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Patient Expectations and Isotretinoin Treatment— A Psychological Perspective

Updated: Mar 27

Authors:

Jake Bivas1, Nicole Sweeden2, Rania Eddik2, Harpriya Khela3, Moshe Shalom4

1City University of New York Macaulay Honors College, New York, NY

2Nevada State College, Clark County, NV

3Royal College of Surgeons, Dublin, Ireland

4Tel Aviv University Sackler Faculty of Medicine, Tel Aviv, Israel

 


Abstract

The use of isotretinoin (ITT) for the treatment of acne vulgaris and other cutaneous diseases has been associated with potential side effects, including depression, myopic changes in vision, and inflammatory bowel disease. ITT induces apoptosis of sebocytes and keratinocytes, resulting in reduced hyperkeratinization and sebogenesis. ITT’s lipophilic nature allows it to cross the blood brain barrier, altering cellular processes via all-trans-retinoic acid and retinoic acid receptor-mediated gene transcription, resulting in decreased metabolic activity and increased mood dysregulation. Physicians should take into account the increased risk of developing psychiatric disorders when prescribing ITT to patients. The use of ITT has been demonstrated to cause a significant decrease in thyroid hormones T4 and T3, while increasing thyroid-stimulating hormone (TSH) levels, which is positively associated with the incidence of depression. It is important for clinicians to set realistic treatment expectations, especially with adolescents who are experiencing biological thyroid hormonal changes. The severity of acne can be linked to increased depressive symptoms, and ITT’s direct target of the CNS has shown to directly affect mood regulation and behavior. Establishing realistic treatment expectations prior to ITT initiation can prevent negative psychological effects. Low-dose ITT combined with oral prednisolone or azithromycin results in subtherapeutic levels, which only correlate to moderate treatment outcomes and lower patient satisfaction. It is crucial for clinicians to illustrate realistic outcomes to prevent further mental health decline, especially in vulnerable cohorts.

 

Introduction

Isotretinoin (ITT)  is an active derivative of the retinoic acid family and is used for the treatment of severe nodulocystic acne1 Given orally, ITT acts as a prodrug and its metabolites, most notably all-trans-retinoic acid (atRA) and 4-oxo-13cisRA, alter gene expression via positive regulation of the Bcl-2 Associated X-protein (BAX) gene and a host of tumor suppressor genes, as well as negative regulation of genes related to the insulin-like growth factor 1 (IGF1)/phosphatidylinositol 3-kinase (PI3K)/AKT (protein kinase B)/mTORC1 pathway2. ITT also works as an anti-inflammatory and immunoregulatory agent via down-regulation of Toll-Like Receptors 2 and 4, as well as of Helper T cells3. Pharmacologically, these mechanisms induce apoptosis of sebocytes and keratinocytes, ultimately resulting in reduced hyperkeratinization and sebogenesis2. Excessive sebum production, along with proinflammatory changes in sebum composition (“acne sebum”), are thought to be the primary drivers of acne vulgaris pathogenesis4. ITT is also believed to be effective in treating other skin illnesses, including non-melanoma skin cancers, rosacea, pityriasis rubra pilaris, condyloma acuminata, granuloma annulare, Darier’s disease, fat warts, lichen planus, folliculitis decalvans, sebaceous hyperplasia, and cutaneous T cell lymphoma5

            The use of oral ITT is associated with several adverse side effects. Common - occurring in roughly 90% of patients - and less severe adverse side effects generally occur due to sebaceous gland down-regulation6. The common adverse effects include dry skin and mucous membranes, cheilitis , cutaneous xerosis, erythema, desquamation, dryness of nasal mucosa, epistaxis, worsening or triggering atopic dermatitis, dry eyes, inflammation of the eyelids, and more4.Other, less common, adverse effects include acne flares, musculoskeletal system adverse events, abnormal healing, psychiatric adverse events, inflammatory bowel disease, female infertility, diminution of ovarian reserve, and teratogenicity4.

