Chian Jue Kuo

Effects of symptomatic severity on elevation of plasma soluble interleukin-2 receptor in bipolar mania

BACKGROUND Circulating soluble interleukin-2 receptors (sIL-2Rs) and soluble interleukin-6 receptors (sIL-6Rs) are stable immune measures. Elevated plasma sIL-2R levels are present in patients with schizophrenia, major depression, and bipolar mania, but not with minor psychiatric disorders. The increased plasma sIL-2R levels are state-dependent in bipolar mania. However, altered production of plasma sIL-6R and the effects of clinical characteristics on plasma sIL-6R and sIL-2R levels in bipolar disorder remains uncertain. METHODS Plasma sIL-2R and sIL-6R levels were measured in 31 Taiwanese bipolar manic (DSM-IV) patients with Young Mania Rating Scale (YMRS) scores of > or =26 as well as during the subsequent remission (YMRS< or =12), and equal numbers of age- and gender-matched healthy controls. The relationships of clinical variables such as age, age of onset, smoking, medication status, coexisting psychotic features, number of prior episodes, duration of illness, presence of depression before or following the manic episode, and manic severity to plasma sIL-2R and sIL-6R levels in acute mania along with remission were examined. RESULTS Plasma sIL-2R but not sIL-6R levels were significantly higher in acute mania than in subsequent remission (P<0.05) and controls (P<0.0005). In acute mania, the plasma sIL-2R levels were significantly correlated to YMRS scores (r=0.34, P<0.05). The remaining clinical variables had no effect on plasma sIL-2R and sIL-6R levels in acute mania or remission. There was a significantly positive relationship between the reduction of plasma sIL-2R levels from the acute to follow-up measurements (DeltasIL-2R) and symptomatic improvement of acute mania (DeltaYMRS) (r=0.61, P<0.001). LIMITATIONS Our sample included medicated and unmedicated patients in acute mania. The psychotropic medication may have divergent effects on the plasma sIL-2R levels in acute mania and subsequent remission. CONCLUSIONS Elevation of plasma sIL-2R but not sIL-6R levels in bipolar mania supports the idea that the immunomodulatory mechanism may vary in different psychotic disorders. In contrast to being a trait marker in schizophrenia and depressive disorder, plasma sIL-2R levels may be considered a biological indicator of manic severity in a group of bipolar affective patients.

Inflammatory markers and their relationships with leptin and insulin from acute mania to full remission in bipolar disorder.

BACKGROUND Weight gain and increased production of leptin may be associated with immuno-modulation and insulin resistance in bipolar disorder. The links among inflammatory markers, leptin, and insulin of bipolar patients from acute mania to full remission remain unclear. METHODS Thirty-three healthy, bipolar I patients under 45 years of age were enrolled. We measured the circulating levels of high-sensitivity C-reactive protein (hs-CRP), anti-inflammatory mediators (interleukin-1 receptor antagonist [IL-1Ra] and soluble tumor necrosis factor receptor 1 [sTNF-R1]), leptin, and insulin during acute mania and subsequent partial and full remission. The results were compared with 33 age- and gender-matched healthy subjects. RESULTS The levels of IL-1Ra and hs-CRP of bipolar patients in both acute mania and partial remission were significantly higher than their levels of control subjects. The hs-CRP level of bipolar patients was also elevated in full remission. The elevation of IL-1Ra and hs-CRP levels in acute mania was independent of each other. They were also independent of the body mass index (BMI) and levels of leptin and insulin measurements. The levels of leptin were all positively associated with insulin levels in the normal subjects and bipolar patients in three phases. However, a significant relationship between leptin and immunoparameter was only seen in full remission with sTNF-R1 (r=0.51). Furthermore, IL-1Ra was inversely correlated with sTNF-R1 (r=-0.37, p<0.05) during partly remission, and while levels of IL-1Ra tended to normalize when patients remitted, levels of hs-CRP and sTNF-R1 showed the opposite trend. CONCLUSIONS Activated inflammation was found in acute mania, as evidenced by high levels of IL-1Ra, hs-CRP, and sTNF-R1. The production of leptin may be more tightly linked to insulin than the immunomodulators. Chronic inflammation may exist in bipolar patients and is reflected by elevations of IL-1Ra and hs-CRP levels in acute mania and persistent higher hs-CRP in full remission.

