THE USE OF PSYCHOTROPIC DRUGS IN DERMATOLOGY

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Bruce H . Thiers, MD, Consulting Editor

THE USE OF PSYCHOTROPIC DRUGS IN DERMATOLOGY Madhulika A. Gupta, MD, FRCPC, and Aditya K. Gupta, MD, FRCPC

In at least one third of dermatology patients, effective management of the skin condition involves consideration of the associated emotional and psychosocial In certain dermatologic disorders, the placebo response is greater than 30%,5.29, 59 which confirms further the important role of psychosomatic factors in dermatology. Psychotropic drugs are an important part of the dermatologists’ therapeutic armamentari~m?~, This article updates the possible dermatologic uses of the following major classes of psychotropic agents: (1) the antianxiety and hypnotic agents (see Tables 4 and 5), (2) the antidepressants (see Tables 6 and 7), and (3) the antipsychotic agents (see Tables 8 and 9). The specific guidelines, side-effect profile, drug-drug in teractions, and most current indicationss6 always should be obtained for any particular psychotropic agent before it is prescribed. When considering the use of psychotropic agents in dermatology, two major factors should be considered: (1)proper diagnosis of the psychiatric disorder and (2) determination of the existence of proper indications for use of psychotropic agents. When assessing for possible psychiatric comorbidity, the dermatologist should consider the two major classifications in psych~dermatology~~~ 43, 47.* (1) 297

cutaneous associations of psychiatric disorders (see Table 1) and (2) the psychiatric aspects of dermatologic disorders (see Table 2). When the presence of psychiatric comorbidity is established, psychotropic agents may not be the primary treatment of choice because other treatment modalities, such as psychotherapy and cognitive-behavioral therapy, may be a more effective or appropriate form of treatment. In some instances, psychotropic agents are used in dermatology because some of their properties are beneficial in primary dermatologic disorders, independent of psychiatric comorbidity, such as the use of the antidepressant doxepin in the treatment of urticaria because of its strongly antihistaminic proper tie^.^^ Few studies have examined the use of psychotropic agents in dermatologic disorders in the absence of psychiatric comorbidity,’ and this potentially important area of psychodermatology requires more systematic study. Massage therapy64may be of benefit in conjunction with psychotropic agents. CUTANEOUS ASSOCIATIONS OF PSYCHIATRIC DISORDERS

Table 1 can serve as a general guideline for use of psychotropic agents in the dermato-

From the Division of Dermatology, Department of Medicine, University of Toronto (AKG), Toronto; and the Department of Psychiatry, University of Western Ontario (MAG), London, Ontario, Canada

DERMATOLOGIC CLINICS VOLUME 18 NUMBER 4 . OCTOBER 2000

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Table 1. CUTANEOUS ASSOCIATIONS OF PSYCHIATRIC DISORDERS Dermatologic Complaint That Is a Primary Psychiatric Symptom

Delusions Delusions of parasitosis or bromhidrosis; delusions of disfigurement related to the skin

Hallucinations Tactile hallucinations, may present as complaints about cutaneous infestation

Body image disorders related to the skin Dermatologic nondisease,8 dermatologic complaints that are not consistent with objective findings (e.g., complaints about scars, wrinkles, acne)

Self-Inflicted Dermatoses Dermatitis artefacta Cutaneous lesions are wholly self-inflicted, however, the patient typically denies their self-inflicted nature30; in some cases, dermatitis artefacta may complicate an underlying dermatologic condition (e.g., in cases of severely excoriated acne, in which the patient denies repetitive self-excoriation)

Neurotic excoriations and acne excoriee Lesions are produced as a result of repetitive selfexcoriation, which may be initiated by an itch or other cutaneous dysesthesia or because of the urge to excoriate an acne pimple or other irregularity on the skin30; patients typically acknowledge the selfinflicted nature of their 1esions

Associated Psychiatric Disorder

Primary Psychotropic Agent

Delusional disorder, somatic type? or monosymptomatic hypochondriacal psychosis; shared psychotic disorde? @lie a deux); major depressive disorder with psychotic features3;incipient schiz~phrenia~~~~ Schizophrenia with somatic delusions3;elderly patients with dementia, relative sensory deprivation, or peripheral neuropathy may experience tactile hallucinations; substanceinduced psychotic disorde? (e.g., sympathomimetic intoxication). Body dysmorphic disorder or dysm~rphophobia~; eating disordeP; major depressive disorder, obsessive-compulsive disorder, social phobia and narcissistic personality disorde?

Antipsychotics; antidepressants may be used for comorbid depressive disease, anxiolytics and hypnotics may be used in conjunction with antipsychotics in some cases Antipsychotics; some antidepressants (e.g., doxepin) have been used in peripheral neuropathy; if drug intoxication is suspected, a systemic workup should first be carried out

None in most cases; antipsychotics may be used if concerns reach delusional proportions; antidepressants, especially SSRIs, may be used in cases of major depression, obsessivecompulsive disorder, and social phobia and as an adjunctive therapy in some cases of eating disorders. Most patients require a detailed psychiatric assessment before a decision is made to use psychotropic drugs

None in most cases; antipsychotics Severe personality disorder and antidepressants may be wherein the cutaneous lesions serve as an appeal for help67; used as adjunctive therapies in posttraumatic stress disorder; in posttraumatic stress disorder3 and dissociative symptoms this patient population, a when the patient injures the psychiatric history should skin sometimes without any include specific enquiry about memory of self-inj~ry~’; rule out history of psychologic trauma and abuse; early diagnosis is sexual abuse2’ and child abuse42 critical because it may prevent in pediatric patient; major depression, psychosis, unnecessary surgery and obsessive-compulsive disorder, chronic morbidity in some patients30 malingering, and Munchausen’s syndrome30 Antidepressants, especially SSRIs; Depression,3O obsessiveantianxiety and antipsychotic compulsive disorder,30 drugs may be used as personality with perfectionistic adjunctive therapies where traits, presence of significant indicated psychosocial stressor in 33-98% of patients30; body image problems, including eating disorders, in acne e x ~ o r i k e ~ ~ , ~ ~