Clinically, ITT dosage and treatment duration depends on the condition being treated5. Typical dosages range from 0.1 to 8.2 mg/kg/day, with inflammatory conditions such as rosacea and granuloma annulare being on the lower end and hyperkeratotic conditions such as psoriasis and pityriasis rubra pilaris on the higher end5. According to clinical studies, the standard dosage rate for ITT to treat acne vulgaris is 1.0 mg/kg/day7.


Known Effects of Isotretinoin

ITT has proven to be an effective method of treating acne vulgaris, among other cutaneous diseases8. A prospective observational study of 100 patients with moderate and severe acne was conducted to better understand factors associated with treatment efficacy, tolerability, and acne relapse8. They showed similar treatment efficacy between males and females, better clinical and quality of life outcomes in patients who received the highest cumulative dose, and greater clinical improvement in patients with moderate acne8. Regarding recurrence, only 9% of patients presented with acne recurrence during the first year following ITT treatment8. More specifically, recurrence occurred more often in females (12%) than in males (6%). As expected, recurrence was highest in the severe acne cohort and lowest in patients who were treated with a  high cumulative dose8. One study by De et al9 followed patients with moderate to severe acne and found the 10-year recurrence rate in patients receiving standard dose of ITT (1 mg/kg/day) to be 22-30%, and 39-82% for patients on a low dose regimen (<0.5 mg/kg/day)9. Collectively, these studies support the claim that ITT’s efficacy and tolerability over a long period of time is dosage-dependent.

            ITT treatment efficacy can also be improved through co-administration of other medications10. Mehra et al11 showed that low-dose ITT (<1.0 mg/kg/day) combined with oral prednisolone showed complete recovery in 75% of patients with minimal side effects within eight months. Plewig et al12 also showed significant reductions in inflammatory lesions, sebaceous gland size and keratinization when ITT was combined with prednisolone and/or tretinoin cream12. Other trials concluded that low-dose ITT combined with azithromycin, an antibiotic that can reduce inflammatory response by inhibiting production of proinflammatory molecules13, is also effective and can further reduce the recurrence rate with minimal adverse side effects9. Use of low-dose ITT treatment may therefore be preferred from an economical perspective, especially when combined with certain topical steroids or antibiotics.

            ITT is thought to be associated with a higher risk of developing depressive symptoms, however, the literature is unclear14. Although retrospective and database studies have identified a link between ITT therapy and depression, suicidality and use of mental health services, prospective studies have found no association14. Other systematic reviews have also found no association between the ITT therapy and depression15. This discrepancy likely points towards a subset of patients that are at an increased risk of developing depressive symptoms who have yet to be identified. Biologically, an association does appear plausible due to ITT’s ability to cross the blood brain barrier and disrupt serotonergic systems and frontal orbital activity16.

This potential risk may lead some medical providers to prescribe lower-than-optimal doses of ITT to patients, especially those with a personal or family history of mood or affective disorders. However, this risk can be mitigated and should not come at the cost of subtherapeutic levels of ITT that can further worsen mental health17. A growing body of research supports the idea that depressive symptoms are linked to folic acid and/or vitamin B deficiencies, which result in lower levels of dopamine, norepinephrine, and serotonin, providing a neurochemical diathesis for depression18. In order to reduce the risk of depression in patients taking ITT, it may be favorable to supplement with folic acid and vitamin B12. This regimen can prevent rising blood homocysteine levels, which are commonly linked to depression and decreased cognitive function19,20,21.

 

Expectations in Elective Medical Treatment

Conventionally, patients have played a more passive role in the traditional healthcare setting22. This passive role may result in an ill clinician-patient dynamic where the patient is not active in their care, and thus may develop unrealistic expectations regarding their treatment outcomes. Modern medicine seeks to change this by involving patients in their healthcare decisions22.

While it has been demonstrated that higher patient satisfaction is associated with improved health outcomes for the patient, care is limited by practicalities such as time constraints and the patients’ own knowledge of their disease or condition23. A study evaluating hospital and general practice patients, found that many unmet expectations included helpfulness of reception staff, respectfulness of the physician and treatment towards patients, physician knowledge of the patient’s condition, condition management, information on the benefits and side effects of treatment, and other outcome expectancies24. One of the ways to close the gap between patient expectations and reality is to allow patients to participate in decisions regarding their care and to provide adequate recovery support25. This increased patient involvement may lead to increased patient satisfaction and reduce the development of unrealistic treatment expectations as a strong patient-physician relationship is built.

