Divalproex, lithium and suicide among Medicaid patients with bipolar disorder

BACKGROUND: Suicide completion and attempted suicide are major concerns for people with bipolar disorder. Studies in the private sector have suggested that lithium treatment may be superior to divalproex therapy with regard to minimizing suicidal behavior among individuals with bipolar disorder. However, few data are available regarding Medicaid patients diagnosed with bipolar disorder. METHODS: Subjects were 12,662 Oregon Medicaid patients diagnosed with bipolar disorder and treated with medication between 1998 and 2003. Outcomes measures were completed suicide and emergency department visits for suicide attempts (including non-fatal poisoning). Cox proportional hazards models were used to adjust for demographics, co-morbidity, and concurrent psychotropic medication use. RESULTS: Divalproex was the most common mood stabilizer (used by 33% of subjects) followed by gabapentin (32%), lithium (25%), and carbamazepine (3%). There were 11 suicide deaths and 79 attempts. Adjusted hazard ratios (versus lithium users) for suicide attempts were 2.7 for divalproex users (p<0.001), 1.6 for gabapentin users (not significant) and 2.8 for carbamazepine users (not significant). For suicide deaths, the adjusted hazard ratios were 1.5 for divalproex users (not significant), 2.6 for gabapentin users (p<0.001), and not available for carbamazepine users. LIMITATIONS: It should be noted that subjects were not assigned at random to medication use, data on prior suicide attempts were not available, medication use was measured by automated pharmacy records, and duration of mood stabilizer utilization may have been brief. CONCLUSIONS: Lithium may have a protective effect with regard to suicide attempts among Medicaid patients with bipolar disorder. It remains unclear whether or not lithium protects these patients against completed suicide.     

Thyroid abnormalities during chronic lithium treatment in Hong Kong Chinese: a controlled study.

Fifty Chinese psychiatric patients on chronic lithium treatment and the same number of sex- and age-matched control outpatients were assessed by a thyroidologist and underwent laboratory investigations. Lithium patients had a higher rate of goitres (50% vs 10%, P < 0.0001) and a higher mean TSH level (P < 0.005) than controls. Thyroid antibodies were detected in 7 older manic-depressive patients as opposed to 1 control, but not in patients with recurrent unipolar mania. Five patients, but no controls, had single or multiple episodes of hyperthyroidism, which was followed in 2 of them by biochemical hypothyroidism. It is suggested that variations in iodine status, dietary goitrogens, immunogenetic makeup and their complex interactions with chronic lithium treatment may contribute to ethnically different patterns of thyroid abnormalities.     

Use of lithium in the medically ill

For more than one hundred years (about 1845-1950), lithium salts were used to treat disorders belonging to 'the uric acid diathesis' ('gouty diseases'). It was introduced into modern psychiatry as an antimanic agent, but its current use is mostly as a prophylactic in bipolar and unipolar manic-depressive illness. In the present context, however, this psychiatric use may, in some instances, create special nonpsychiatric problems such as lithium poisoning, renal diabetes insipidus, and weight gain. Moreover, most lithium patients are outpatients, so that medical complaints caused by the treatment are in most cases presented to the general practitioner, the neurologist, the nephrologist, the cardiologist, etc. rather than to the psychiatrist. Lithium treatment is frequently accompanied by both short-term and long-term side effects and some of these, e.g. the thyroid-depressing effect and leukocytosis, may be medically exploited. Like manic-depressive illness, some medical disorders such as certain types of headache have a periodic course and appear to respond favorably to long-term lithium treatment. Cooperation between researchers in biological psychiatry and nephrologists has resulted in the suggestion that lithium may be used as an indicator of proximal sodium and water reabsorption, which has later led to the suggestion that the renal lithium clearance is an indicator of proximal renal tubular function.     