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Table 1. CUTANEOUS ASSOCIATIONS OF PSYCHIATRIC DISORDERS (Continued) Dermatologic Complaint That Is a Primary Psychiatric Symptom

Trichotillomania Nonscarring alopecia as a result of self-plucking of hai?; patients deny that their alopecia is selfinduced in 43% of cases6

Associated Psychiatric Disorder

Primary Psychotropic Agent

A variant of obsessive-compulsive disorder,69Impulse Control Disorder Not Elsewhere Classified (DSM IV)3; dissociative disorders and psychogenic amnesia are u n d e r r e c ~ g n i z e das~ ~ a ~cause ~~ for the hair-pulling; other disorders" include depressive illness, borderline personality disorder, eating disorder, schizophrenia, and subnormal intelligence; among children, a disturbed parent-child relationship or a stressful life situation, such as the birth of a sibling or loss of a loved one, are usually present rather than a primary psychiatric disorder

Antidepre~sants,6~ especially the SSRIs, have been reported to be effective among a subgroup of patients. The heterogeneity of the underlying psychopathologic factors should be recognized and the underlying psychiatric pathology should be diagnosed, especially in the pediatric population, before psychotropic agents are used

SSRIs = Selective serotonin reuptake inhibitors

logic patient whose primary diagnosis is a psychiatric disorder. Whenever a primary psychiatric disorder is suspected, a full psychiatric assessment should be performed before a decision regarding drug treatment is made. When prescribing psychotropic agents, the clinician always should determine whether the patient poses a significant suicide risk, in which case the total amount of medication in the prescription should be a nonlethal dose.

PSYCHIATRIC ASPECTS OF DERMATOLOGIC DISORDERS

Some of the major dermatologic disorderspsoriasis, atopic dermatitis, urticaria and angioedema, alopecia areata, and acne-can be influenced significantly by psychosomatic factors (Table 2). These disorders all have been reported to be exacerbated by psychosocial stressz4and have been associated with primary psychiatric disorders." In certain disorders, such as psoriasis33 and atopic dermatiti~,'~, l7 the stress resulting from having to cope with the impact of the disorder on the quality of life (e.g., the impact of the cosmetic disfigurement and other aspects of the disease) has been reported to have an

adverse impact on the course of the disorder. Aggressive treatment of the dermatologic disorder most likely would relieve the psychosocia1 stress in the patient. A short course of anxiolytics may prevent a flare-up, for example, in psoriasis and atopic dermatitis patients who are experiencing acute stress as a result of having to cope with their disorder. For instance, a psoriasis patient whose psoriasis is stress reactive and who is feeling anxious about attending a function because of selfconsciousness about the psoriasis may benefit from taking a short course of an antianxiety medication (see Tables 4 and 5), such as lorazepam, 0.5 to 1 mg, to attenuate the anxiety. This medication likely would mitigate a stress-related flare-up of the psoriasis. The most commonly encountered comorbid psychiatric disorders3in dermatology are major depressive disorder, obsessive-compulsive disorder, and body dysmorphic disorder. Their most salient diagnostic features are summarized in Table 3. Dissociative disord e r ~which ,~ typically arise as a result of traumatic life experiences, such as sexual abuse, are underrecognized in dermatology and often play a role in the pathogenesis of selfinflicted d e r m a t o s e ~such , ~ ~ as dermatitis artefacts and trichotillomania. When assessing the dermatologic patient

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Table 2. PSYCHIATRIC ASSOCIATIONS OF SOME DERMATOLOGIC DISORDERS Derrnatologic Disorder

Atopic dermatitis

Psoriasis

Urticaria and angioedema

Alopecia areata

Psychosocial Stress

Disease-related stress, interpersonal and family-related stress important predictors of symptom stress associated with onset in 70% of cases14 Disease-related and stress from other psychosocial stressors important in >70% of adults5'/ and 90% of children" with psoriasis

Stress, including catastrophic events, reported to be the main exacerbating or precipitating factor among 77% of patients*; stress-related exacerbation observed in 77% of patients with cholinergic urticaria and 82% with dermatographismg >20% of patients with alopecia areata report more stress before the onset and/or exacerbation of symptomsz4;conclusions regarding the role of stress in alopecia areata are inconsistentz4

Psychiatric Cornorbidity

Adult patients often anxious and had difficulties in dealing with anger in comparison to c o n t r ~ l s ' ~ , ~ ~ ; depressive symptoms associated with greater pruritus severityM A wide range of psychopathology has been reported, including depression, high anxiety and obsessionality, and difficulties with the expression of angeP; depressive symptoms correlated directly with greater pruritus severity in psoriasis34;18% prevalence of alcoholism observed in psoriasis vs. 2% in other dermatologic controlsM;consumption of >80 g of ethanol/ d may have an adverse effect on treatment outcome among psoriatic men37 A wide range of psychopathologic characteristics have been reported in the earlier literature49;the most frequently reported are difficulties with the expression of anger and hostility; pruritus severity in urticaria increased with increasing severity of depressive symptoms34;recurrent idiopathic urticaria has been associated with panic disorder, which responded to SSRI antidepressantsz3 The incidence of psychiatric illness in alopecia areata is 33-93%"; one survey of 31 patients reports a 74% lifetime prevalence of 21 psychiatric disorders, with a 39% prevalence of major depression and 39% prevalence of anxiety disorder7

SSRI = Selective serotonin reuptake inhibitor. Adapted from Gupta MA, Gupta AK Psychodermatology: An update. J Am Acad Dermatol 34:1030-1046, 1996; with permission.

for the use of psychotropic drugs, a multidimensional biopsychosocial model should be employed. If psychosocial stress is the main factor, psychotropic drugs are not likely to be of long-term benefit, and other psychiatric interventions, such as group and individual psychotherapy, usually are indicated. Antianxiety agents, such as benzodiazepines (BZDs), should not be used for the long-term management of stress, but they may be used for the short-term (<2 weeks' duration) relief of anxiety. When a comorbid psychiatric disorder is diagnosed (see Table 3), it may be treated in conjunction with the dermatologic disorder.

