Neurological and Psychiatric Effects of Dermatology Drugs

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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 recent review.¹ “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.

FDA-approved psoriasis drugs

Cyclosporin A. 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

Acitretin. 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.

Methotrexate. 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.

Apremilast. 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.

FDA-approved biologics for psoriasis

Tumor necrosis factor α-inhibitors. The use of TNFα 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 TNFα-inhibitors in patients with a personal or family history of demyelinating disorders.

Interleukin inhibitors. 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

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

Oral dapsone. 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.

Intravenous immunoglobulin. 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.

Thalidomide. 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.

FDA-approved acne drugs

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

Isotretinoin 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.

FDA-approved drugs for melanoma

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

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

Iplimumab 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.

IFNα-2b 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.

Take Home Points

• 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.

References:

1. Liu M, Huang YY, Hsu S, Kass JS. Neurological and Neuropsychiatric Adverse Effects of Dermatologic Medications. CNS Drugs. 2016;30:1149-1168.