46 Practical Dermatology January 2005

he number of therapeutic options to manage acnevulgaris continues to grow. Although the variety ofeffective agents spans topical gels and creams, oralformulations, and even lights and lasers, no availableintervention offers relief in a single application.

Rather, control of acne requires repeated use of multipleagents over a period of time. Acne therapy is unavoidably aprocess.

Perhaps the single most important thing a dermatologistcan do to promote compliance with acne therapy is to provide

clear-cut, attainable goals and long-term expectations. Ofcourse all patients would love to wake-up acne-free the dayafter starting therapy, but most will be satisfied simply to seesome improvement from office visit to office visit.

Beyond goal-setting, there are numerous other strategiesdermatologists can use to promote compliance. Often, suc-cess depends on dispelling myths and anticipating patientbehavior in order to keep individuals from taking steps thatcould actually combat the benefits of pharmacologic therapy.Following are some key points to consider.

By Joseph Bikowski, MDSewickley, PA

T

January 2005 Practical Dermatology 47

The Basics of Skin CareBasic skin care is an integral part of acne therapy and key toencouraging long-term compliance. The products patients useto cleanse and moisturize the face can influence the “sensitivi-ty” of the skin and subsequently the tolerability of topical med-ications. Similarly, inappropriate cosmetic products applied tothe face can produce irritation and possibly encourage develop-ment of comedones, thus counteracting medical therapy.Education about proper skin care is not a “bonus” for patientswhen time permits. It is an integral part of the acne treatmentplan. You can provide additional supplementary informationwith every patient visit, but patients need to learn the basics attheir first appointment.

The best approach to daily cleansing remains to use a soap-free moisturizing cleanser, such as Cetaphil (Galderma), andtepid water. Rather than loofahs, sponges, or washcloths, patientsshould apply cleansers with their fingertips and rub gently.

Daily use of a non-comedogenic or non-acnegenic moistur-izer will benefit a wide range of acne patients, including thosewith “oily” skin. The level or rate of sebum production does notindicate stratum corneum hydration. Therefore, patients withsurface “oiliness” may still experience xerosis.1 Additionally,studies suggest that increased skin hydration enhances penetra-tion of topical therapies.2 The selection of formulation—lotion, cream, or gel—depends on patient preference and couldvary for an individual based on factors such as seasonal climatechanges, etc.

Additionally, encourage patients to select products with-out dyes or fragrances and that contain fewer than 10 ingre-dients. The 10-ingredient recommendation is based on theconventional wisdom that the fewer the ingredients, the lowerthe potential that irritants or allergens are included.

For female patients, discuss use of cosmetics. Generallythere are no restrictions on cosmetics use, except that patientsmust be sure to choose products that are non-comedogenic ornon-acnegenic. While there is no industry-wide definition for“non-comedogenic” or “non-acnegenic,” cosmetic and skincare products that bear the label generally have been testedand are appropriate for acne patients. The meaning of addi-tional marketing tags, such as “oil-free,” is less clear; thereforethese phrases should not influence product selection.

Sunscreen use is a topic many dermatologists may over-look in acne care. All patients should practice appropriate sunprotection, and the discussion of skin care basics is a perfecttime to encourage healthy sun exposure avoidance habits inacne patients. Some patients will find that using a moisturiz-ing sunscreen product daily is a convenient way to simplifytheir regimen.

As with moisturizers and make-up, multiple non-comedo-genic sunscreen products are available; many are marketedspecifically for use on the face. Sunscreen products come inlotion, cream, gel, and spray formulations. The patient mayselect the non-comedogenic product and formulation theyprefer based on feel, price, or other preferences.

48 Practical Dermatology January 2005

I provided a fuller discussion of skin care ingredients andproduct selection for acne patients in the July 2004 issue ofPractical Dermatology.

The Acne BasicsTeaching patients the basics of acne pathogenesis will help dispelmyths that could hinder compliance and will encourage patientsto become more active participants in their own care. An indi-vidual is more likely to use a product as directed when he or sheunderstands the “how” and “why” of its use. At a minimum,patients should understand that four known factors contributeto the cutaneous manifestations of acne. These are increasedsebum production, increased and faulty keratinization, P acnescolonization, and inflammation.

When you select a regimen for the patient, describe whichelement of acne pathogenesis each product targets. Describe howit works, how it does not work, and even why you have chosenthe particular product over other available products. Stress that,just as acne results from the interaction of multiple factors, itseffective management will require the combined activity ofnumerous products.