ANTIANXIETY AND SEDATIVE AGENTS

BZDs are the most commonly used antianxiety drugs in (Table 4). BZDs are used for

the short-term relief of symptoms of anxiety; however, they are not indicated for the treatment of anxiety associated with the stress of everyday life.56,70 Some other situations that may be encountered frequently in the dermatologic patient in which BZDs may be used include anxiety associated with a depressive disorder, anxiety during medical procedures, insomnia, and relief of acute alcohol withdrawal-related symptoms.56,70 Buspirone and zolpidem are non-BZD drugs that achieve anxiolytic and hypnotic effects that are comparable to the BZDs with fewer unwanted side effects. The BZDs are depressants of the central nervous system and are believed to facilitate the action of gamma-aminobutyric acid (GABA), the major inhibitory neurotransmitter in the central nervous system, by causing it to bind more tightly to the GABA type A receptor. Table 5 provides some general clinical guidelines for the use of BZDs. Three factors (see Table 4) determine the selection of

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Table 3. SOME PSYCHIATRIC DISORDERS (DSM IV) THAT ARE COMMONLY COMORBID WITH DERMATOLOGIC DISORDERS Psychiatric Disorder

Major depressive disorder

Obsessivecompulsive disorder

Body dysmorphic disorder

Major Symptoms

Characterized by one or more major depressive episodes (i.e., at least 2 of depressed mood or loss of interest or pleasure), accompanied by 2 4 of the following symptoms of depression that represent a change from previous functioning: psychomotor agitation or retardation, decrease or increase in appetite or sleep, fatigue or loss of energy, feelings of worthlessness or excessive or inappropriate guilt, indecisiveness or decreased concentrating ability, and recurrent thoughts of death with or without suicidal ideation. The psychomotor agitation in some patients can present as prominent anxiety and should not be misdiagnosed as a primary anxiety disorder. In dermatology, certain somatic symptoms, such as a burning sensation in the scalp or tongue or unexplained cutaneous dysesthesias, may be depressive equivalents, and the patient with clinically mild acne who is excessively preoccupied about his or her skin may have an underlying depressive disorder Recurrent obsessions or compulsions severe enough to be time-consuming or cause marked distress or significant impairment. Obsessions are defined as recurrent and persistent thoughts, impulses, or images that are experienced as intrusive and inappropriate; that cause marked anxiety or distress; and that cannot be eliminated from consciousness by logical effort. Compulsions are repetitive behaviors, such as hand washing, hair plucking, picking of the skin or lesions on the skin, bathing, or mental acts such as checking or counting that the person feels driven to perform in response to an obsession and which, if resisted, produces anxiety Presents as a preoccupation with an imagined defect in appearance; or if a slight anomaly is present, the individual's concern is excessive; also referred to as dysrnorphophobiu. Complaints commonly involve imagined or slight flaws of the face or head, such as thinning hair, acne, wrinkles, scars, vascular markings, paleness or redness of the complexion, swelling, facial disproportion or asymmetry, or excessive facial hair. Some associated features include excessive grooming behavior, such as excessive hair combing, hair removal, hair picking, or ritualized makeup application. Most individuals experience marked distress over their supposed deformity and feelings of self-consciousness over their defect, which often leads to vocational and social impairment

SSRIs = Selective serotonin reuptake inhibitor. Datafrom references 3 and 24.

Commonly Used Psychotropic Agents

Antidepressants, no major differences in antidepressant efficacy among various classes of antidepressants; SSRIs are used more frequently than the tricyclic and heterocyclic antidepressants because of their more advantageous adverse-effect profile, especially lower cardiotoxicity. Antipsychotics may be used in conjunction with antidepressants for delusional depression or depression with psychotic features

Clomipramine and SSRIs are effective; the antiobsessional activity of the drugs appears to be mediated by their serotonin agonist activity. Antianxiety agents, such as the benzodiazepine clonazepam, has been used as adjunctive therapy. Pimozide has been used as an adjunctive therapy; however, its efficacy has not been confirmed in controlled trials

SSRI antidepressants, onset of action about 6 weeks, which is longer than the 3 to 4 weeks average time for onset of antidepressant effect; the antipsychotic pimozide has been used in delusional states presenting as body dysmorphic disorder; the efficacy of pimozide has not been confirmed with controlled studies. Most patients have complex psychopathology and require cognitive-behavioral therapy in conjunction with psychotropic agents

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Table 4. PHARMACOLOGIC PROPERTIES AND DOSAGES OF BENZODIAZEPINES

Generic (Brand) Name

Relative Potency or Equivalent Dose (mg)

Onset of Action After Oral Dose

Alprazolam (Xanax) Chlordiazepoxide (Librium) Clorazepate (Tranxene) Diazepam (Valium) Estazolam (ProSom) Flurazepam (Dalmane) Lorazepam (Ativan) Oxazepam (Serax) Temazepam (Restoril) Triazolam (Halcion)

0.5 10 7.5 5 0.33 5 1 15 5 0.25

Intermediate Intermediate Fast Fast Fast Fast-intermediate Intermediate Intermediate-slow Intermediate Fast

Average Elimination Half-Life, Including Active Metabolites (h) (short or long acting)

12 (short) 100 (long) 100 (long) 100 (long) 17 (short) 100 (long) 15 (short) 8 (short) 11 (short) 2 (short)

Usual Daily Dose (mg)

0.254.5 t.i.d. 5-10 t.i.d. or q.i.d. 7.5-15 b.i.d. to q.i.d. 2-10 b.i.d. to q.i.d. 1-2 daily 15-30 daily 1 b.i.d. to t.i.d. 10-15 t.i.d. to q.i.d. 7.5-30 daily 0.125-0.25 daily

b i d . = 2 times per day; t.i.d. = 3 times per day; q.i.d. = 4 times per day. Dutufrom references 24, 41, 56, and 70.