Lithium,anticonvulsants and suicidal behavior in bipolar disorder

BACKGROUND: Lithium has been found to be effective in reducing suicide rates during long term treatment of patients with bipolar disorders. Data on the efficacy of anticonvulsant mood stabilizers in reducing suicide risk are sparse. METHOD: Charts of 140 bipolar patients treated continuously for a minimum of 6 months during a 23-year period of private practice by the senior author were extracted from nearly 4000 patient records. Data extracted from the charts were incidence of completed suicide, number of suicide attempts, and number of hospitalizations for suicidal ideation or behavior per 100 patient-years of either 'on' or 'off' lithium or anticonvulsant mood stabilizer monotherapy. RESULTS: Only one completed suicide (during a period off of lithium) occurred in the patients studied. Incidence of non-lethal suicidal behavior was not different during treatment with lithium, compared with anticonvulsants. Being on a mood stabilizer significantly protected against suicidal behavior. The relative protective effect was more modest than in reports from other treatment settings. LIMITATIONS: This was a retrospective chart review study of naturalistically treated patients. CONCLUSIONS: Treatment of patients with bipolar disorder with either lithium or anticonvulsant mood stabilizers was associated with reduced risk of suicidal behavior. This study did not find evidence for a difference in the protective effect of the two types of mood stabilizing medications against non-lethal suicidal behavior in the naturalistic setting of private practice.     

Long-term naturalistic treatment of depressive symptoms in bipolar illness with divalproex vs. lithium in the setting of minimal antidepressant use

OBJECTIVE: Risks have been associated with the long-term use of antidepressant in the treatment of bipolar disorder. We review our naturalistic experience with divalproex versus lithium in treating depressive symptoms of bipolar illness. METHOD: All patients with bipolar disorder treated with lithium or divalproex were identified in a university outpatient psychiatry clinic sample over one year (n=38 patients, 41 treatment trials). Treatment response was based on standard prospective symptom rating scales. Mean duration of follow-up was 90 weeks. RESULTS: Lithium and divalproex were equally effective and tolerated in the total sample. Antidepressant effects were noted despite sparing use of standard antidepressant agents (19% received them). Lithium non-responders responded well to divalproex (50%), and vice versa (44%). Divalproex monotherapy (24%) was more common than lithium monotherapy (7%, P=0.07) and was notably effective in treating depressive symptoms, with a 7/10 response on the CGI-BP and improvement on the HDRS (14.8+/-9.2 to 7.6+/-7.8, P=0.003, duration of prospective follow up 26.7 weeks). CONCLUSIONS: Lithium and divalproex were equally effective and tolerated in this naturalistic sample, but responders may represent distinct subgroups. Both agents, but particularly divalproex, demonstrated long-term antidepressant effects, with limited adjunctive standard antidepressant use.     

Factors associated with patients' knowledge of and attitudes towards treatment with lithium

BACKGROUND: Treatment with lithium is often compromised by poor adherence, by side-effects and by patients' having serum levels outside the therapeutic range. These factors may be affected by patients' knowledge and attitudes towards lithium, and we set out to establish factors associated with knowledge about and attitudes towards lithium among a large representative sample of patients. METHOD: Patients known to be taking lithium in Grampian during 1995 were surveyed postally during 1998 with the Lithium Knowledge Test (LKT) and the Lithium Attitudes Questionnaire (LAQ). Scores on these measures were analysed against patients' sociodemographic and clinical characteristics by stepwise multiple regression. RESULTS: Of 742 patients, 411 (55%) completed an LKT and 362 (49%) completed an LAQ. Stepwise multiple regression established that positive attitudes towards lithium on the LAQ were associated with higher serum lithium levels (P=0.005) and with continuing to take lithium (P<0.001). Higher knowledge on the LKT was associated with positive attitudes on the LAQ (P=0.002), with younger age (P<0.001), and with shorter duration of treatment (P=0.01) LIMITATIONS: The study was retrospective and the response rate was relatively low. CONCLUSIONS: Education about lithium is likely to be of particular importance in the elderly and 'refresher courses' are advisable for those who have been on lithium for lengthy periods. Interventions which modify attitudes, rather than enhancing knowledge, are likely to be helpful in promoting adherence.     

A preliminary communication of an insight scale in the assessment of lithium non-adherence among Chinese patients in Hong Kong

BACKGROUND: Studies on the relation between insight and medication adherence are limited in Chinese populations. METHOD: Eighty Chinese outpatients with mood disorder and on lithium for at least one year were asked to complete an 11-item insight scale. Lithium adherence was determined by: (a) subjective report; (b) doctor's clinical impression; or (c) serum lithium level. RESULTS: The overall insight score (median = 9, range 1-11) exhibited no significant difference between adherent (N = 58, 72.5%) and non-adherent (N = 22, 27.5%) patients. A two-factor model emerged on factor analysis. Lithium adherent (median = 7, range 1-7) patients had a significantly higher score than non-adherent (median = 6, range 0-7) patients on the 'medical help seeking' factor (Mann-Whitney U-test Z = 2.00, P < 0.05) but not the 'perception of illness' factor. CONCLUSION: The overall conceptual structure of insight in Chinese and Western patients appears similar, but further study is required to explore the complexity of Chinese patients' explanatory models of their illness and to enhance the validity of the insight scale.     