Sebum. Take a moment to explain to patients that no avail-able agent reliably targets sebum production. While oralisotretinoin can diminish sebum production, no available prod-uct—prescription or otherwise—can efficiently and predictablyregulate sebum production. Certain topical products work toabsorb surface “oil” and diminish its appearance, but they don’tdecrease production or diminish the underlying role of sebum inacne pathogenesis. Similarly, tell patients that aggressive facewashing fails to diminish the underlying activity of sebum inpathogenesis.

P acnes colonization. Make it clear that P acnes colonizationis just part of and not the sole cause of acne vulgaris, therefore allbut the most mild cases of the disease require use of other topi-cal or systemic agents in addition to topical antibacterials (suchas benzoyl peroxide).

Concern about antibiotic resistance has moved beyond themedical community to discussions in popular health magazines,news magazines, and even health and news television programs.Therefore, patients—even teens—and parents may have ques-tions that you should be prepared to answer. Assure concernedpatients that you prescribe systemic antibiotics in a manner thatlimits resistance risks and explain how other elements of thetreatment plan—including topical retinoids or topical antimi-crobials (benzoyl peroxide)—help diminish reliance on systemicantibiotics. To limit bacterial resistance risks, benzoyl peroxideshould be used in conjunction with any topical or systemicantibiotic. Topical formulations that incorporate benzoyl perox-ide as well as a topical antibiotic (benzoyl peroxide/clindamycinor benzoyl peroxide/erythromycin preparations) are beneficial.

The market for antibacterial/antimicrobial liquid soaps andwaterless skin cleansers grew tremendously in recent years. Thelatter class of products contain mostly alcohol, which is poten-tially very irritating on acne-prone facial skin. The antibacteri-al agents incorporated into hand and body soaps, such as tri-closan, have not been shown to be particularly effective againstP acnes. Therefore, these agents will not benefit acne patientsand they should avoid using them on the face.

Hyperkeratinization. As you explain the role of follicularplugging, dispel the common myth that “dirt” causes acne.This will hopefully prevent overzealous skin cleansing andscrubbing, which could actually lead to irritation and exacerba-tion of acne.

Inflammation. Patients will be interested to learn that topi-cal and systemic antibiotics may confer anti-inflammatory bene-fits in addition to their anti-P acnes activity. Similarly, describethe anti-inflammatory action of topical retinoids and retinoidanalogues. Again, knowing how agents work may give patients agreater sense of control over their disease and its management.

Therapy-Specific TipsAs noted, the majority of patients will require a combinationregimen to manage their acne. The goal of this article is not todiscuss all available therapies or outline all effective regimens.Rather, I propose strategies to improve compliance with certaindrugs or classes of drugs and provide guidelines for establishingtreatment regimens that encourage compliance.

When devising combinations, try to limit the total number ofproducts a patient will use or apply and attempt to design regi-mens with a maximum of two daily treatment periods, if possi-ble. For example, avoid prescribing a topical agent qam, anotheragent qpm, and a systemic agent tid. Instead, keep it simple witha twice-daily or, if possible, once-daily usage schedule.

Don’t underestimate the value of slow titration to helppatients adjust to potentially irritating retinoid therapies (i.e.tretinoin, tazarotene). Applying these topical agents every othernight for two weeks and every night thereafter is a legitimateapproach to help sensitive skin patients adjust to therapy. Butdon’t fall into the trap of believing every patient needs such anapproach. There is a sense that daily application is more “habit-forming” and therefore more compliance-friendly than alter-nate-day dosing.

Topical Therapy TipsTopical Antibiotics/Antibacterials. Several factors bear con-sideration when selecting a compliance-friendly topical antibi-otic/antibacterial product. Products that require refrigerationare not a good option for many acne patients—particularlythose who may be away at school, travel frequently, or other-wise don’t have constant access to a refrigerator.

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The newer, once-daily clindamycin 1%/benzoyl peroxide5% topical gel is as effective as other combinations that areapplied twice daily.

A foam vehicle is now available in acne therapy with recentFDA approval of clindamycin phosphate foam 1%. Due to thenewness of the product, experience is limited, but the uniqueformulation could have benefits for certain patients. Malepatients tend to find foam formulations cosmetically elegant,and they are particularly useful for application to hair-bearingareas, including the beard area. Additionally, foams are gener-ally convenient and cost-effective for application to large sur-face areas, such as the chest, shoulders, or back.