Table 5. GUIDELINES FOR USE OF BENZODIAZEPINES Possible Uses in Dermatology Short-term (7-10 day) relief of anxiety (e.g., social anxiety) or to minimize the impact of stress in situations in which the skin disorder is stress reactive, such as atopic dermatitis and psoriasis (see Tables 1 and 2), short-term anxiety resulting from stressful life events; short-term treatment of insomnia; management of the alcoholic patient (eg., in psoriasis); short-term treatment of anxiety during medical procedures; insomnia. Some cutaneous reactions: exacerbation of porphyria with chlordiazepoxide, fixed drug eruption, bullous lesions, maculopapular and morbilliform rashes, photosensitivity, erythema multiforme, erythema nodosum, pruritus, hair loss, hirsuitism, ankle and facial edema General Prescribing Guidelines Determine the underlying basis for the anxiety-a dermatology patient who has a major depressive disorder can present with prominent symptoms of anxiety or insomnia, and the use of BZD alone in such cases is likely to worsen the symptoms; inquire about a history of alcohol abuse and other substance abuse to screen for addictive potential Start the BZD at a low dose, and instruct the patient about the sedative properties and the abuse potential of the drug. When used for 1-2 weeks in moderate doses, usually there is no evidence of tolerance or dependence Optimal dosing of BZD varies with the diagnosis and patient response; the minimum effective dose should be used for the shortest time period, and the need for continued therapy should be assessed continually. Be aware of respiratory depressant effect of BZD Prolonged use or use of large doses increases the risk for developing psychologic or physical dependence. Do not stop BZD abruptly. Taper dosage gradually, especially of high-potency agents with short half-lives (see Table 4), to minimize risk of withdrawal symptoms, such as delirium and seizures Rapidly acting drugs (see Table 4) are most effective for fast relief (e.g., in situational anxiety) Use oxazepam, lorazepam, or temazepam in patients with liver disease because they are not metabolized by the liver and in instances in which there is concurrent use of medications (eg., erythromycin, fluconazole, itraconazole, and ketoconazole) that are CYP3A3/4 inhibitors Avoid the concurrent use of triazolam and CPY3A3/4 inhibitors ketoconazole and itraconazole because of risk of marked decrease in metabolism of triazolam, which is a CPY3A3/4 substrate70 Dutafrom references 19, 24, 41, and 70.

THE USE OF PSYCHOTROPIC DRUGS IN DERMATOLOGY

BZD: receptor affinity, which determines potency; lipophilicity, which determines onset of action; and half-life, including the halflife of the metabolites, which determines the duration of action. Certain long half-life BZDs (see Table 4), such as diazepam and clonazepam, are metabolized in the liver by the cytochrome P-450 3A3/ 4(CYP3A3/ 4) isoenzyme (see Table lo), and medications such as itraconazole, fluconazole, ketoconazole, and erythromycin, which inhibit the activity of CYP3A3/4 isoenzyme, may decrease the rate of elimination of these BZDs and produce excessive central nervous system depression. Other commonly used shorter-acting BZDs, such as alprazolam and triazolam (see Table 4), are metabolized by the CYP3A3/ 4 isoenzymes; for example, concurrent use of triazolam (see Table 10) with ketoconazole and itraconazole has resulted in a marked decrease in the rate of elimination of triazolam and psychomotor impairment in the patient.70Concurrent use

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of triazolam and these antifungal drugs is not re~omrnended.~~ Lorazepam, oxazepam, and temazepam are metabolized by direct conjugation with glucuronic acid, and their levels are least like& to be affected by the inhibition of CYP3A3/4 isoenzymes and liver disease (see Table 5).70

ANTIDEPRESSANT AGENTS The antidepressants (Tables 6 and 7), which can be classified as the tricyclic antidepressants (TCAs), selective serotonin reuptake inhibitors (SSRIs), and the atypical group, are used for the treatment of major depressive disorder (see Table 3), depressed phase of manic depressive disorder, and obsessivecompulsive disorder (see Table 3). Some other uses include pain control (e.g., in diabetic neuropathy) and the treatment of social anxiety disorder3 or social phobia. Paroxetine (see Tables 6 and 7),56, starting at a dosage of 20

Table 6. ANTIDEPRESSANT DOSAGE AND POSTSYNAPTIC RECEPTOR AFFINITIES OF SOME AGENTS*

Generic (Trade) Name

Selective serotonin reuptake inhibitors Fluoxetine (Prozac) Sertraline (Zoloft) Paroxetine (Paxil) Fluvoxamine (Luvox) Citalopram (Celexa) Tricyclic compounds Clomipramine Amitriptyline (Elavil and others) Doxepin (Sinequan, Adapin) Trimipramine (Surmontil) Imipramine (Tofranil) Atypical antidepressants Bup rop ion (Wellbutrin) Nefazodone (Serzone) Venlafaxine (Effexor)

Usual Daily Starting Doset (mg)

Usual Daily Dose Ranget (mg)

Relative Histamine H,-Receptor Blocking Potency

Relative Anticholinergic Potency

Relative a,Adrenergic Receptor Blocking Potency

10-20 50 10-20 50

1040 50-200 20-50 100-200

Low 1absent Low / absent Low / absent Low 1absent

Low 1absent Low absent Very mild Low 1absent

Low 1absent Lowlabsent Low / absent Low / absent

20

2040

Low 1absent

Low / absent

Low / absent

25-50 50-75

100-200 100-150

Moderate High

High High

Moderate Moderate /high

25-75

100-150

High

High

High

25-75

75-100

High

High

Moderate

25-75

100-150

Moderate

Moderate

High

100

200-300

Absent

Mildlabsent

Absent

lO(n50

200400

High

Mildlabsent

Mildlabsent

75-150

Mild

Mild

Mild

37.5-75

*All antidepressants are contraindicated in combination with monoamine oxidase inhibitors. tDoses 2150 mg imipramine or equivalent should be used with close monitoring for adverse reactions Datafrom references 19, 24, 41, and 70.