A comparison of haloperidol,lithium carbonate and their combination in the treatment of mania

Previous investigations of the treatment of mania have resulted in uncertainty about the efficacy of lithium versus a neuroleptic. In addition there have been reports of toxicity with a haloperidol—lithium combination. In order to determine the comparative efficacy of lithium vs haloperidol vs a combination of haloperidol—lithium, we studied 21 severely ill manic patients who all met rigorous criteria for bipolar illness and who required inhospital treatment. Subjects were randomly assigned to 3 groups: (A) Lithium plus placebo (B) Placebo plus haloperidol and (C) Lithium plus haloperidol. The study was conducted in double blind fashion for 3 weeks with the dosages of the medications varied according to clinical response or untoward effects. Subjects on haloperidol and placebo or the haloperidol—lithium combination were significantly improved after 7 days in comparison to the lithium-treated group. Groups B and C did not differ from each other, either in degree of improvement or in side effects. Inspite of the relatively small sample size the results suggest (1) that haloperidol is superior to lithium for treating severely ill acute mania and (2) that while a haloperidol-lithium combination does not result in a significant increase in side effects, it is not superior to haloperidol alone.     

Delirious mania: clinical features and treatment response

OBJECTIVE: To examine clinical characteristics and treatment responses of patients presenting with delirium and mania to a psychiatric inpatient unit. METHOD: Chart review of 16 cases admitted to McLean Hospital with delirium and mania was conducted. We examined the demographics, psychiatric symptoms, clinical course, and response to treatment with medications and electroconvulsive therapy (ECT). RESULTS: Patients with delirium and mania had negative medical and neurological work-ups and were more likely to be younger, female and with a prior diagnosis of bipolar disorder. Sudden onset of symptoms, incontinence/inappropriate toiletting, and denudativeness are distinctive features of the syndrome. Consistent and significant benefit was seen with ECT. In many cases, high dose benzodiazepines were helpful. In a small number of cases, clozapine was also beneficial but this effect took an average of four weeks to be seen, while atypical antipsychotics, lithium and valproate produced variable results and took an average of three and a half weeks to work, if at all. Typical antipsychotics and anticholinergic drugs led to clinical worsening. LIMITATIONS: Most patients were on more than one medication and hence treatment responses cannot be definitively ascribed to a specific intervention. Studies of larger groups of such patients in different clinical settings need to be done to confirm our observations. CONCLUSIONS: Delirious mania is a severe psychiatric syndrome which can be accurately recognized and effectively treated. The definitive treatment for this condition is ECT. In cases where ECT is not available, high dose benzodiazepines should be used. Clozapine, quetiapine, lithium and valproate cannot be considered first-line treatments and these medications take an unacceptably long time to work even when helpful; typical antipsychotics and anticholinergic drugs should be avoided.     

Are there racial differences in the way patients with psychotic disorders are treated at their first hospitalization?

BACKGROUND: It is now well documented that both black and white patients with severe mental illness are likely to use different types of treatment facilities, have different lengths of hospital stays, and receive different types and dosages of psychotropic medications. It is still uncertain, however, whether these differences exist at the early stages of treatment. METHOD: We examined treatment patterns for a countywide sample of patients with psychotic disorders recruited at their initial psychiatric hospitalization. Illness characteristics, prior treatment histories, admission conditions, and psychotropic medication use during this hospitalization were compared for both black and white patients. RESULTS: Black patients were less likely to have had out-patient treatment prior to their first hospitalization and were more likely to be hospitalized in public than in community psychiatric units than were white patients. Black patients were also more likely to be hospitalized primarily for a behavioral disturbance and escorted to the hospital by the emergency medical services or police, while white patients were more often hospitalized primarily for subjective suffering. These patterns were particularly significant for those with a non-schizophrenia diagnosis. However, there were few statistically significant differences between black and white patients on psychotropic medication use during the first hospitalization. CONCLUSIONS: Differences during the early stages of treatment between black and white patients with psychotic disorders appear to arise most prominently before, rather than during, their first hospitalization.     