Topical Retinoids. Retinoids help regulate keratinization,and we’ve recently begun to more fully-appreciate their anti-inflammatory benefit. Topical retinoids demonstrate the abili-ty to decrease inflammatory lesions associated with acne.3-5

Therefore, they should be part of every patient’s treatment planfrom the initiation of therapy.

When it comes to compliance with topical retinoid therapy,however, irritation may be a concern. From scientific studies tomarketing materials, much has been written about the role ofvehicles in producing or minimizing irritation and/or enhanc-ing patient satisfaction. Interestingly, dermatologists suspectedthat lotion or cream formulations produced less irritation orprovided more patient comfort than gel formulations did.However, recent evidence suggests vehicle selection could bemore complex than this. When Leyden et al6 evaluated the tol-erability of topical retinoids in a series of randomized, investi-gator-masked, split-face studies in 262 patients with acne, theyfound that the best-tolerated formulations were tazarotenecream and adapalene gel. Though patients with sensitive skindemonstrated similar trends in tolerability, at any given con-centration sensitive skin patients experienced greater increasesin erythema and dryness.

These findings support the need for patient-specific treat-ment selection. Sometimes, ultimate choice of vehicle willhinge on patient preference; give the patient the choice ofcream, lotion, or gel.

The wealth of studies comparing topical retinoids (adapa-lene, tazarotene, tretinoin microsphere) reveals that all areeffective, but taken together these studies may not reveal thatany particular agent is significantly better than the rest.Similarly, the various studies taken together allow for someinterpretation regarding associated irritation, particularly sincethe studies often compare different application regimens anddosing schedules.7-11 Nonetheless, the microsphere formulationsof tretinoin have largely replaced tretinoin due to decreasedirritation. The retinoid analogue adapalene is still widely asso-ciated with minimal irritation11,12 and is often my first choicewhen irritation is a concern. Though it may demonstrate bet-

ter efficacy, tazarotene may also be the most irritating topicalretinoid. Properly balancing efficacy and tolerability to opti-mize patient care depends on the skill of the dermatologist.

Systemic Therapy TipsOral Antibiotics. The anti-inflammatory benefits of systemicantibiotics contribute significantly to their efficacy in acnemanagement. In fact, subantimicrobial dose doxycyclinedemonstrates efficacy in both acne and rosacea, and continuesto garner interest from clinicians.22,23

The tetracyclines have largely replaced erythromycin in acnemanagement, due to P acnes resistance to the latter.24

Tetracycline has also been associated with high rates of resist-ance, therefore minocycline and doxycycline are more common-ly prescribed.25 Minocycline is associated with less GI upset thandoxycycline is. However, there is an increased incidence of CNSside effects, i.e. vertigo, with minocycline. The CNS side effectprofile can be improved by the use of a slow-released minocy-cline formulation, such as Dynacin (Medicis). Interestingly,branded minocycline pellet-containing capsules have a 90 per-cent GI tract absorption, whereas the generic powder formula-tions have about 70 percent GI tract absorption.

Doxycycline may be associated with more significant GIupset than minocyline. However, taking doxycycline in themorning with food can minimize GI side effects withouthindering absorption. Additionally, time-release formula-tions (Doryx, Warner-Chilcott) allow for absorption in thesmall intestine rather than the stomach, and subsequentlyfewer gastric symptoms. Chelation in the presence of dairyproducts is not a significant concern with doxycycline orminocycline.

Bluish hyperpigmentation of the eyes, teeth, nails, and skinis a risk associated with minocycline therapy. While this is nota concern with doxycycline, possible photosensitivity is.Patients should undertake sun protection strategies (avoidanceas well as use of topical sunscreens), but there is no proof sun-screens can protect against doxycycline-related phototoxicity.Risk of phototoxicity appears to be dose-dependent, with the50mg daily dose significantly less likely to induce toxicity com-pared to a 200mg daily dose.30

Expect interest in subantimicrobial dose doxycycline toincrease. At subantimicrobial doses, tetracyclines reduceinflammation via anticollagenolytic, antimatrix-degradingmetalloproteinase and cytokine down-regulating properties.Results of a double-blind, placebo-controlled trial in the treat-ment of moderate facial acne and an open label study in thetreatment of rosacea confirm the efficacy of subantimicrobialdose doxycycline.22 Lower doses diminish concerns about bac-terial resistance and may be associated with fewer adverseeffects.

