Veronica Hackethal, MD

Certain drugs used to treat severe dermatologic diseases can have various neuropsychiatric adverse effects. Generating awareness of potential neuropsychiatric adverse events of these drugs is important because, while many of them may be mild and reversible, others can be more serious, sometimes permanent, and potentially fatal.

The most serious reactions are found with psoriasis drugs, especially non-biologic medications such as cyclosporine A and methotrexate, according to a 

 “Given the number of systemic dermatologic therapies and the wide variety of their neurological and neuropsychiatric adverse effects, neurologists, psychiatrists, dermatologists, oncologists, and primary care providers must be aware of recorded neuropsychiatric adverse reactions,” wrote first author Melinda Liu, MD, of Baylor College of Medicine in Houston, Texas, and colleagues. “Prescribers should provide information about such adverse effects, offer methods for monitoring for them, particularly during the early months of treatment, and remain aware of the potential need to discontinue the medication,” the authors advised.

The following is a brief overview of drugs discussed in the article. The review includes a range of studies, from randomized controlled trials to case reports. It covers FDA-approved medications for dermatologic diseases that usually require systemic medications.

. Neuropsychiatric adverse effects are dose- and duration-dependent. Treatment for over one year is strongly discouraged. Neurological adverse effects occur in up to 40% of patients, and many are reversible with treatment cessation. Headaches, paresthesias, and tremors are most common. Posterior reversible encephalopathy syndrome (PRES), a rare but serious (though reversible) condition which may involve headache, confusion, seizures, vision loss, nausea, or vomiting.

Other rare neurological adverse events that have been reported include progressive multifocal leukoencephalopathy (PML), psychosis, cerebellar syndrome, mania, seizures, and drug-induced Parkinsonism

. Neurological adverse effects include idiopathic intracranial hypertension (IIH) and peripheral neuropathy. The drug should be avoided with statins, corticosteroids, colchicine and penicillamine due to neurological and muscular adverse events.

Due to reports of IIH with retinoids (isotretinoin, acitretin), tetracyclines (see below), and cyclosporin A (see below), these drugs should not be co-administered as they may incur possible additive risk. It should be noted that women are at increased risk of IIH.

. Cases of psychosis and mania, as well as leukoencephalopathy, have been reported. To decrease toxicity, concurrent folate administration, strict adherence to contraindications, and regular assessment of kidney and liver function is advised.

. Dose-dependent adverse events are usually self-limited and mild to moderate. There have been some reports of depressed mood, but the quality of the evidence is questionable.

. The use of TNFÎ± inhibitors (eg, infliximab, etanercept, adalimumab) has in some cases resulted in psychosis, mania, optic neuritis, transverse myelitis, Guillain-Barre syndrome, and chronic inflammatory demyelinating polyneuropathy (CIDP). Because of rare reports that the drug may promote demyelinating disorders, the American Academy of Dermatology recommends avoiding TNFÎ±-inhibitors in patients with a personal or family history of demyelinating disorders.

. There have been case reports of PRES with long-term ustekinumab but not secukinumab from medications such as ustekinumab, secukinumab, and ixekizumab. There is some concern for depression with ixekizumab.

FDA-approved autoimmune skin disease drugs

. Used for treating autoimmune bullous diseases, SLE-related skin disorders, and atopic dermatitis, 

 have been linked to neuropsychiatric disorders. These disorders are dose-dependent, with doses of 40 mg and above strongly linked to such disorders. Women are up to 6 times more likely to experience these disorders than men.

In decreasing order of frequency, depression, mania, psychosis, and delirium have been reported. Behavioral effects include sleep disorders and steroid euphoria (decreased anxiety and depression). Cognitive effects, sometimes called reversible corticosteroid-induced dementia, include poor concentration, poor memory, and anomic aphasia. Three quarters of patients experience remission after discontinuing therapy. Dementia may resolve more slowly, with possible residual cognitive problems.

. The first-line for leprosy and dermatitis herpetiformis, dapsone is usually well-tolerated but has rarely been associated with psychosis and mania. Adverse neurological effects include optic neuropathy and peripheral neuropathy, which can develop after prolonged therapy or overdose and usually resolves within one year of stopping therapy.

. IVIG is used for graft-versus host disease (GVHD) and Kawasaki syndrome. Mild neuropsychiatric effects include anxiety, irritability, nervousness, and tremor. Moderate neurological effects include aseptic meningitis (rare, transient). Severe neurological adverse effects include stroke, with one single-center study reporting 0.6% overall incidence. All neurological adverse events are more likely to occur during the initial dose.

. This medication is used for erythema nodosum leprosum (ENL) and multiple myeloma. The most common neurological adverse effects include drowsiness, somnolence, and constipation due to autonomic neuropathy. Common neurological adverse effects include peripheral neuropathy and muscle weakness, which usually resolve within 4 months with the same or decreased dose. Rarely, seizures, migraines, hallucinations, and syncope have occurred.