In one study on scar reduction treatment, 187 patients were surveyed for expectations and willingness to receive treatment26. It was shown that older patients expressed more realistic expectations for scar reduction, while younger patients had more unrealistic expectations for treatment26. Perceived treatment efficacy was significantly different across sampled demographics with regards to gender, age, and race26. Younger patients (ages 18-39) were more likely to think that scar treatments were more effective at softening, removing, or reducing scars than patients 40 years of age and older26. This may suggest that physicians fail to provide realistic expectations of scar treatment, principally to the relatively younger cohort. Given the likely correlation between ITT and depression, physicians should take extra care to disclose the realistic outcomes of acne treatment.

 

Neurological Disorders and Their Association with Isotretinoin

            One complication of acne vulgaris (AV) is the psychosocial consequences that can be attributed to the perceived deterioration of physical appearance27, especially in patients who present with a higher grade of acne28. Cutaneous disorders, such as AV, are known to cause anxiety and depression in patients, and many depressive symptoms that occur in IT patients are found to be linked to the severity of the cutaneous disorders27,28,29. In a study conducted by DeLuca et al., one patient reported that her suicidal ideation was primarily the result of her severe acne vulgaris30, and a similar study indicated that patients with bipolar disorders who are treated with ITT are at significantly increased risk for developing exacerbated mood fluctuations, including suicidal ideations, regardless of adherence to psychiatric medical treatment31. These findings suggest that patients being treated for AV are susceptible to depressive complications prior to ITT treatment. One study done by Erdoğan Y. et al. demonstrated that depression and anxiety scores did not significantly differ between the patients before and after IT treatment, and that the suicide risks were similarly after ITT27.

Previous studies have suggested that the observed relationship between IT and the development of depression and anxiety is due to a lack of proper study design and the inability to properly evaluate comorbid psychiatric disorders before beginning ITT27,32. Ng CH et al. suggested that depression is a rare, idiosyncratic adverse effect that can evolve during ITT in predisposed patients32. Psychological distress that occurs during ITT may be through worsening acne and acne flares during treatment, as cutaneous disorders can themselves lead to psychological distress29, 33, 34. While it is still unclear whether ITT directly causes depressive symptoms in some individuals, it is possible that acne flareups during ITT lead to the perception of unmet treatment expectations, which can precipitate depressive symptoms in this predisposed population.

It has been shown that in patients who do experience a decrease in acne severity through ITT, suicide probability and anxiety scores are either decreased or maintained27, 29. This is expected, as successful acne treatment is likely to have positive psychological effects and decrease acne-related suicidal thoughts and anxiety. Acne patients that had a history of suicidal behavior were at a lower risk of attempting suicide again after ITT, due to acne enhancement after a successful treatment31.  Ultimately, while ITT has been shown to improve AV, physicians should keep in mind that these patients may be more susceptible to depressive symptoms than the average person and realistic treatment expectations should be set prior to ITT initiation.

 

The Association Between Isotretinoin, TSH and T3/T4     

            It has been demonstrated that ITT can lead to a significant decrease in thyroid hormones T4 and T3 and increase in thyroid-stimulating hormones (TSH) 5. While these changes did not exceed lower or upper limits of normal physiological values, respectively, 5 thyroid fluctuations such as these have been observed to have a positive association with the incidence of depression28. The hypothalamic-pituitary adrenal (HPA) and hypothalamic–pituitary thyroid (HPT) axes have been shown to be affected as a result of ITT in adolescents with Major Depressive Disorder (MDD), indicated by elevated cortisol and TSH levels, respectively, when compared to healthy control35. While one study suggested that high-normal TSH levels did not show an association with depression38, other studies have demonstrated a positive association between subclinical hypothyroidism and depression37.