Oral Isotretinoin. Recent FDA advisories regarding oralisotretinoin (Accutane, Amnesteem, Claravis, Sotret) have putit back in the spotlight. Exactly how new regulations will affectphysicians and patients remains unclear, as manufacturers andthe FDA are still working to devise new policies. Meanwhile,we must be prepared to address patients’ concerns about oralisotretinoin.

The careful patient selection and extensive education associ-ated with oral isotretinoin therapy help dermatologists identifyreliably compliant patients. Because patient failure to complywith mandatory testing will result in retraction of the prescrip-tion by the prescriber, the threat of therapy withdrawal is apotentially powerful motivator for therapeutic compliance withisotretinoin therapy.

The drying effects formerly associated with isotretinointherapy have largely diminished with widespread adoption ofthe 0.5mg/kg/day dosage regimen (to a 120-150mg/kg totalbody dose).

Despite widespread reports and much speculation, there isno evidence linking depression or suicide with isotretinointherapy.26-29 In fact, studies show that rates of depression andanxiety actually dropped among acne patients treated withisotretinoin.26 Another study found that the rate of anti-depres-sant use was similar among patients taking isotretinoin andthose taking minocycline.27 The relative risk estimate for sui-cide or attempted suicide was 0.9 when comparing currentisotretinoin exposure with nonexposure in another study.29

Nonetheless, it is wise to inform patients and/or parents to callyou immediately if they sense any mood change.

Putting it Together:Compliance-Boosting RegimensIt’s just common sense that as regimens become more complexcompliance diminishes. Try to keep treatment as simple as pos-sible for the patient.

Co-application of topical antibiotic/antibacterial agents andtopical retinoids is permissible and can simplify regimens. Datasuggest that when benzoyl peroxide formulations are co-applied with topical tretinoin, the tretinoin product becomesunstable and rapidly depleted. However, similar tretinoin inac-tivation does not occur when benzoyl peroxide is co-appliedwith tretinoin gel microsphere formulations.13 Importantly,topical retinoids may enhance penetration of topical antimicro-bials when applied immediately before an antimicrobial formu-lation.5

Samples can play an important role in promoting compli-ance. When you have samples on hand, you can demonstrateto the patient exactly how to apply a particular product andhow much to use. Patients may be most motivated to begintherapy in the hours and days following a visit; samples capital-ize on this “excitement” by allowing the patient to immediate-

ly begin therapy. This may prove particularly helpful foryounger patients who may have to wait for a parent to visit thepharmacy or for individuals whose prescription plans requireuse of mail-order services.

One combination regimen that is effective for moderate tosevere grades I, II, and III acne (mixed open and closed come-dones and papules and pustules) incorporates the three Ds:Differin (adapalene, Galderma), Dynacin or Doryx, and Duac(Stiefel). Benefits of these oral antibiotic formulations areaddressed above.

Either of the above systemic antibiotics administered qdplus adapalene qpm for a month helps reduce both inflamma-tory and non-inflammatory lesions. After one month, addDuac qam. Once the patient achieves an acceptable level ofcontrol, taper the systemic medication and continue topicaltherapy for maintenance.

Beyond MedicationsBeyond giving patients straightforward directions about whatto do to manage their acne, be sure to address habits that canworsen the condition. Mechanical manipulation can exacerbateacne regardless of the therapeutic regimen in place. Cautionpatients not to pick or pop acne lesions and be vigilant forexcoriators.

Also, be aware of patterns of distribution of lesions. Thosealong the hairline might be signs of acne mechanica related tothe wearing of helmets or caps. Acne mechanica results fromthe combination of pressure, friction, rubbing, squeezing,and/or heating of the skin.14,15 Lesions along the jawline andchin—particularly in male patients—could implicate sportshelmet chin-straps, while back and shoulder lesions could becaused by sports equipment, such as shoulder pads.

Few interventions can comfortably or effectively diminishthe pressure, friction, and heating of athletic equipment orother apparel, but concomitant pharmacologic therapy canprovide some improvement. It’s important to counsel patientsabout acne mechanica. During a particular sports season, phar-macologic therapy may yield only a moderate level of controlof acne, whereas improved results or clearance may be possibleonce the season ends and aggravating factors are withdrawn.15

Finally, be prepared to address lifestyle issues and dispelmyths that the patient may associate with acne. There’s a wide-spread belief that sun exposure can clear acne. While ongoingresearch suggests that UV radiation could influence P acnes andlasers and light sources continue to gain popularity as treat-ment options,16-21 patients must understand the differencebetween medically-based light therapy and potentially danger-ous unprotected sun-exposure. Also, be sure to note that if andwhen physicians use light therapy, it is in combination withmedications to manage acne, not as an alternative to these samemedicines.

