Winston W. Shen

Omega-3 fatty acids in major depressive disorder: A preliminary double-blind, placebo-controlled trial

Patients with depression have been extensively reported to be associated with the abnormality of omega-3 polyunsaturated fatty acids (PUFAs), including significantly low eicosapentaenoic acid and docosahexaenoic acid in cell tissue contents (red blood cell membrane, plasma, etc.) and dietary intake. However, more evidence is needed to support its relation. In this study, we conducted an 8-week, double-blind, placebo-controlled trial, comparing omega-3 PUFAs (6.6 g/day) [corrected] with placebo, on the top of the usual treatment, in 28 patients with major depressive disorder. Patients in the omega-3 PUFA group had a significantly decreased score on the 21-item Hamilton Rating Scale for Depression than those in the placebo group (P < 0.001). From the preliminary findings in this study, omega-3 PUFAs could improve the short-term course of illness and were well tolerated in patients with major depressive disorder.

Polyunsaturated fatty acid deficit in patients with bipolar mania

The aim of this study is to test the hypothesis that there is a depletion of polyunsaturated fatty acids of erythrocyte membranes in patients with bipolar disorder and to connect the previous therapeutic and psychoimmunological findings. Fatty acid compositions of erythrocyte membranes in 20 bipolar manic patients and 20 healthy controls were analyzed by thin-layer chromatography and gas chromatography. The major finding was significantly reduced arachidonic acid (20:4n-6) and docosahexaenoic acid (22:6n-3) compositions in bipolar patients as compared to normal controls with P values of 0.000 and 0.002, respectively. There were no differences in total omega-3 and omega-6 polyunsaturated fatty acids. This abnormality may be related to the mechanisms of action of mood stabilizers and the previous findings on the abnormal psychoimmunology of patients with bipolar disorder. Larger sample sizes of medicated patients or drug-free manic, well-controlled designs on the diet and smoking, and fatty acid composition measurements during full remission after the index episode are warranted in future studies.

Immunologic variables in acute mania of bipolar disorder

Macrophages, lymphocytes and their products, may be involved in the pathophysiology of psychiatric disorders. The cell-mediated immune activation response of manic patients during pre-medication and medication stages remains unclear. The purpose of this case-control study was to investigate the plasma levels of immunologic variables, including interleukin (IL)-1 receptor antagonist (IL-1RA), soluble CD 4 (sCD4) and sCD8, and TH1 (interferon [IFN]-gamma and IL-2) and TH2 (IL-4 and IL-10) cytokines in patients with pre-medicated, medicated bipolar mania. The study subjects, aged 16-44 years, were physically healthy patients with Young Mania Rating Scale (YMRS) scores > or =26, and normal controls, aged 19-40 years, were matched for sex. The immune variables were measured in acute mania and in consequent remission (YMRS scores < or =12) among bipolar patients. The plasma levels of IL-1RA, sCD4, and sCD8 were found significantly increased in pre-medicated acute manic patients as compared to normal controls. But only IL-1RA and sCD8 were found different in remitted bipolar patients as compared to normal controls. For TH1 cytokines, culture supernatant level of IFN-gamma was found significantly lower in manic patients of both acute and remission stages as compared to normal controls. No significant difference was found in IL-2 level in pre-medicated acute manic patients compared to controls. For TH2 cytokines, no significant differences in IL-4 and IL-10 levels were observed. We showed that cell-mediated immune response was activated in patients with bipolar disorder during the pre-medication, medication, and the remission stages. Our study findings suggest that the immune-modulation in patients with bipolar disorder may be abnormal.

Genetic polymorphisms of cytochrome P450 enzymes influence metabolism of the antidepressant escitalopram and treatment response.

AIMS The antidepressant escitalopram (S-CIT) is metabolized by the cytochrome-P450 (CYP) enzymes CYP 2D6, 2C19 and 3A4. This study evaluated the impact of CYP2D6, 2C19 and 3A4 genetic polymorphisms on plasma concentrations of S-CIT and patient treatment response. MATERIALS & METHODS A total of 100 patients diagnosed with major depressive disorder were recruited to the study and their depression symptoms were assessed using the Hamilton Depression Rating Scale. The genetic polymorphisms *4, *5 and *10 on CYP2D6, *2, *3 and *17 on CYP2C19, and *18 on CYP3A4 were selected based on their function and respective allele frequencies in Asian populations. Polymorphisms were analyzed using the SNPstream genotyping system, PCR and direct sequencing methods. The steady-state serum concentrations of S-CIT and its metabolites S-desmethylcitalopram and S-didesmethylcitalopram were analyzed by HPLC. According to semiquantitative gene dose (SGD) and gene dose (GD) models for allele combinations of these polymorphisms, CYP2D6 was clustered into intermediate (0.5, 1 and 1.5 SGD) and extensive (2 SGD) metabolizers, while CYP2C19 was clustered into poor (0 GD) and extensive (1 and 2 GDs) metabolizers. RESULTS The group of patients with intermediate CYP2D6 metabolism (0.5 SGD) had a significantly higher frequency of remitters from major depressive disorder during the 8-week treatment (p = 0.0001). Furthermore, CYP2C19 poor metabolizers had significantly higher S-CIT serum levels than did extensive metabolizers at weeks 2, 4 and 8 (p < 0.05). The allele frequencies in CYP3A4*18 and CYP2C19*17 were too low to permit further subgroup analyses. CONCLUSION Our results suggest that the genetic polymorphisms in CYP2C19 may be influencing S-CIT serum concentrations, and that specific CYP2D6 polymorphisms may be predicting patient treatment outcomes based on gene dosage analyses.