In healthy individuals, TSH and thyroid hormone levels are affected by factors such as gender and age35.  As ITT patients are most commonly adolescents38, an age range during which thyroid hormonal changes are known to occur, they are predisposed to developing thyroid-related depressive symptoms through this mechanism35,39.  This susceptibility to thyroid changes further places IT patients at risk of developing depressive symptoms, and clinicians should keep this in mind when discussing treatment plans and expectations with patients.

 

Effects of Retinoic Acid in The Central Nervous System

            ITT is a retinoic acid (RA) and derivative of vitamin A that is involved in hippocampal function and mood regulation through its actions in the prefrontal cortex40,41. One study on brain tissue function in patients on ITT also found decreased metabolic activity in the orbitofrontal cortex using fluorodeoxyglucose positron emission tomography42. These central nervous system (CNS) effects are thought to be mediated through the lipophilic nature of retinoids such as IT, that allows them to cross the blood-brain barrier, resulting in alterations in various cellular processes via  all-trans-retinoic acid and retinoic acid receptor-mediated gene transcription43.  This provides some evidence for the headaches that are commonly experienced by patients on ITT that have been shown to also lead to increased mood dysregulation41.

 

Acne Relapse after ITT

While IT is recognized as an effective treatment for AV44, the risk of relapse is always present. A study done by Sa A. et al. revealed that 70.3% of patients reported that they were not informed about the potential relapse of ITT by health care providers, and of those, 46.2% of these subjects experienced relapse28. The average time to relapse from ITT is approximately 460 days, and those who did relapse discontinued their treatment one month earlier than those who did not relapse45. One major concern with the current literature on acne relapse is that there is no standardized definition of relapse, and studies use a variety of acne severity scales46. Defining a threshold for AV relapse would be beneficial to future research, however, patient satisfaction is a subjective measure, and meeting individual patient expectations cannot be defined objectively. As such, it is important for clinicians to be clear about the possibility of AV recurrence, to set clear and realistic expectations for their patients prior to treatment initiation.

While relapse from ITT has been recognized for a long time, the cause of relapse is still largely unknown. Previous studies have shown that the times at which the daily dose of IT was taken (before or after meals), completion of treatment course, dose of oral IT, and topical retinoid maintenance therapy, are all factors that significantly influence relapse28,46,47. It should be noted that one study found relapse occurred more often in younger patients46, while risk factors such as smoking, family history, and BMI did not influence relapse rates32. As discussed previously, younger patients may be at higher risk for developing depressive symptoms due to ITT, and the potentially increased risk of relapse may exacerbate these effects.

Tran et al., recommends continuing treatment for at least 2 months after complete acne clearance to prevent AV relapse45, and Demirci Saadet E. suggests that extension of treatment time by one month after achieving complete clinical improvement is enough to significantly decrease the risk of relapse46. Although patients who receive a higher dose of ITT tend to present with better results45, 49, they are also at a higher risk of IT side effects28,33, including relapse28. Ibrahim et al. recommends beginning treatment with a lower dose of IT (0.2-0.3 mg/kg), to avoid acne flares, which affect 15% of IT patients47.

Acne flares are known to be a risk factor for psychological distress, which may accompany the initiation of IT therapy48. As such, it has been proposed that changing the dose of IT during the treatment course may decrease the chance of acne flares and relieve the psychological effects that may accompany the use of higher doses of IT33.

            In hopes of preventing AV recurrence and its accompanying psychological consequences27, we strongly recommend that clinicians use patient-based data to decide therapy duration on a case-by-case basis rather than using set duration policies. We also recommend that clinicians extend treatment for two months following complete AV clearance49,50, as well as follow up with the patient approximately 460 days after treatment completion25, to reduce both the risk of relapse and perceptions of unfulfilled patient expectations.   

As cutaneous disorders are known to directly cause anxiety and depression4, supporting studies have found that acne vulgaris significantly impairs quality of life (QOL), especially in patients who present with a higher grade of acne, female gender, obesity, illiteracy, and poverty.24 As IT patients are already susceptible to developing depression23,27, it is the main misleading cause in directly linking ITT to any new depressive symptoms mainly because of the lack in study design to properly evaluate the comorbid psychiatric disorders before ITT27.To further support this, Halvorsen et al. demonstrated an association between acne and social impairment, mental health problems, and suicidal ideations4. As depression may occur during ITT, it is not a frequent side effect6 as most of the depressive symptoms that occur in ITT patients are found to be linked to the severity of the cutaneous disorders4,24,25. However, IT is still shown to indirectly worsen the course of certain neurologic disorders that are present and have been derived from cutaneous disorders4, 32. 