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50 Practical Dermatology January 2005

The diet/acne controversy also persists. I don’t believe theresearch to this point warrants a discussion of diet with all acnepatients, but we must be prepared to answer patients’ ques-tions. Perhaps the safest advice we can offer patients is to con-firm that low-fat, high-fiber diets continue to demonstratenumerous benefits for overall health while high-fat, high-calo-rie/minimally nutritious foods pose potential long-term healthrisks. If the patient believes that certain foods exacerbate acne,then he or she should avoid them.

Final ThoughtsIt’s impossible to overstate the value of written patientinstructions. Hand-outs can help ensure that patients under-stand instructions as you give them and they allow for futurereference, potentially eliminating unnecessary phone calls orabandonment of therapy. As you describe potential side-effects from the minor to the more significant, be sure to statewhich ones are causes for concern and should prompt a callto the office.

Direct patients to worthwhile information sources. Again,this may limit phone calls to the office. Personally review anywebsites before recommending them. Sites containing informa-tion contrary to your views will only engender confusion. Somereliable sites sponsored by pharmaceutical companies include:

• www.dynacin.com• www.differin.com/teens/index.shtml

• www.tazorac.com/timeout.asp• www.duacgel.com• www.dermik.com/skin/acne/Acne.jspProvide appropriate refills, and schedule follow-up at the

appropriate times. Educate front-desk staff. If they mustschedule a patient beyond your proposed time frame (say 14weeks, rather than 12), have them check that the prescriptionwill carry the patient through.

Sometimes when a patient presents for follow-up I discov-er that he or she didn’t use their medication as I directed thembecause someone (or some website) told them not to. Whenyou know that your proposed treatment regimen differs from“typical” uses, acknowledge this point to the patient and offera rationale to encourage compliance.

From time to time I learn that a pharmacist’s advice contra-dicted my instructions or the pharmacy placed a label on thebottle that seemed to conflict with my instructions. Someoverzealous pharmacists deserve a call from your office.Generally, though, it pays to simply remain cognizant of allthe information that is circulating and attempt to counteractit. Tell every patient what to do and why, then add, “The phar-macist may tell you something else, but do what I tell you. Ifyou have any questions or concerns, call me.”

With these thoughts in mind and a focus on setting realis-tic short and long-term goals, you can encourage patients toget the most from acne therapy.

January 2005 Practical Dermatology 51

1. Centurian SA. Mositurizers. E-medicine. www.emedicine.com/derm/topic 506.htm.2. Lippol BC. How to optimize drug penetration through the skin. Pharm Acta Helv. 1992;67:294-300.3. Wolf JE Jr. Potential anti-inflammatory effects of topical retinoids and retinoid analogues. Adv Ther 2002 May-June; 19(3):109-18.4. Millikan LE. The rationale for using a topical retinoid for inflammatory acne. Am J Clin Dermatol 2003;4(2):75-80.5. Shalita A. The integral role of topical and oral retinoids in the early treatment of acne. J Eur Acad Dermatol Venereol2001;15 Suppl 3:43-9.6. Leyden JJ, at al. Tolerability of Topical Retinoids. Presented at Academy ’04, New York, NY in Retinoids inDermatology: Evolution and Revolution. 7. Brand B, Gilbert R, Baker MD, et al. Cumulative irritancy comparison of adapalene gel 0.1% versus other retinoidproducts when applied in combination with topical antimicrobial agents. J Am Acad Dermatol 2003 Sep;49(3Suppl):S227-32.8. Webster GF, Guenther L, Poulin YP, et al. A multicenter, double-blind, randomized comparison study of the effica-cy and tolerability of once-daily tazarotene 0.1% gel and adapalene 0.1% gel for the treatment of facial acne vul-garis. Cutis 2002 Feb;69(2 Suppl):4-11.9. Leyden JJ, Tanghetti EA, Miller B, et al. Once-daily tazarotene 0.1% gel versus once-daily tretinoin 0.1%microsponge gel for the treatment of facial acne vulgaris: a double-blind randomized trial. Cutis 2002 Feb;69(2Suppl):12-19.10. Leyden J, Lowe N, Kakita L, Draelos Z. Comparison of treatment of acne vulgaris with alternate-day applicationsof tazarotene 0.1% gel and once-daily applications of adapalene 0.1% gel: a randomized trial. Cutis 2001 Jun; 67(6 Suppl):10-16.11. Brand B, Gilbert R, Baker MD, Poncet M, Greenspan A, Georgeian K, Soto P. Cumulative irritancy potential ofadapalene cream 0.1% compared with adapalene gel 0.1% and several tretinoin formulations. Cutis 2003Dec;72(6):455-8.12. Waugh J, et al. Spotlight on adapalene in acne vulgaris. Am J Clin Dermatol 2004;5(5):369-71.13. Nyirady J, Lucas C, Yusuf M, et al. The stability of tretinoin in tretinoin gel microsphere 0.1%. Cutis 2002Nov;70(5):295-8.14. Mills OH Jr, Kligman A. Acne mechanica. Arch Dermatol.1975 Apr;111(4):481-3.15. Basler RS. Acne mechanica in athletes. Cutis 1992 Aug;50(2):125-8.