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Table 7. GUIDELINES FOR USE OF ANTIDEPRESSANTS Possible Uses in Dermatology Antidepressants are indicated for the treatment of major depressive disorder and obsessive-compulsive disorder independent of depressive symptoms (see Table 3). The SSRI paroxetine is indicated for the management of social phobia,56.6sand the SSRIs have been used in body dysmorphic disorder. There are case studies of their efficacy in depressive equivalents, such as glossodyniaZ8;clomipramine for trich~tillomania~~; amitriptyline for postherpetic neuralgia72;amitriptyline or desipramine for the pain of diabetic n e ~ r o p a t h y doxepin ~~; for chronic idiopathic ~rticaria,2~,~" idiopathic cold urticaria:* and a range of other pruritic disorderd5; t r i m i ~ r a m i n eand ~ ~ topical 5% doxepin" cream for pruritus of atopic dermatitis. Some cutaneous reactions: photosensitivity, increased sweating, pruritus, maculopapular rashes, urticaria, petechiae, pruritus, cutaneous vasculitis, erythema multiforme, alopecia, edema of the face and tongue General Prescribing Guidelines Evaluate patient to determine the presence of correct indications; assess suicide potential; perform complete blood count, liver and renal function tests, and ECG if indicated by cardiac history or potential for cardiotoxicity present SSRIs have replaced TCAs as the drug of first choice when treating depression because of their safety, much lower cardiovascular side effects, and better tolerability. Treatment can be initiated with a dosage of SSRI that is in the therapeutic range, in contrast to TCAs, in which the dosage often has to be increased gradually. An SSRI should be chosen if antiobsessional effects are desired or anxiety is a prominent symptom; strongly antihistaminic antidepressants, such as doxepin, trimipramine, or amitriptyline, should be chosen if sedative or antihistaminic effects are desired; dermatology patients may respond to a dosage of medication that is lower than the antidepressant dosez8when the TCA is being used for its antihistaminic or sedative properties A period of 4-6 weeks usually is necessary for a significant antidepressant effect to become established, and the patient should be advised about this when therapy is initiated because this is likely to improve compliance; the antidepressant should be continued for 6-12 months after an acute episode of major depression Adverse effects (refer to information on specific agent before pre~cribing~~): Cardiovascular-orthostatic hypotension related to a,-adrenergic receptor blocking potency, ECG changes such QT prolongation and T wave inversion, intraventricular conduction defects and arrhythmias, risk of cardiotoxicity increased when used in conjunction with antihistamines (e.g., diphenhydramine, hydroxyzine) Anticholinergic-blurred vision, precipitation of narrow-angle glaucoma, urinary retention, decreased bowel motility, dry mouth Hematologic-agranulocytosis rare Neurologic-lowering of seizure threshold, sedation, with SSRIs may experience restlessness and anxiety SSRI = Selective serotonin reuptake inhibitor; ECG = electrocardiogram; TCAs Data from reference 19, 24, 41, and 70.

mg daily, has been shown to be effective in the treatment of social anxiety disorder. This drug may be of benefit to the patient who experiences social phobia because of self-consciousness about their skin disorder. The exact mechanism of action of the TCAs is not known. TCAs (see Table 6) increase the synaptic concentration of norepinephrine, serotonin (5-HT), or both in the central nervous system by inhibition of their reuptake by the presynaptic neuronal membrane, in addition to changing postsynaptic P-adrenergic receptor sensitivity. TCAs produce prominent peripheral and central nervous system anticholinergic effects because of their high binding affinity for muscarinic acetylcholine receptors, sedative effects resulting from strong binding affinity for histamine HIreceptors, and orthostatic hypotension as a result of a-adrenergic receptor blockade (see Table 6).70The TCAs have a quinidine-like effect on the heart and similar to quinidine

=

tricyclic antidepressants.

can moderately slow ventricular conduction in therapeutic doses and in an overdose can cause severe conduction block and ventricular arrhythmia^.^^ The SSRIs (see Table 6) inhibit 5-HT reuptake, enhancing serotoninergic function, and their relatively selective effect on 5-HT is believed to be the basis for their antiobsessional activity. In contrast to the TCAs, SSRIs have minimal histamine HI, cholinergic, and aladrenergic blocking effects (see Table 6). Some SSRIs, such as fluoxetine and fluvoxamine, are moderate inhibitors of CYP3A3/4 isoenzymes (see Table 10) and can slow down the metabolism of medications that are metabolized by CYP3A3/4. Concurrent use of pimozide, a CYP3A3/4 substrate (see Table lo), and fluoxetine has been associated with b r a d y ~ a r d i a .In ~ ~vitro studies have shown that fluvoxamine blocks the metabolism of the antihistamines astemizole and terfenadine, which are CYP3A3/ 4 substrates (see Ta-

THE USE OF PSYCHOTROPIC DRUGS IN DERMATOLOGY

ble 10). This block can result in potentially fatal QT prolongation and torsades des pointes. The coadministration of fluvoxamine with astemizole and terfenadine is contruindic~ted.~~, 70 Coadministration of fluoxetine with single doses of terfenadine (a CYP3A3/ 4 substrate) showed no increases in terfenadine levels.56 In vitro studies have shown that ketoconazole, a potent CYP3A3/ 4 inhibitor, is at least 100 times more potent than fluoxetine as an inhibitor of the metabolism of several substrates of this Benzodiazepines that are metabolized by hepatic oxidation, such as alprazolam and triazolam, should be used with caution because the clearance of these drugs is likely to be reduced by agents such as fluvoxamine and fluoxetine (see Table 10). Alternatively the SSRI paroxetine is a weak inhibitor of CYP3A3/ 4, and interactions with medications that are metabolized by CYP3A3/4 are unlikely.70 The TCA oral doxepin, 10 mg three times daily for 2 weeks, has been shown to be effective in the treatment of chronic idiopathic and cold urticaria.,O. 52 Topical doxepin also is used for the treatment of pruritus.'l The efficacy of doxepin in urticaria is not related directly to its antidepressant effect. The H, and H, antihistaminic and anticholinergic properties of the TCAs are important reasons for their efficacy. Dermal blood vessels possess H, and H, histamine receptors, and combined H, and H, antihistamine therapy is more effective than H, antihistamines alone in chronic urticaria. The TCAs doxepin, amitriptyline, and trimipramine (see Table 6) are potent H,-receptor (e.g., doxepin is 800 times more potent than diphenhydramine) and H,receptor antagonists.58The strongly antihistaminic TCA trimipramine (50 mg/d) has been used to treat the pruritus of atopic dermati ti^.^^ Using a double-blind, placebocontrolled design, a study involving 13 patients with alopecia areata reported that 5 of the 7 patients taking the TCA imipramine and none taking the placebo had significant hair growth after 6 months.55These initial reports require further follow-up using controlled studies. There are case studies on the efficacy of SSRI antidepressants in the treatment of

