M. A. Guptaa, MD, FRCPC and A. K. Guptab, MD, FRCPC
aDepartment of Psychiatry, University of Western Ontario, London, Ontario, Canada and bDivision of Dermatology, Department of Medicine, University of Toronto, Toronto, Ontario, Canada
Antidepressant drugs can be an important component of the dermatologists’ therapeutic armamentarium. When considering the use of psychotropic agents in dermatology two major factors should be considered: (1) the accurate diagnosis of the comorbid psychiatric disorder, and (2) the presence of proper indications for the use of antidepressant agents. Antidepressant drugs are used in the management of the psychiatric syndromes,13 which are most frequently comorbid with dermatolgic disorders, i.e., Major Depressive Disorder, Obsessive-Compulsive Disorder, Body Dysmorphic Disorder, Post-traumatic Stress Disorder and Social Phobia. The antihistaminic and analgesic properties of some antidepressants such as doxepin and amitriptyline, are also be of benefit in the treatment of some pruritic and neuralgic states. The specific guidelines, side effect profile, drug-drug interactions, and the most current indications should always be obtained for any particular antidepressant agent before it is prescribed.
antidepressant, serotonin reuptake inhibitors, tricyclic antidepressants
Antidepressants (Table 1)1–5, can be classified as tricyclic antidepressants (TCAs), selective serotonin reuptake inhibitors (SSRI) and the atypical group. TCAs increase the synaptic concentration of norepinephrin (NE) and/or serotonin (5HT) in the central nervous system (CNS) by (1) inhibiting their reuptake in the presynaptic neuronal membrane, and (2) changing post-synaptic β-adrenergic receptor sensitivity. TCAs produce prominent peripheral and CNS anticholinergic effects, as well as sedative effects due to strong binding affinity for histamine H1 receptors, and orthostatic hypotension due to alpha adrenergic receptor blockade. The TCAs have a quinidine-like effect on the heart and, like quinidine, can moderately slow ventricular conduction in therapeutic doses. An overdose can cause severe conduction block and ventricular arrhythmias.
The SSRIs inhibit serotonin reuptake, thereby enhancing serotoninergic function. Their relatively selective effect on 5HT is believed to be the basis for their antiobsessional activity. In contrast to TCAs, the SSRIs have very minimal histamine H1, cholinergic and β1-adrenergic blocking effects.
In drug-drug interactions involving the use of psychotropic agents in dermatology, the cytochrome P450(CYP)2D6 and CYP3A3/4 are the most important. Some SSRIs such as fluoxetine and fluvoxamine are moderate inhibitors of cytochrome P450 3A3/4 (CYP 3A3/4) isoenzymes, and can slow down the metabolism of medications that are metabolized by CYP3A3/4 isoenzymes. Concurrent use of the antipsychotic agent pimozide, a CYP3A3/4 substrate, and fluoxetine has been associated with bradycardia.1 In vitro studies have shown that fluvoxamine blocks the metabolism of the antihistamines astemizole and terfenadine, which are CYP3A3/4 substrates. This can result in potentially fatal QT prolongation and torsades des pointes. The co-administration of fluvoxamine with astemizole and terfenadine is contraindicated.1,2 Co-administration of fluoxetine with single doses of terfenadine (a CYP3A3/4 substrate), showed no increases in terfenadine levels.2 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 enzyme.2 Alternately, the SSRI paroxetine is a very weak inhibitor of CYP3A3/4 and interactions with medications that are metabolized by CYP3A3/4 are unlikely.1,2 The SSRIs paroxetine, fluoxetine and sertraline are also inhibitors of CYP2D6 isoenzyme, and can increase the blood levels of drugs that are metabolized by the CYP2D6 isoenzyme such as the tricyclic antidepressants, antipsychotics, codeine, and cardiac antiarrhythmics.1,2
Possible Uses Of Antidepressants For Conditions That Are Not Psychiatric Disorders
The TCA, oral doxepin, 10mg taken three times daily for 2 weeks, has been shown to be effective in the treatment of chronic idiopathic, and cold urticaria.6,7,8 Topical 5% doxepin cream is also used for the treatment of pruritus.9 The efficacy of doxepin in urticaria is not directly related to its antidepressant effect. The H1 and H2 antihistaminic and anticholinergic properties of the TCAs are important reasons for their efficacy. Doxepin, amitriptyline and trimipramine are potent H1-receptor (e.g., doxepin is 800 times more potent than diphenhydramine) and H2 receptor antagonists. The strongly antihistaminic TCA, trimipramine (50mg/day) has been used to treat the pruritus of atopic dermatitis.10 Amitriptyline has been shown to be effective for postherpetic neuralgia11, and amitriptyline or desipramine for the pain of diabetic neuropathy.12