A randomised,controlled trial of fluoxetine in methadone maintenance patients with depressive symptoms

BACKGROUND: Lithium is known to induce subclinical or overt hypothyroidism and changes of thyroid volume in manic-depressive patients. Little is known about alterations of thyroid echogenicity due to drug-induced dysfunction. METHODS: Twenty manic-depressive patients receiving lithium therapy for at least 6 months and 20 euthyroid volunteers without any antidepressive medication as control group, matched in age and gender, were investigated by laboratory measurements and thyroid ultrasonography including standardized grey scale analyses in representative regions of interest (ROI). RESULTS: Thyroid function was normal in all patients (mean FT4 1.1+/-0.2 ng/dl, mean TSH 1.6+/-0.9 micro U/ml) and controls (mean FT4 1.5+/-0.4 ng/dl, TSH 1.1+/-0.3 micro U/ml). Except for two patients, no thyroid autoantibody levels could been detected. Thyroid volumetry revealed significant higher mean values for the lithium treated patients (16.9+/-11.9 ml) compared with the controls (11.4+/-4.5 ml, P<0.05) with a considerable number of goiters (six patients vs. one control). Thyroid echogenicities in both groups were similar (patients 23.9+/-3.7 grey scales, Grauwerteinheiten = GWE, controls 24.2+/-1.3 GWE) and did not depend on the size of the organs. CONCLUSION: Lithium treatment contributes to increased thyroid volumes, probably due to inhibition of thyroid function and TSH upregulation, but not to changes of thyroid echo levels in patients with still euthyroid function. Further echogenicity studies on patients with lithium-induced overt hypothyroidism and autoimmune activity will be of special interest.     

Long-term outcome of lithium prophylaxis in bipolar disorder with mood-incongruent psychotic features: a prospective study

BACKGROUND: No study has assessed systematically up to now the long-term outcome of lithium prophylaxis in bipolar patients with vs. without mood-incongruent psychotic features. METHODS: All bipolar patients with mood-incongruent psychotic features who started lithium prophylaxis at a lithium clinic during 14 years were followed up prospectively for 5 years, along with a control group of non-psychotic bipolars. RESULTS: Psychotic patients were significantly less likely than controls to be still on lithium after 5 years, and to present a reduction of at least 50% of time spent in hospital during the lithium treatment period compared with a pre-treatment period of the same duration. The time to 50% risk of readmission was significantly increased among both groups during lithium treatment. 39.6% of prospective episodes in psychotic patients did not include mood-incongruent psychotic features. LIMITATIONS: This is a naturalistic study carried out at a lithium clinic. No control group of bipolar patients who did not receive lithium was available. CONCLUSIONS: Lithium exerts a significant impact on the course of bipolar disorder with mood-incongruent psychotic features, although this impact is less pronounced than in classical manic-depressive illness.     

Effect of lithium carbonate on serotonin uptake in blood platelets of patients with affective disorders

Lithium carbonate treatment for 2-3 weeks produced a significant decrease in the maximum velocity (Vmax) of serotonin (5-HT) uptake, a measure of the number of 5-HT uptake sites in blood platelets from bipolar patients. The decrease was more pronounced in bipolar manic patients than bipolar depressed patients. There was no significant affect on the affinity for 5-HT (Km) of the uptake sites in the platelets of manic or depressed bipolar patients although Km did decrease (indicating increased affinity) in the majority of subjects from both groups of patients. However, lithium treatment of at least 1 year duration was associated with significant increases in Vmax without affecting Km. Lithium in vitro, at concentrations up to 1 mM, had no effect on the Km or Vmax of 5-HT uptake in blood platelets of normal controls. The possible mechanisms of the inhibitory and stimulatory effect of lithium carbonate treatment on platelet 5-HT uptake are discussed.     

Service utilization and associated direct costs for bipolar disorder in 2004: an analysis in managed care

BACKGROUND: Bipolar disorder is a chronic and costly condition. This analysis examines health care costs associated with bipolar disorder in 2004 and contrasts them with those for depression, a better understood mental illness. METHODS: Health care costs associated with bipolar disorder and non-bipolar depression were determined using private payer administrative claims. Individuals having 2 claims with a primary ICD-9-CM code for bipolar disorder or depression were categorized as bipolar disorder or non-bipolar depression patients, respectively. Comparisons between patient groups were adjusted for demographic differences and comorbid diagnoses. RESULTS: On average, bipolar patients (n=6072) used significantly more psychiatric resources per person than depression patients (n=60,643), and had more mean psychiatric hospital days, psychiatric and medical emergency room visits, and psychiatric office visits (p<.001 for all). Bipolar patients were slightly less likely to be treated with antidepressants, but substantially more likely to be treated with antipsychotics, anticonvulsants, lithium, and benzodiazepines (p<.001 for all). Mean direct per-patient costs were $10,402 for bipolar patients and $7494 for depression patients (p<.001), with the primary differences observed for psychiatric medication ($1641 vs. $507) and psychiatric hospitalization ($1187 vs. $241). LIMITATIONS: Patients were categorized based on diagnostic codes in administrative claims data, which may not always be accurate. Results may not generalize beyond private payer populations in the US. CONCLUSIONS: Bipolar disorder is associated with significantly greater per-patient total annual health care costs than non-bipolar depression, as well as significantly greater psychiatric costs. Bipolar disorder, a chronic condition often suboptimally treated, may represent a good target for disease-management programs.     