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neurotic excoriationsz2and stress-induced urticaria associated with panic attacks.23 Lithium compounds are used in the treatment of mood disorders, including recurrent depression and bipolar disorder, and may precipitate or exacerbate psoriasis.10, Lithium-induced psoriasis can occur within a few months and usually occurs within the first few years of treatment and tends to be resistant to conventional antipsoriatic treatment.65 If the psoriasis becomes intractable, the lithium has to be discontinued, and the psoriasiform eruption usually remits within a few months.65Divalproex sodium ( D e ~ a k o t e )56~ ~ , and carbamazepine (Tegret01)~l can be used in place of lithium. Other anticonvulsant drugs, such as lamotrigine (Lamictal), have been used as mood stabilizer^.^, Lamotrigine can be associated with serious rashes, including Stevens-Johnson syndrome and, in rare cases, toxic epidermal n e c r ~ l y s i s Coadministra.~~ tion of lamotrigine with divalproex sodium may increase the risk for serious and it is recommended that lamotrigine be discontinued at the first sign of a

ANTIPSYCHOTIC AGENTS The common feature of all antipsychotics is the blockade of central nervous system dopamine receptors.19,41, 70 Extrapyramidal symptoms, especially extrapyramidal side effects, such as parkinsonism, are mediated by the dopamine-blocking effect of these agents. The typical antipsychotics (e.g., the phenothiazines, thioxanthines, butyrophenones, and diphenylbutylpiperidines) (Table 9) include agents introduced before the availability of clozapine in the early 1990s and are characterized by a higher tendency to produce extrapyramidal symptoms and minimal effect on the negative symptoms of psychotic disorder, such as lack of motivation, flattened affect, and social ~ithdrawal.~', 70 The newer atypical agents (see Table 8) have lower rates of extrapyramidal symptoms (possibly because of 5HT,-receptor antagonism) and potentially are effective for the negative and positive symptoms, such as delusions and hallu~inations.'~* 41, 70 Acute dystonias, a form of extrapyrami-

Generic (Trade) Name

Data from references 19, 41, 56 and 70.

Phenothiazines Chlorpromazine (Thorazine) Perphenazine (Trilafon) Trifluoperazine (Stelazine) Thioxanthines Thiothixene (Navane) Butyrophenones Haloperidol (Haldol) Diphenylbuty lpiperidine Pimozide (Orap) Atypical antipsychotics Olanzapine (Zyprexa) Risperidone (Risperidal) Quetiapine (Seroquel)

Very low Low (dose dependent) Very low

Medium Low Low

High Moderate High

2.510 2-6 50400

Low

Low

1-10

1 (high)

5 mg (high) 1 (high) 50 (medium)

High

Low

Low

1-10

2 (high)

High

High

Low

Low

6-30

4 (high)

High Moderate

Low

Relative Risk of Extrapyramidal Effects

Low Low

High

Relative Anticholinergic Effect

Low Medium

High

Relative Sedative Effect

EM0 6-20

300400

Adult Daily Antipsychotic Dosage Range (ms)

8 (medium) 5 (high)

100 (low)

Approximate Equivalent Dosage (Potency)

Table 8. PHARMACOLOGIC PROPERTIES AND DOSAGES OF ANTIPSYCHOTIC DRUGS

High Moderate High

Low

Low

Low

Low Low

High

Relative Risk of Orthostatic Hypotension

THE USE OF PSYCHOTROPIC DRUGS IN DERMATOLOGY

dal symptoms, can result from any dose of any class of antipsychotic agent. Young, muscular men are at the highest risk for acute dystonias, and in rare instances this can present as laryngeal spasm, which can be acutely life-threatening. Another potentially lifethreatening complication of antipsychotic drug therapy is neuroleptic malignant syndrome, which is an acute disorder of thermoregulation and neuromotor control and has a reported mortality rate of 20% when untreated.19, 41, 70 Most cases of neuroleptic malignant syndrome occur within the first 2 weeks of initiation of antipsychotic drug therapy or with increase in the dose of antipsychotic agent; however, neuroleptic malignant syndrome can occur at any time. The usual initial signs include fever (often > 40°C), muscle rigidity, altered consciousness, and autonomic instability, such as diaphoresis and fluctuating blood pressure. Patients with neuroleptic malignant syndrome almost always have elevated creatine phosphokinase levels. The most important step in effective treatment is early recognition and withdrawal of the offending antipsychotic agent, followed by supportive measures.19,41, 70 A commonly encountered side effect of antipsychotic drugs is akathisia, another extrapyramidal symptom, which usually manifests as restlessness and an uncomfortable inner feeling and can be mistaken as anxiety or agitation. The initial treatment of akathisia should involve lowering of the antipsychotic dosage. The dermatologist prescribing antipsychotics should be aware of tardive dyskinesia or a late-onset movement disorder, which typically occurs after 2 years of antipsychotic drug use but can occur earlier and is usually irreversible in greater than 50% of cases.19,41, 70 All the typical antipsychotics (see Table 8) seem to have similar risk for tardive dyskinesia, and the newer atypical agents that have lower extrapyramidal symptoms may have a lower potential for tardive dyskinesia, but this has not been confirmed.41,56 It is recommended that informed consent be obtained from patients who are expected to use antipsychotic agents for more than 3 months.41