Possible Uses of Antidepressants For Conditions That Represent Psychiatric Pathology
Major Depressive Disorder13
This disorder is characterized by one or more major depressive episodes (i.e., depressed mood or loss of interest or pleasure), and is accompanied by ≥4 vegetative symptoms such as change in sleep, appetite, fatigue, psychomotor agitation or retardation, and a reduced ability to concentrate. A wide range of dermatologic disorders4,5 such as atopic dermatitis, psoriasis, chronic idiopathic urticaria, alopecia areata, and acne are comorbid with depressive illness. Depression severity has been directly correlated with pruritic severity in psoriasis, atopic dermatitis and chronic idiopathic urticaria.14 Patients with clinically mild acne who blame their vocational problems on their acne may be clinically depressed. Antidepressants have been used to treat neurotic excoriations and ‘depressive equivalents’ such as a burning sensation in the scalp and glossodynia.1,2 Clomipramine has been used to treat trichotillomania.15 When prescribing psychotropic agents, the clinician should always determine whether the patient poses a significant suicide risk, in which case the total amount of medication in the prescription should be a non-lethal dose.
|Generic (trade) name||Usual daily starting dose* (mg)||Usual daily dose range*(mg)||Relative histamine H1-receptor blocking potency||Relative anticholinergic potency||Relative β1- adrenergic receptor blocking potency|
|Selective serotonin reuptake inhibitors (SSRI):|
|Amitriptyline (Elavil and others)||50–75||100–150||high||high||moderate/high|
|Doxepin (Sinequan, Adapin)||25–75||100–150||high||high||high|
Table 1: Antidepressants: dosage and post-synaptic receptor affinities of some agents1–5
* Doses above 150 mg of imipramine or equivalent should be used with close monitoring for adverse reactions. All antidepressants are contraindicated in combination with monoamine oxidase inhibitors.
Obsessive Compulsive Disorder13 (OCD)
Symptoms include repetitive behaviors such as hand washing, hair plucking, picking of the skin including skin lesions, and ritualistic grooming. It may be the underlying pathology in trichotillomania, and neurotic excoriations and acne excoriee. Agents that inhibit 5- HT reuptake such as clomipramine and the SSRIs are effective in OCD. SSRIs are generally effective for OCD in higher doses when compared with the antidepressant dosage,1,2 e.g., OCD may require 60-80mg/day of fluoxetine while a depressive illness will typically respond to a lower dose.
Body Dysmorphic Disorder13 (Dysmorphophobia)
Patients with this condition exhibit a preoccupation with an imagined defect or a minor anomaly involving the face or head, such as thinning hair, wrinkles, acne, scars, vascular markings, or excessive facial hair. SSRI antidepressants may be effective, but the onset of action usually takes longer (about 6 weeks).
Post-traumatic Stress Disorder13(PTSD)
This condition is often under-recognized in dermatology. Patients have a history of having experienced a traumatic event that involved the threat of death, injury or severe harm and their response involved intense fear, horror and helplessness. PTSD patients who experience trauma such as sexual abuse, severe emotional abuse or neglect, loss of a caregiver in early life, or a very chaotic childhood may self-inflict lesions, e.g., dermatitis artefacta and trichotillomania, or self-excoriate an existing skin lesion, e.g., acne excoriee. Since some patients experience dissociative episodes, they may not recall self-inflicting the lesions. SSRI antidepressants help attenuate some symptoms of hyperarousal in PTSD and decrease the frequency of self-injury.
Patients with social phobia experience fear being humiliated or embarrassed in public, and this may lead to the avoidance of certain social situations. A cosmetically disfiguring skin condition can theoretically contribute to the development of social phobia. SSRIs, nefazodone, and venlafaxine may be effective in the management of social phobia in some patients.
Some Guidelines For The Use Of Antidepressant Agents1–5
- Evaluate the patient to determine the presence of correct indications, assess suicide potential, and perform complete blood count, liver and renal function tests, as well as ECG, if indicated by cardiac history or if there is potential for cardiotoxicity present.