In the study done by Suuberg A., while it has been determined that idiosyncratically susceptible patients may exist, or that individuals with a family history or personal history of mental illness may be susceptible to depression, the authors suggest that there is not enough evidence to prove any direct association between IT and depression32. In a study conducted by DeLuca et al., a patient reported that her suicidal ideation was largely a result of her severe acne vulgaris50 .Since the severity of acne can be linked to increased depressive symptoms4,7,24,27, and IT’s direct target of the CNS has shown to directly affect mood regulation and behavior32,51, it is possible that a recurrence of acne lesions, or the unmet expectations of complete recovery, may lead to worsening of depressive symptoms.

Schaffer et al., found that patients with bipolar disorders who are treated with ITT for acne are at a risk for clinically significant exacerbation of mood symptoms, such as suicidal ideations, even if they are concurrently using psychiatric medications. Since depression, anxiety, and suicidal thoughts are common in acne patients4,24,25,27, IT has been reported to cause these psychiatric symptoms27 without directly linking IT to these symptoms18,6. Truitt et al., concluded that there is not enough evidence to suggest that ITT should be discontinued in future acne patients whose “underlying root cause of major depressive disorder and suicidal ideation is identified as severe acne vulgaris”50 .This helps support the emphasis made to properly evaluate depressive disorders in acne patients before considering IT treatments due to its indirect biological effects on the CNS. 

 

Improvement of Depressive Symptoms Seen with ITT Patients

In the study done by Erdoğan Y et al., as acne severity decreased with effective ITT of acne lesions, no increase in the suicide probability was observed. This shows that the successfully treated cases of acne using ITT, are more likely to have positive psychological effects27 .Likewise, in the study done by Nikam B et al., there was a decrease in anxiety score in ITT patients as disease severity improved4.

In many reported cases, ITT has shown to increase QOL scores and improve anxiety and depression in acne patients18,27,52 .Additionally, acne patients with a history of suicidal behavior were at a lower risk of attempting suicide again after ITT, compared to acne patients without any such history31 .This may be due to improvement of acne lesions after successful treatment in patients with acne-related suicidal thoughts31 .In the study done by Hekmatjah et al., the critical aspect which defines the association between systemic anti-acne treatments and mental health outcomes is the knowledge gap53 .To support this study, Sa A et al. revealed that 70.3% of the subjects reported that they were not informed about potential acne relapse by health care providers; 46.2% of these subjects ended up relapsing24  .Given the correlation between satisfactory patient outcomes and positive psychological effects, it can be inferred that patients who did not expect to relapse, may experience negative psychological effects upon recurrence. Physicians should take care to communicate reasonable treatment outcomes to their patients, preventing the development of unrealistic expectations. Additionally, physicians should note that the suggested isotension-depression relationship coupled with unknowing acne relapse, may further lead to negative psychological effects, such as depression.

 

Correlation Between Patient Expectations and Cost of Treatment

In the United States, healthcare costs have greatly increased in just a short period of time. In 2000, healthcare expenditures made up almost 14% of the U.S. gross domestic product (GDP)36 . In 2004, that percentage jumped to 16% of the GDP – demonstrating a significant upward trend36, making the United States’ healthcare the most expensive in the world, with costs that continue to rise much faster than in similar countries54. Despite this annual healthcare expenditure, the United States’ quality of health and well-being measures are still not the best among industrialized countries36. Given health care costs, patients would expect better treatment outcomes. However, as preferred from an economical perspective, low-dose ITT is occasionally combined with oral prednisolone or azithromycin, for only 75% complete recovery rates13. This results in patients receiving ITT at subtherapeutic levels. Given the potential correlation between ITT usage and depression, coupled with patients expecting better treatment outcomes due to health care costs, clinicians should take extra care to illustrate realistic outcomes, to prevent further mental health decline.