Second-Generation Antipsychotic Medications and Risk of Pneumonia in Schizophrenia

This study assessed the association between second-generation antipsychotic medications and risk of pneumonia requiring hospitalization in patients with schizophrenia because the evidence is limited in the population. We enrolled a nationwide cohort of 33,024 inpatients with schizophrenia ranged in age from 18 to 65 years, who were derived from the National Health Insurance Research Database in Taiwan from 2000 to 2008. Cases (n = 1741) were defined as patients who developed pneumonia after their first psychiatric admissions. Risk set sampling was used to match each case with 4 controls by age, sex, and the year of the first admission based on nested case-control study. Antipsychotic exposure was categorized by type, duration, and daily dose, and the association between exposure and pneumonia was assessed using conditional logistic regression. We found that current use of clozapine (adjusted risk ratio = 3.18, 95% CI: 2.62-3.86, P < .001) was associated with a dose-dependent increase in the risk. Although quetiapine, olanzapine, zotepine, and risperidone were associated with increased risk, there was no clear dose-dependent relationship. Amisulpride was associated with a low risk of pneumonia. The use of clozapine combined with another drug (olanzapine, quetiapine, zotepine, risperidone, or amisulpride), as assessed separately, was associated with increased risk for pneumonia. In addition, with the exception of amisulpride, each drug was associated with increased risk for pneumonia at the beginning of treatment. Clinicians who prescribe clozapine to patients with schizophrenia should closely monitor them for pneumonia, particularly at the start of therapy and when clozapine is combined with other antipsychotics.

15-year outcome of treated bipolar disorder.

BACKGROUND Prior reports suggested that bipolar patients in Taiwan had comparable long-term outcome to Western patients despite markedly lower rates of co-occurring substance use disorders. Thus, predictors of long-term outcome identified from Taiwanese bipolar samples may be less influenced by substance abuse. METHODS One hundred and one patients with bipolar disorder (DSM-III-R) having been naturalistically treated for at least 15 years were recruited. These patients were annually followed for 2 years to assess overall outcome, psychiatric symptoms, rehospitalization, work, and social adjustment. A combination of medical record reviews and direct personal interviews with patients and family members provided the clinical data. RESULTS Of these patients, 16.8% expressed a poor overall long-term outcome, even though only two (2.0%) patients exhibited alcohol dependence during the follow-up period. Multivariate regression showed that full compliance with medication was the strongest predictor of favorable overall long-term outcome, followed by younger age at onset and male sex. Younger age at onset as well as male sex, but not full compliance, also predicted a favorable psychosocial outcome. LIMITATIONS Recruiting our sample from a clinical population with uncontrollable long-term treatment limits the generalizability of the findings. CONCLUSIONS Compliance with pharmacotherapy is important to achieve a favorable overall long-term outcome of bipolar disorder. A portion of bipolar patients may have an unfavorable psychosocial outcome regardless of the psychopharmacological intervention or presence of substance abuse.

Persistent inflammation and its relationship to leptin and insulin in phases of bipolar disorder from acute depression to full remission

A proinflammatory phase with various immunomodulatory mechanisms has been noted in bipolar mania and major depression. Weight gain and increased production of leptin may be associated with immunomodulation and insulin resistance in bipolar disorder. However, immunomodulation and its linkage with leptin and insulin in the depressive episode of bipolar disorder remain unclear. We investigated alterations in inflammatory markers and their relationship with leptin and insulin levels in patients with phases of bipolar disorder from acute depression to full remission.

Causes of Death of Patients with Methamphetamine Dependence: A Record-Linkage Study

INTRODUCTION AND AIMS Methamphetamine use leads to increased likelihood of premature death. The authors investigated the causes of death and risk of mortality in a large cohort of patients with methamphetamine dependence. DESIGN AND METHODS A cohort of 1254 subjects with methamphetamine dependence, admitted to a psychiatric centre in Taiwan from January 1990 to December 2007, was retrospectively studied. Diagnostic and sociodemographic data for each subject were extracted from the medical records based on a chart review process. Mortality data were obtained by linking to the National Death Certification System and standardised mortality ratios (SMRs) were estimated. The risk and protective factors for all-cause deaths were explored by means of survival analyses. RESULTS During the study period, 130 patients died. Of them, 63.1% died unnatural deaths, while the remaining 36.9% died natural deaths. The 1 year cumulative rates for unnatural and natural deaths were 0.018 and 0.006, respectively, and the 5 year rates were 0.046 and 0.023, respectively. The cohort had excessive mortality (SMR = 6.02), and women had a higher SMR for unnatural deaths than men (26.19 vs. 9.82, P = 0.001). For all-cause deaths, comorbidity with other substance use disorders was associated with increased risk of death, despite that being married was associated with a reduced risk. DISCUSSION AND CONCLUSIONS A substantial proportion of the deceased died natural deaths, but most died unnatural deaths. The findings show significant evidence to provide valuable insight into premature deaths among methamphetamine-dependent users. This information is valuable for development of prevention and intervention programs.

Risk of Cardiovascular Diseases and Stroke Events in Methamphetamine Users: A 10-Year Follow-Up Study.