Chronic treatment with lithium increases the ecto-nucleotidase activities in rat hippocampal synatosomes

Lithium is a mood-stabilizing treatment used in bipolar and other psychiatric disorders. The molecular mechanisms underlying lithium action remain poorly understood. Adenosine is a neuromodulator that possesses anticonvulsant and neuroprotective properties and the ecto-nucleotidase pathway is a metabolic source of the extracellular adenosine. Here we investigated the effect of lithium on the ecto-nucleotidase pathway in synaptosomes from hippocampus and cerebral cortex of adult rats. Male Wistar rats received standard rat chow with lithium chloride (2.5 mg/g of chow) and NaCl (17 mg/g of chow) during 4 weeks. The serum lithium levels were 1.18 +/- 0.05 mEq./L. ATP and AMP hydrolysis was significantly increased (20 and 35%, respectively) in hippocampal synaptosomes of rats chronically treated with lithium chloride. No significant differences were observed in the hydrolysis of the three nucleotides by cortical synaptosomes. In conclusion, the modulation of the ecto-nucleotidase pathway may be a new explanation for the potential neuroprotective lithium action in hippocampal lesions.     

Lithium response and Val66Met polymorphism of the brain-derived neurotrophic factor gene in Japanese patients with bipolar disorder

Lithium is a first-line agent for the treatment of bipolar disorder. A significant association between the Val66Met polymorphism of the brain-derived neurotrophic factor gene and bipolar disorder has been reported. We investigated whether this polymorphism is associated with the response to lithium treatment in Japanese patients with bipolar disorder. Patients had been treated with lithium carbonate for more than 1 year, and the response was retrospectively evaluated. No significant differences were found in the genotype distribution or allele frequency between responders and non-responders. Our results suggested that the brain-derived neurotrophic factor Val66Met polymorphism might not greatly contribute to the efficacy of lithium in bipolar disorder.     

Prophylactic treatment response in bipolar disorder: results of a naturalistic observation study

BACKGROUND: The objective of this study was to evaluate effectiveness of commonly used prophylactic treatments for bipolar disorder in a naturalistic setting and to explore factors associated with treatment response. METHODS: We reviewed charts of 120 patients with a confirmed diagnosis of bipolar I or bipolar II disorder. The sample consisted of 37 males and 83 females, in the age range of 20 to 81 years (mean age 45+/-14 years), treated at an outpatient psychiatry program in a teaching hospital. In contrast to controlled clinical trials, we did not exclude subjects with co-morbid conditions and/or substance abuse. Treatment outcome was evaluated using a scale for retrospective assessment of prophylactic treatment response. The scale rates the degree of improvement in the course of treatment weighted by the likelihood of response being attributable to the treatment. The inter-reliability of the assessments was good with concordance of ratings of 90% and weighted kappa of 0.8. RESULTS: Rates of full response to individual mood stabilizers were: lithium 30%, carbamazepine 0%, valproate 13%, lamotrigine 11%, and olanzapine 25%. Lithium responders were more likely to be bipolar II, and had a typically episodic course of illness with earlier onset in comparison with non-responders. Responders to valproate had higher rates of psychosis. LIMITATIONS: Data were obtained by chart reviews. CONCLUSIONS: Less than one-third of patients treated with lithium achieved remission; the effectiveness of other treatments in this naturalistic sample was even lower.     

Case-control study of GP attendance rates by suicide cases with or without a psychiatric history.