In one study based in Japan, 133 psoriasis patients were surveyed on the topics of medical costs, satisfaction, and willingness to pay for treatment55. Patients who were most satisfied with their dermatological treatment paid less than ¥5000 monthly55. 39% of those surveyed indicated they were ‘satisfied’ or ‘very satisfied’ with the treatment they received, and the study found no sex-based differences in the ‘satisfied’ groups55. In contrast, a large U.S.-based study on patient satisfaction found that patients in the highest satisfaction group had greater total expenditures and greater prescription drug expenditures than those in lower patient satisfaction groups49. While these two studies had contradicting results, together they signify a deficiency in the literature regarding patient expectations, satisfaction, and how they relate to the cost of treatment.

 

Conclusion

Isotretinoin (ITT) is an active derivative of the retinoic acid family and is used for the treatment of acne vulgaris in addition to other cutaneous diseases, in a dose-dependent manner1. ITT induces apoptosis of sebocytes and keratinocytes, ultimately resulting in reduced hyperkeratinization and sebogenesis2. Although patients receiving a higher dose tend to present with better results45, 47, they are also at a higher risk of IT side effects33, including inflammatory bowel disease4, myopic changes in vision26  and potential depressive symptoms.

Despite the literature being unclear, retrospective and database studies have identified a link between ITT therapy and depression14. An association seems likely as ITT’s lipophilic nature allows it to cross the blood brain barrier, and alter cellular processes via all-trans-retinoic acid and retinoic acid receptor-mediated gene transcription, resulting in decreased metabolic activity43 and increased mood dysregulation41. Physicians should take this mechanism into account when prescribing ITT to patients at increased susceptibility of developing psychiatric disorders.


The use of ITT has been demonstrated to cause a significant decrease in thyroid hormones T4 and T3, while also increasing thyroid-stimulating hormone (TSH) levels 5 .Given that such alterations are positively associated with the incidence of depression, physicians should set realistic treatment expectations. This is further emphasized as the combination of such hormonal fluctuations and unmet expectations, are more likely to result in depression. This is especially important with the adolescent age group as they are experiencing biological thyroid hormonal changes38. The susceptibility of this age group developing depression with ITT treatment is further demonstrated as younger patients are increasingly likely to think that scar treatments are more effective at softening, removing, or reducing scars, than patients 40 years of age and older26. Thus, physicians should take extra care to establish realistic treatment outcomes with this particular cohort.

A study completed by Sa A. et al. revealed that 70.3% of patients reported that they were not informed about the potential relapse of ITT by health care providers, and of those, 46.2% of these subjects experienced relapse28. Given the correlation between satisfactory patient outcomes and positive psychological effects, it can be inferred that relapsed patients who faced unmet expectations, may experience negative psychological effects, such as depressive symptoms, upon recurrence. As such, it is important for clinicians to be clear about the possibility of AV recurrence, to set clear and realistic expectations prior to treatment initiation.

Cutaneous disorders, such as AV, cause anxiety and depression, at levels linked to the severity of the disease27,28,29. Additionally, it has been shown that patients with bipolar disorders undergoing ITT treatment are at increased risk for developing exacerbated mood fluctuations, including suicidal ideations31. Since the severity of acne can be linked to increased depressive symptoms24,27,52, and ITT’s direct target of the CNS has shown to directly affect mood regulation and behavior3,32, it is possible that a recurrence of acne lesions, and/or the unmet expectations of complete recovery, may lead to worsening of depressive symptoms. These symptoms may be prevented by establishing realistic treatment expectations prior to ITT initiation.

As preferred from an economical perspective, low-dose ITT is occasionally combined with oral prednisolone or azithromycin, for only 75% complete recovery rates13. This results in patients receiving ITT at subtherapeutic levels, which as discussed, correlates to only moderate treatment outcomes. Since patient satisfaction is correlated to treatment outcomes, such economically preferred subtherapeutic levels, lower patient satisfaction. The potential correlation between ITT usage and depression, coupled with patients expecting better outcomes due to health care costs, emphasizes the need for clinicians to illustrate realistic outcomes, to prevent further mental health decline.

 

References

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