16. Kalayciyan A, Oguz O, Bahar H, Torun MM, Aydemir EH. In vitro bactericidal effect of low-dose ultraviolet B inpatients with acne. J Eur Acad Dermatol Venereol. 2002 Nov;16(6):642-3.17. Pollock B, Turner D, Stringer MR, Bojar RA, Goulden V, Stables GI, Cunliffe WJ. Topical aminolaevulinic acid-pho-todynamic therapy for the treatment of acne vulgaris: a study of clinical efficacy and mechanism of action. Br JDermatol. 2004 Sep;151(3):616-22.18. Orringer JS, Kang S, Hamilton T, Schumacher W, Cho S, Hammerberg C, Fisher GJ, Karimipour DJ, Johnson TM,Voorhees JJ. Treatment of acne vulgaris with a pulsed dye laser: a randomized controlled trial. JAMA. 2004 Jun16;291(23):2834-9.19. Elman M, Lask G. The role of pulsed light and heat energy (LHE) in acne clearance. J Cosmet Laser Ther. 2004Jun;6(2):91-5.20. Friedman PM, Jih MH, Kimyai-Asadi A, Goldberg LH. Treatment of inflammatory facial acne vulgaris with the1450-nm diode laser: a pilot study. Dermatol Surg. 2004 Feb;30(2 Pt 1):147-51.21. Elman M, Lebzelter J. Light therapy in the treatment of acne vulgaris. Dermatol Surg. 2004 Feb;30(2 Pt 1):139-46.22. Bikowski JB. Subantimicrobial dose doxycycline for acne and rosacea. Skinmed. 2003 Jul-Aug;2(4):234-45. 23. Del Rosso JQ, Bikowski JB. Skin & Aging. November 2004. 36-4224. Eady EA. et al. Erythromycin resistant Propionibacteria in antibiotic treated acne patients: association with thera-peutic failure. Br J Dermatol 1989;121:51-7.25. Eady E, Jones C, Gardner K, et al. Tetracycline-resistant propionibacteria from acne patients are cross-resistant toto doxycycline but sensitive to minocycline. Br J Dermatol 1993;128:556-560.26. Ferahbas A, Turan MT, Esel E, Utas S, Kutlugun C, Kilic CG. A pilot study evaluating anxiety and depressive scoresin acne patients treated with isotretinoin. J Dermatolog Treat. 2004 Jun;15(3):153-7.27. Hersom K, Neary MP, Levaux HP, Klaskala W, Strauss JS. Isotretinoin and antidepressant pharmacotherapy: aprescription sequence symmetry analysis. J Am Acad Dermatol. 2003 Sep;49(3):424-32.28. Hull PR, D'Arcy C. Isotretinoin use and subsequent depression and suicide: presenting the evidence. Am J ClinDermatol. 2003;4(7):493-505. Review.29. Jick SS, Kremers HM, Vasilakis-Scaramozza C. Isotretinoin use and risk of depression, psychotic symptoms, sui-cide, and attempted suicide. Arch Dermatol. 2000 Oct;136(10):1231-6.30. Layton AM, Cunliffe WJ. Phototoxic eruptsion due to doxycycline: A dose-related phenomenon. Clin Exp Dermatol1993 Sep; 18(5):425-7.

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