BACKGROUND: Targets for reduction in suicide deaths have been set against a background of an increasing number of people committing suicide. It is often assumed that a reduction can be effected by increasing the detection in primary care of patients at risk. This presupposes that there are indicators that enable suicide risk to be detected reliably. AIM: To compare the characteristics of those who commit suicide with an age- and sex-matched control group in terms of level of general practitioner attendance, diagnosis and pharmacological treatment of mental illness, and to compare those suicides with and without a psychiatric history in terms of general practitioner attendance and history of pharmacological treatment. METHOD: From a total of 48 deaths attributed to suicide and undetermined causes in the Forth Valley in 1993, general practice case notes were located for 41. Live controls were matched to index cases by age, sex and practice. Information on consultations, referrals to secondary care, medication and diagnoses in the previous 10 years was extracted from general practice and, for suicides, psychiatric case notes. RESULTS: Over the 10-year period, suicide patients attended their general practitioner at a higher level than control subjects. However, the number of suicide patients who attended their general practitioner in the month before their death did not differ in comparison with control subjects over a similar period. Suicide cases, in comparison with control subjects, were more likely to have received a psychiatric diagnosis from their general practitioner, been prescribed psychotropic medication and received referral to specialist mental health services. Those suicide patients with a psychiatric history had a significantly higher number of general practitioner consultations than those without a psychiatric history in four out of the five years preceding death. Those suicide patients without a psychiatric history did not differ significantly from control subjects on any of the variables assessed. CONCLUSION: For those people committing suicide who do not have a psychiatric history and whose consultation patterns do not differ from the norm, it is difficult to suggest how general practitioners might improve their detection of relevant suicidal risk factors. For those patients with a psychiatric history who commit suicide, until we have more detailed information regarding the specific content of general practitioner's consultations before death and how these differed from other consultations of the deceased, then it is premature to assume that general practitioners are failing to identify indicators of impending suicide.     

Mortality of patients with mood disorders: follow-up over 34-38 years

BACKGROUND: All follow-up studies of causes of death in affective disordered patients have found they have markedly elevated suicide rates and a less reproducible increased mortality from other causes. The reported rates by gender, disorder type and treatment are more variable. METHODS: Hospitalised affective disordered patients (n=406) were followed prospectively for 22 years or more. Later, mortality was assessed for 99% of them at which time 76% had died. RESULTS: Standardised Mortality Rates (observed deaths/expected deaths) for patients were elevated especially for suicide and circulatory disorders in both men and women. Women actually had higher suicide rates but that did not take into account the twofold increase in general population rates for men. Unipolar patients had significantly higher rates of suicide than bipolar Is or IIs. In all groups long term medication treatment with antidepressants alone or with a neuroleptic, or with lithium in combination with antidepressants and/or neuroleptics significantly lowered suicide rates even though the treated were more severely ill. Although at the age of onset the suicide rates were most elevated, from ages 30 to 70 the rates were remarkably constant despite the different courses of illness. LIMITATIONS: The patients were identified as inpatients and followed prospectively. The treatments were uncontrolled and are not quantifiable but were documented during the follow-up. CONCLUSIONS: Men and women hospitalised for affective disorders have elevated mortality rates from suicide and circulatory disorders. Unipolars have higher suicide rates than bipolar Is or IIs. Long term medication treatment lowers the suicide rates, despite the fact that it was the more severely ill who were treated.     

Skin manifestations induced by TNF-alpha inhibitors in juvenile idiopathic arthritis

The tumor necrosis factor alpha (TNFα) inhibitors have been used with good clinical results in the treatment of juvenile idiopathic arthritis (JIA). Anti TNFα therapy is generally well tolerated. Besides the site injection reactions, other various cutaneous manifestations have been encountered as adverse events. Here, we report four young patients receiving treatment with anti-TNFα (infliximab, adalimumab, and etanercept) for JIA developing different skin manifestations more than 1 year after the initiation of therapy. They underwent a dermatological exam. All four patients were ACR-Ped 30 responders to anti-TNF drugs. The first patient developed cutaneous vasculitis, the second one had lichen planus manifestations, while the third and the fourth developed psoriatic palmoplantar pustulosis accompanied by plaque-type psoriasis localized to the scalp. None of the patients had a personal or family history of dermatological diseases. In the first two patients, skin lesions healed with topical treatment after the discontinuation of anti-TNF agent, while psoriatic lesions did not resolve despite discontinuation of the drug and dermatological treatment. TNF inhibition can be both anti-inflammatory and pro-inflammatory. Cutaneous manifestations could be considered as a paradoxical adverse event of the anti-TNF-alpha treatment not only in rheumatoid arthritis but also in juvenile idiopathic arthritis.