- SSRIs have replaced the TCAs as the drug of first choice when treating depression because of their safety, their much lower cardiovascular side effects and better tolerability. Furthermore, treatment can be initiated with a dosage of SSRI that is in the therapeutic range, in contrast to the TCAs where the dosage often has to be gradually increased.
- An SSRI should be chosen if anti-obsessional effects are desired, or anxiety is a prominent symptom. Strong 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 dose when the TCA is being used for its antihistaminic/sedative properties.
- For a significant antidepressant effect to become established 4–6 weeks of treatment are usually necessary and the patient should be advised about this when therapy is first initiated, as 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 a specific agent prior to prescribing1,2):
- Cardiovascular-orthostatic hypotension related to β1-adrenergic receptor blocking potency
- ECG changes such as QT prolongation and T wave inversion, intraventricular conduction defects and arrhythmias
- Increased risk of cardiotoxicity when used in conjunction with antihistamines, eg., 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
- Some cutaneous reactions include photosensitivity, increased sweating, pruritus, maculopapular rashes, urticaria, cutaneous vasculitis, erythema multiforme and alopecia.
Antidepressant agents can play an important role in the management of a wide range of dermatologic disorders. The strongly antihistaminic properties of some tricyclic antidepressants are beneficial in conditions such as urticaria and pruritus. TCAs and SSRI antidepressants are used for the treatment of Major Depressive Disorder, a disease that can coexist with a wide range of skin disorders. TCAs that act on serotonin and the SSRIs are effective in the treatment of Obsessive-Compulsive Disorder, which may underlie many self-induced dermatoses. The SSRIs are also effective in some cases of Body Dysmorphic Disorder, often seen in patients who present with cutaneous body image problems, Posttraumatic Stress Disorder, which underlies some self-induced dermatoses, and Social Phobia, which may coexist with cosmetically disfiguring skin disorders.
- The United States Pharmacopeial Convention, Inc. Drug information for the healthcare professional. USP-DI Vol 1, 20th ed. Englewood, CO: Micromedex Inc. (2000).
- Physicians’ Desk Reference, 54th edition. Montvale, NJ: Medical Economics Data Production Company (2000).
- Janciak PG. Handbook of Psychopharmacotherapy. Philadelphia: Lippincott, Williams & Wilkins pp 259–289 (1999).
- Gupta MA, Gupta AK. The use of antidepressant drugs in dermatology. J Eur Acad Dermatol Venereol in press 2001.
- Gupta MA, Gupta AK. The use of psychotropic drugs in dermatology. Dermatol Clin 18(4):711–25 (2000 Oct).
- Greene SL, Reed CE, Schroeter AL: Double-blind cross-over study comparing doxepin with diphenhydramine for the treatment of chronic urticaria. J Am Acad Dermatol 12(4):669–75 (1985 Apr).
- Harto A, Sendagorta E, Ledo A. Doxepin in the treatment of chronic urticaria. Dermatologica 170(2):90–3 (1985).
- Niettaanmaki H, Myohanen T, Fraki JE. Comparison of cinnarizine, cyproheptadine, doxepin, and hydroxyzine in the treatment of idiopathic cold urticaria:usefulness of doxepin. J Am Acad Dermatol 11(3):483–9 (1984 Sep).
- Drake LA, Fallon JD, Sober A. Relief of pruritus in patients with atopic dermatitis after treatment with topical doxepin cream. The Doxepin Study Group. J Am Acad Dermatol 31(4):613–6 (1994 Oct).
- Savin JA, Paterson WD, Adam K, Oswald I. Effects of trimeprazine and trimipramine on nocturnal scratching in patients with atopic eczema. Arch Dermatol 115(3):313–5 (1979 Mar).
- Watson CP, Evans RJ, Reed K, Merskey H, Goldsmith L, Warsh J. Amitriptyline versus placebo in postherpetic neuralgia. Neurology 32(6):671–3 (1982 Jun).
- Max MB, Lynch SA, Muir J, Shoaf SE, Smoller B, Dubner R. Effects of desipramine, amitriptyline, and fluoxetine on pain in diabetic neuropathy. N Engl J Med 326(19):1250–6 (1992 May).
- American Psychiatric Association. Task Force on DSM-IV. Diagnostic and Statistical Manual of Mental Disorders: DSM IV. Washington DC: American Psychiatric Association (1994).
- Gupta MA, Gupta AK, Schork NJ, Ellis CN. Depression modulates pruritus