. Minocycline and tetracycline in particular are associated with the development of IIH, which usually resolves with acetazolamide.

 is less commonly associated with neurological adverse events, but these include tension or migraine-type headache. Rarely it is associated with IIH. There have been conflicting reports of mood changes, and a few reports of stiff-person syndrome. These problems usually resolve after cessation of therapy.

 is used for melanoma with BRAF mutations. There have been case reports of facial nerve palsy and acute inflammatory demyelinating polyneuropathy with this drug.

 is used to delay monotherapy-induced resistance to BRAF inhibition. There have been case reports of intracranial hemorrhage with this drug.

 is used for unresectable metastatic melanoma, with a reported rate of neurological adverse events of 0.1%. These include headache, dizziness, lethargy, and weakness, as well as transient sensory and motor peripheral neuropathies. There have been case reports of demyelinating and autoimmune disorders and mild encephalitis/encephalopathy with reversible lesion in the callosal splenium (MERS). Symptoms usually resolve within days to weeks of stopping treatment and administering glucocorticoids, IVIG, or sometimes plasmapheresis.

 is used for metastatic melanoma. About 30% to 45% of patients who use these drugs experiences a major depressive episode, which is usually dose- and treatment length- dependent. Prevention and treatment includes dose modification, pre- or concurrent SSRIs, and psychiatric referral. Mania or hypomania has been associated with dose reduction or pauses in therapy.

• Review of systemic medications for dermatologic diseases describes a wide range of neuropsychiatric adverse events, which range from mild and reversible to permanent and potentially fatal.

• The most serious reactions are found with psoriasis drugs, especially non-biologic medications such as cyclosporine A and methotrexate.

• Neurologists, psychiatrists, dermatologists, oncologists, and primary care providers may all need to be aware of the neuropsychiatric adverse reactions of systemic dermatologic drugs. 

Neurological and Neuropsychiatric Adverse Effects of Dermatologic Medications

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A review of systemic medications for dermatologic diseases describes a wide range of adverse events, which range from mild and reversible to permanent and potentially fatal.

Neurological and Psychiatric Effects of Dermatology Drugs

Glaucoma represents the leading cause of blindness in the US and affects about 2.7 million Americans, according to the CDC. While glaucoma can develop in anyone, African Americans, people with diabetes, those with a family history of glaucoma, and people over age 60 are at increased risk.

About 44% of patients with glaucoma are treated with timolol eye drops, a beta-blocker that is systemically absorbed and may cause psychiatric adverse effects. Elderly white women with underlying cognitive impairment may be at risk for visual hallucinations related to the use of timolol eye drops for glaucoma, according to a 

“This case series highlights an important, although rare, adverse effect of this medication that clinicians should be aware of, especially when using it in elderly patients who may have coexisting CNS pathology. It is important that this adverse effect be recognized and appropriately managed to prevent otherwise unnecessary investigations and treatment,” wrote first author Tavish Nanda, MD, of Columbia College of Physicians and colleagues.

The systemic absorption of topical timolol increases the risk of adverse effects. Some studies have suggested that when used at the standard 0.5% ocular dose, the presence of timolol in the systemic circulation may be equivalent to a 10-mg oral dose. Elderly patients may be at increased risk. Even with reduced dosages of 0.25%, elderly patients may experience plasma timolol concentrations that are twice as high as those in younger patients.

Decades of use have contributed to the known adverse-effect profile of timolol. This includes systemic effects similar to those of oral beta-blockers, such as bradycardia, bronchospasm, fatigue, and confusion. Rarely, psychiatric adverse effects have been reported, including psychosis, depression, auditory hallucinations, and nightmares.

Although visual hallucinations are a recognized adverse effect of oral beta-blockers, only 2 studies have looked at this problem with 

To generate awareness of this adverse effect, 

 describe a case series of 4 patients seen at the University of California, San Francisco and Columbia University Medical Center. Notably consistent features of these patients include:

• All 4 were elderly white women aged 66 to 93 years

• All 4 had normal comprehensive neuro-ophthalmic exams

• All 4 likely had some degree of underlying CNS disease, particularly cognitive impairment

• All 4 had visual hallucinations after administering timolol eye drops

• The visual hallucinations in all 4 women were similar and involved geometric shapes and changes in color vision in both eyes

• Visual hallucinations resolved after discontinuing timolol, and returned upon retrial

The researchers note that underlying CNS pathology may have increased these patients’ susceptibility to the adverse effects of timolol. One of the patients had long-standing 

, and 3 had some degree of cognitive impairment or early dementia. Blood-brain barrier dysfunction in these disease states may have been involved.

White women may be more susceptible to the adverse effects of beta-blockers, owing to a genetic predisposition for lower enzyme activity, as well as lower BMI and less muscle mass than men. Moreover, women may be more likely to report psychiatric symptoms than men.

Nanda and colleagues suggest that 2 to 3 minutes of punctal occlusion after instilling eye drops may decrease the amount of topical timolol absorbed systemically, though this technique has yet to be studied.

Ophthalmic timolol hallucinations: a case series and review of the literature

 Shore JH, Fraunfelder FT, Meyer SM, et al. 

Psychiatric side effects from topical ocular timolol, a beta-adrenergic blocker

 McMahon CD, Shaffer RN, Hoskins HD Jr, et al. 

Adverse effects experienced by patients taking timolol

Clinicians should be aware of recent research that highlights an important, although rare, adverse effect of this medication used to treat glaucoma.

Author | Veronica Hackethal, MD

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