721

The dermatologic literature suggests that pimozide is the drug of choice for treating delusions of parasitosis, starting at 1 mg/d and increasing the dosage every 5 to 7 days by 1 mg to a maximum of 4 mg daily.44Because this recommendation is based mainly on nonempiric data, it is important to be aware that pimozide is not the first-line drug for the treatment of p s y ~ h o s i sSudden .~~ unexpected deaths have been reported when patients received dosages of pimozide in the range of 1 mg/kg; the possible mechanism was ventricular arrhythmias caused by QT pr~longation.~~ An additive effect on QT prolongation should be anticipated if pimozide is administered with TCAs, phenothiazines, or antiarrhythmic agents that prolong QT int e r ~ a lPimozide .~~ is partially metabolized by CYP3A3/4 isoenzyme (Table lo), and coadministration of pimozide with macrolide antibiotics, such as clarithromycin and erythromycin, which are inhibitors of CYP3A3/4, is ~ontraindicated.~~, 70 Pimozide prolongs the QT interval, and macrolide antibiotic use in patients with prolonged QT intervals has been associated with ventricular arrhythmias and sudden death?" 70 The atypical antipsychotic quetiapine (see Table 8) is largely metabolized by the CYP3A3/4 isoenzyme, and caution is advised if potent CYP3A3/ 4 inhibitors, such as erythromycin, fluconazole, itraconazole, or 70 ketoconazole, are used conc~rrently.~~, DRUG-DRUG INTERACTIONS INVOLVING THE CYTOCHROME P-450 ISOENZYMES

The cytochrome P-450 (CYP) mixed function oxidase system constitutes the major drug-metabolizing enzymes that have the highest concentration in the liver microsomes and take part in phase I multistep drug biotransformation processeP involving oxidation and reduction. In humans, the enzymes of the CYP1, CYP2, and CYP3 families are responsible for most drug biotransformation reactions,66and the important isoenzymes in drug interactions include the CYPlA2, CYP2D6, and CYP3A3 and 3A4 (or CYP3A3/ 4). In drug-drug interactions involving the

722

GUPTA & GUPTA

use of psychotropic agents in dermatology, the CYP2D6 and the CYP3A3/ 4 isoenzymes are the most important. The SSRI antidepressants (see Table 6) such as paroxetine, fluoxetine, and sertraline, are inhibitors of CYP2D6 isoenzyme and can increase the blood levels of drugs that are metabolized by the CYP2D6 isoenzyme, such as TCAs (see Table 6), antipsychotics (see Table 8), codeine, and cardiac antiarrhythmi~s.'~ SSRI antidepressants often are coadministered with low-dose TCAs (e.g., at doses equivalent to 25 to 50 mg of imipramine) to obtain a therapeutic plasma concentration of the TCA and an enhanced antidepressant effect. If SSRIs are coadministered with a full dose of a TCA (see Table 6), cardiac side effects, including arrhythmia, heart block,

and sudden death, are possible as the TCA concentrations reach toxic 1e~els.l~ The drug interactions involving the CYP3A3 /4 isoenzymes involve agents that are inhibitors or inducers of the isoenzyme or its substrate. Inhibition of drug metabolism as a result of the inhibition of the CYP3A3/4 isoenzymes is the most important mechanism because it leads to increased concentrations of the substrate and increases the risk of substrate drug-related toxicity. When the drug is an inducer of CYP3A3/ 4, the metabolism of the substrate drug is increased, leading to decreased and possibly subtherapeutic levels of the substrate drug. Table 10 lists some of the CYP3A3/4 inhibitors and inducers and substrates that are of relevance when using psychotropic agents in the dermatologic patient.

Table 9. SOME GUIDELINES FOR USE OF ANTIPSYCHOTICS Possible Uses in Dermatology Strongly antihistaminic phenothiazine agents (see Table 8), such as promethazine and trimeprazine, are used for the treatment of pruritus, urticaria, angioedema, and dermatographism.7° Psychotic states, such as delusions of ~ ~been promoted parasitosis and other delusions and hallucinations related to the skin (see Table 1);p i m ~ z i d ehas as the drug of choice for treating delusions of parasitosis; choice of drug should be determined by the side-effect profile (e.g., consider a low-potency drug if sedation or fewer neurologic side effects are desired); small doses of antipsychotic agent may be used in nonpsychotic anxiety; case report26of efficacy of olanzapine in self-induced dermatoses including acne excoriee and trichotillomania; Pimozide has been used in 30 previously treated metastatic melanoma patients, and 17% showed a favorable response53;the favorable response was attributed to its dopamine antagonist properties, and the authors" suggest that this finding merits further study. Some cutaneous reactions: Photosensitivity and photo-induced eruptions common with phenothiazine antipsychotics, especially chlorpromazine'2;blue-gray discoloration of the skin with long-term use of phenothiazines; seborrheic dermatitis secondary to the dopamine-blocking effect4, lupuslike syndrome, allergic rash (usually macupapular, urticaria], or pruritic), angioedema, exfoliative dermatitis, Stevens-Johnson syndrome, erythema multiforme, case report of pustular eruption with olanzapine,' bullous pemphigoid and ri~peridone'~ Some Guidelines for Use Determine presence of proper indications; perform complete blood count, liver and renal function tests, and ECG if indicated by history or if using pimozide All antipsychotics generally are equally effective for the treatment of psychotic symptoms in equipotent doses; choice of drug determined by side-effect profile (e.g., use low-potency drug if sedation or fewer neurologic side effects desired, choose high-potency agent for fewer cardiovascular effects) Adverse effects Neurologic (discussed in text)-extrapyramidal side effects including acute dystonia, akathisia, parkinsonism, tardive dyskinesia (may occur early, eg., after 3-6 months of antipsychotic drug use, often not entirely reversible), neuroleptic malignant syndrome (rare emergency, may develop within hours to months after initiation of therapy), lowering of seizure threshold especially with low-potency agents Cardiovascular-orthostatic hypotension, ECG changes including prolongation of QT interval and malignant ventricular arrhythmias Anticholinergic-blurred vision, precipitation of narrow-angle glaucoma, urinary retention, and decreased bowel motility Endocrine-prolactin stimulation may cause amenorrhea and galactorrhea, may have adverse effect on prolactindependent tumors (e.g., breast malignancy) Hematologic-agranulocytosis in <0.1% cases, 1%with clozapine Gastrointestinal-hepatotoxicity, most commonly cholestasis in
THE USE OF PSYCHOTROPIC DRUGS IN DERMATOLOGY