OBJECTIVE Long-term follow-up data regarding the association between methamphetamine use and cardiovascular and cerebrovascular complications are scarce. We investigated the risk of complications in methamphetamine users over a decade. METHODS A total of 1,315 inpatients treated for methamphetamine use were recruited from the Psychiatric Inpatient Medical Claims database in Taiwan between January 1, 1997, and December 31, 2000, and matched with a population proxy comparison group at a ratio of 1:4 through propensity score matching. All patients were monitored for any incident complication until December 31, 2010. Cox proportional hazards model was used to estimate the risk of ICD-9-CM cardiovascular diseases and stroke events. RESULTS The patients were mostly male, and approximately half were younger than 30 years. The methamphetamine cohort had higher incidences of cardiovascular diseases and stroke events than the comparison cohort (87.5/10,000 vs 55.3/10,000 person-years, P < .001) and was significantly associated with an increased risk of the complications (hazard ratio [HR] = 1.55, P < .001), particularly arrhythmia (HR = 1.92, P = .014) and hemorrhagic stroke (HR = 2.09, P = .001). The risk of cardiovascular sequelae was more significant in younger patients (< 30 y) (HR = 2.22, P = .001), whereas the risk of stroke events was higher among the older patients (≥ 30 y) (HR = 1.86, P = .001). CONCLUSIONS Methamphetamine use is significantly associated with a risk of subsequent cardiovascular and cerebrovascular complications. Age appears to be an effect modifier for the risk estimation.

Risk and protective factors for suicide among patients with methamphetamine dependence: A nested case-control study

OBJECTIVE Methamphetamine as a recreational drug has undergone cycles of popularity, with a recent surge worldwide since the 1990s. This study aimed to identify clinical characteristics associated with suicide mortality in patients with methamphetamine dependence by means of a nested case-control design. METHOD In a consecutive series of 1,480 inpatients with methamphetamine dependence (diagnosed according to DSM-III-R and DSM-IV criteria) admitted to a psychiatric center in northern Taiwan from January 1, 1990, through December 31, 2006, 38 deaths due to suicide were identified as cases via record linkage, and 76 controls were randomly selected using risk-set density sampling in a 2:1 ratio, matched for age, sex, and the year of index admission. A standardized chart review process was adopted to collate sociodemographic and clinical information for each study subject. Multivariate conditional logistic regression analysis was used to identify correlates of suicide among these patients. RESULTS For the sociodemographic and symptom profiles at the latest admission, financial independence lowered the risk for suicide (adjusted risk ratio [ARR] = 0.33, P < .05), whereas visual hallucinations elevated the risk (ARR = 2.57, P < .05) for suicide. For the profiles during the postdischarge period, financial independence (ARR = 0.11, P < .05) remained associated with reduced risk for suicide, whereas suicide attempt (ARR = 8.78, P < .05) and depressive syndrome (ARR = 3.28, P = .059) were associated with increased risk of suicide. CONCLUSIONS Both protective and risk factors for suicide mortality were found among inpatients with methamphetamine dependence, and the findings have implications for clinical intervention and prevention.

Psychiatric discharge against medical advice is a risk factor for suicide but not for other causes of death

To the Editor: Discharge against medical advice (DAMA) is common among psychiatric inpatients. A comprehensive review reported that the estimated prevalence ranged from 3% to 51% and increased over time.1 DAMA has received little attention in the medical literature, and most works were published a decade ago. The literature shows that patients requesting DAMA have poorer long-term prognoses,1 have greater rehospitalization rates, overuse emergency care, and underuse outpatient services. Nonetheless, regarding the outcome of suicide mortality and other causes of death, few evidence-based data2,3 have been published. To estimate the risks of DAMA on various causes of death is important for implementing effective postdischarge care. We investigated the association between DAMA and suicide as well as other causes of death by following a large cohort of psychiatric inpatients. We found that DAMA was associated with a significantly higher risk of suicide compared to nonsuicide mortality.

Protective and risk factors for inpatient suicides: A nested case–control study

This study aimed at estimating the protective effect of suicide precautions and clinical risk factors for inpatient suicides. A standardized precaution system was implemented in a large psychiatric center on January 1, 1996. A consecutive series of 33,121 admissions from 1998 to 2008 constituted the post-implementation cohort and 13,515 admissions from 1985 to 1995 constituted the pre-implementation cohort as comparison group. Inpatient suicides were identified via record linkage with national mortality database. For each of 41 inpatient suicides, four controls were randomly selected based on a nested case-control study. A standardized chart review process was employed to collate clinical information for each study subject. Risk and protective factors for inpatient suicides was estimated by conditional logistic regression. The findings showed that, among subjects with shorter lengths of stay, those admitted in post-implementation era had a significantly lower adjusted risk ratio (0.157, p=0.048) for inpatient suicides. Three depression-related symptoms elevated the risk for inpatient suicides: depressed mood (adjusted risk ratio=2.11, P=0.002), loss of energy (adjusted risk ratio=1.99, P=0.018), and psychomotor retardation (adjusted risk ratio=1.67, P=0.066; with marginal statistical significance). Suicide precautions have protective effect against inpatient suicides. A better assessment and prevention efforts is needed, particularly for those with depression-related symptoms.