generalized forms of pustular psoriasis.[26] Other cutaneous manifestations attributed to lithium include acneiform lesions,[27] vaginal ulcerations,[28] mucosal ulcerations,[29] hidradenitissuppurativa,[30] follicular hyperkeratosis,[31] exacerbation of Darrier's disease,[32] lichenoid stomatitis,[33] erythematous maculopapular rash,[34] increased growth of warts, diffuse and localized hair loss, palmoplantar hyperkeratosis with icthyosiform features,[35] follicular mycosis fungoides[36] and geographical tongue.[37] Interestingly topical lithium has been used in the treatment of seborrheic dermatitis at various centers in Europe.[38] Other drugs used in psychiatry as mood stabilizers also have cutaneous adverse effects. Hair loss is a reversible side effect of sodium valproate.[39] Carbamazepine and Lamotrigine; which is one of the preferred medications for bipolar depression, is associated with development of skin rash as a typical hypersensitivity reaction. This risk can be minimized by introducing the drug slowly.[40]

Relevant Drug Interactions

A few relevant drug interactions to be kept in mind while prescribing for patients with psycho-cutaneous disorders are summarized as follows.

Carbamazepine, a drug that is used in psychiatry primarily as a mood stabilizer induces hepatic microsomal enzymes and hence is involved in several drug interactions. Carbamazepine induces the metabolism of corticosteroids which are frequently used in inflammatory dermatological conditions. In addition, this drug also induces the metabolism of doxycycline used in the treatment of acne and cyclosporine an immunomodulator used in the treatment of severe, treatment unresponsive psoriasis and atopic eczema. Anti-fungals like itraconazole and ketoconazole used in dermatology in the treatment of dermatophytic infections are inhibitors of CYP3A4 and hence decrease the metabolism of several drugs including psychotropics like carbamazepine and pimozide. Anti-depressants like fluoxetine and paroxetine inhibit CYP2D6 and fluvoxamine inhibits CYP1A2, CYP3A4 and hence may increase blood levels of drugs metabolized by these enzymes and thereby participate in drug interactions.[41]

Summary and Conclusion

In management of dermatological conditions with underlying primary psychiatric disorders a close liaison is essential between the treating dermatologist and psychiatrist to avoid potential drug interactions and cutaneous or psychiatric adverse effects. Liaison is even more important when the dermatologist becomes the primary care provider in patients who will not accept referrals to psychiatric services. In such cases careful monitoring needs to be done and a contingency plan put in place in case of psychiatric decompensation, complications, or poor outcome. Hence knowledge of indication, contraindication, side effects, and interactions of psycho-tropics is essential for the practicing dermatologist in managing psycho-dermatological conditions.