723

Table 10. SOME CYP3A3/4 INHIBITORS AND INDUCERS AND SUBSTRATES* Inhibitors

Psychotropic agent Antidepressants Fluoxetine Fluvoxamine Sertraline Nefazodone"j Others Fluconazole Itraconazole Ketoconazole Erythromycin Grapefruit juice

Inducers

Psychotropic agent Anticonvulsants Carbamazepine Phenobarbital Phenytoin Others Griseofulvin Phenylbutazone Isoniazid Clotrimazole Dexamethasone

Substrate

Psychotropic agent Antidepressants Doxepin Amitriptyline Sertraline Citalopram Imipramine Antianxiety agents Diazepam Clonazepam Alprazolam Midazolam Triazolam Bromazepam Antipsychotics Pimozide Quetiapine Anticonvulsants Carbamazepine Others Antiarrhythmics Quinidine Lidocaine Digoxin Antihistamines Astemizole Loratadine Fexofenadine Terfenadine Cyclophosphamide Cyclosporine Dapsone Corticosteroids Tacrolimus

*This is a partial overview of some inhibitors and inducers and substrates of CYP3A3/4and does not represent a complete list of all agents that could be of importance when prescribing psychotropic agents to the dermatologic patient. Current sources, such as the product monographs in Physicians' Desk should be used to determine if the potential for a drug-drug interaction exists. Note: Inhibitor Drug Substrate Drug = Increased Levels of Substrate Drug Inducer Drug + Substrate Drug = Decreased Levels of Substrate Drug Data from references 56, 66, 70, and 71.

+

References 1. Adams BB, Mutasim DF: Pustular eruption induced by olanzapine, a novel antipsychotic agent. J Am Acad Dermatol 41:851-853, 1999 2. Alpsoy E, Ozcan E, Cetin L, et al: Is the efficacy of topical corticosteroid therapy for psoriasis vulgaris enhanced by concurrent moclobemide therapy? A double-blind, placebo-controlled study. J Am Acad Dermatol38(2 ptl):197-200, 1998 3. American Psychiatric Association Committee on Nomenclature and Statistics: Diagnostic and Statistical Manual of Mental Disorders, ed 4. Washington, DC, American Psychiatric Association, 1994 4. Binder RL, Jonelis FJ: Seborrheic dermatitis in neuroleptic-induced parkinsonism. Arch Dermatol 119:473475, 1983

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group: Relief of pruritus in patients with atopic dermatitis after treatment with topical doxepin cream. J Am Acad Dermatol 31:613-616, 1994 12. Eberlein-Konig B, Bind1 A, Przybilla B: Phototoxic properties of neuroleptic drugs. Dermatology 194:131-135, 1997 13. Ereshefsky L, Riesenman C, Lam YWF: Antidepressant drug interactions and the cytochrome P450 system. Clin Pharmacokinet 29(suppl):10-19, 1995 14. Faulstich ME, Williamson DA: An overview of atopic dermatitis: Toward a bio-behavioral integration. J Psychosom Res 29:415417, 1985 15. Fried RG: Evaluation and treatment of "psychogenic" pruritus and self-excoriation. J Am Acad Dermatol 30~993-999,1994 16. Gelenberg AJ: Interactions: New antidepressants, nonsedating antihistamines and others. Biological Therapies in Psychiatry Newsletter 18:17, 1995 17. Gil KM, Keefe FJ, Sampson HA, et al: The relation of stress and family environment to atopic dermatitis symptoms in children. J Psychosom Res 31:673-684, 1987 18. Ginsburg IH, Prystowsky JH, Kornfeld DS, et al: Role of emotional factors in adults with atopic dermatitis. Int J Dermatol 32656660, 1993 19. Goldberg RJ: Practical Guide to the Care of the Psychiatric Patient, ed 2. St. Louis, Mosby-Year Book, 1998 20. Greene SL, Reed CE, Schroeter AL: Double-blind crossover study comparing doxepin with diphenhydramine for the treatment of chronic urticaria. J Am Acad Dermatol 12669-675, 1985 21. Gupta MA, Gupta AK: Dermatitis artefacta and sexual abuse. Int J Dermatol 32:82.5826, 1993 22. Gupta MA, Gupta AK: Fluoxetine is an effective treatment for neurotic excoriations: A case report. Cutis 51:386387, 1993 23. Gupta MA, Gupta AK Severe recurrent urticaria associated with panic disorder: A syndrome responsive to selective serotonin reuptake inhibitor (SSRI) antidepressants? Cutis 56:53-54, 1995 24. Gupta MA, Gupta AK: Psychodermatology: An update. J Am Acad Dermatol 34:1030-1046, 1996 25. Gupta MA, Gupta AK: Depression and suicidal ideation in dermatology patients: A comparison of patients with acne, alopecia areata, atopic dermatitis and psoriasis. Br J Dermatol 139:846-850, 1998 26. Gupta MA, Gupta AK Olanzapine is effective in the management of some self-induced dermatoses. Cutis (in press) 27. Gupta MA, Gupta AK, Chandarana PC, et al: Dissociative symptoms and self-induced dermatoses: A preliminary empirical study [abstr]. Psychosom Med 62:116, 2000 28. Gupta MA, Gupta AK, Ellis CN: Antidepressant drugs in dermatology. Arch Dermatol 123:647-652, 1987 29. Gupta MA, Gupta AK, Haberman HF: Psychotropic drugs in dermatology. J Am Acad Dermatol 14633645, 1986 30. Gupta MA, Gupta AK, Haberman HF: The self-inflected dermatoses: A critical review. Gen Hosp Psychiatry 9:45-52, 1987 31. Gupta MA, Gupta AK, Haberman HF: Dermatologic signs in anorexia nervosa and bulimia nervosa. Arch Dermatol 123:1386-1390, 1987 32. Gupta MA, Gupta AK, Haberman HF: Psoriasis and psychiatry: An update. Gen Hosp Psychiatry 9:157166, 1987

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