ABCB1 gene polymorphisms are associated with the severity of major depressive disorder and its response to escitalopram treatment

Objective ATP-binding cassette, sub-family B (MDR/TAP), member 1 (ABCB1) is a drug transporter protein expressed on the epithelial cells of the intestine and the endothelial cells of the blood–brain barrier. Intestinal ABCB1 actively transports drugs from the cell membrane and prevents them from entering the blood stream whereas the blood–brain barrier ABCB1 prevents drugs from entering the central nervous system. In this study, we tested whether genetic polymorphisms within the ABCB1 gene are associated with the severity of depression and the effectiveness of the antidepressant, escitalopram (S-CIT), in treating major depressive disorder (MDD). Methods Twenty single nucleotide polymorphisms in the ABCB1 gene were selected and genotyped in 100 MDD patients who had undergone S-CIT treatment continuously for 8 weeks. The serum concentrations of S-CIT and its metabolites (S-desmethylcitalopram and S-didesmethylcitalopram) were then measured at weeks 2, 4, and 8. Results The ABCB1 genotypes of rs1922242 (P=0.0028) and rs1202184 (P=0.0021) showed significant association with the severity of depressive symptoms as assessed by the Hamilton Rating Scale for Depression adjusted with Hamilton Rating Scale for Anxiety. The haplotype block, rs1882478-rs2235048-rs2235047-rs1045642-rs6949448 (from intron 27 to intron 26), of ABCB1 was found strongly associated with the remission rate (global P=0.003, d.f.=69) in which haplotype T-T-T-C-C was associated with a slower remission rate on S-CIT treatment (P=0.001). The haplotypes may not be indicators of the severity of depression or anxiety. Conclusion Our findings suggest that single nucleotide polymorphisms in the ABCB1 gene may be indicators of the severity of depression and of the likely S-CIT treatment remission response in MDD.

Surgical adverse outcomes in patients with schizophrenia: a population-based study.

Objective: To validate the global features of postoperative adverse outcomes for surgical patients with schizophrenia. Background: Patients with schizophrenia were known to have a higher risk of complications during hospitalization. Quality of care has become the key factor in reducing their potential mortality afterwards. Methods: We present a population-based study of 8967 schizophrenic patients receiving major surgery from the Taiwan National Health Insurance Research Database within the years 2004 and 2007 compared with 35,868 surgical patients without mental disorders. Eight major postoperative complications and mortality after complications were evaluated among schizophrenic patients with different severity. Results: Schizophrenic patients had significantly higher risk for postoperative complications, including acute renal failure, pneumonia, bleeding, septicemia, stroke, and 30-day postoperative mortality (adjusted OR = 2.70; 95% CI: 2.08–3.49), than surgical patients without mental disorders. Among surgical patients with 1 to 2, 3 to 18, 19 to 48, and more than 49 schizophrenia-related outpatient visits within 24-month period preoperatively, the adjusted ORs of 30-day mortality ranged from 1.95 (95% CI: 1.25–3.02) to 3.97 (95% CI: 2.66–5.92) in a frequency-dependent pattern when compared with controls. When compared with surgical patients with schizophrenia-related outpatient services only, OR of 30-day postoperative mortality increased from 2.54 (95% CI: 1.93–3.34) to 3.69 (95% CI: 2.25–6.03) in surgical patients with preoperative hospitalization or emergency visit because of schizophrenia. Conclusions: Surgical patients with schizophrenia showed significantly higher postoperative adverse outcome rates with risk of 30-day mortality nearly threefold when compared with patients without mental disorders. Our findings suggest the urgency revising the protocol of postoperative care for this specific population.

Implication of serum concentration monitoring in patients with lithium intoxication

Abstract  The aim of the present study was to determine the relationships between serum lithium level, duration of lithium intoxication, severity of symptoms, and the outcome of the disease. Subjects with a serum lithium level of ≥1.2 mEq/L were included in the study. Seventy‐eight patients with lithium intoxication were identified between 1 July 1999 and 31 December 2002. The demographic characteristics, clinical manifestations, and concomitant medications were recorded. Most patients with acute lithium intoxication had mild symptoms, independent of the serum lithium levels. In patients with chronic lithium intoxication, the frequency of severe symptoms was higher than in those with acute intoxication. None of the 78 intoxicated patients in the present survey died or suffered from persistent neurological sequelae. Patients with concomitant medications, older age, and existing neurological illness may have an increased susceptibility to lithium toxicity. Regular monitoring of serum lithium level is essential for lithium‐treated patients. Clinicians should pay attention to patients with pre‐existing neurological illness, older age, or receiving medications that may interact with lithium.

Alterations of serum brain-derived neurotrophic factor levels in early alcohol withdrawal

AIMS Alcohol withdrawal-enhanced neurotoxicity contributes to the addictive process. Brain-derived neurotrophic factor (BDNF) plays an important role in neuronal plasticity and learning. In this study, we explored the changes of serum BDNF levels in alcoholic patients at baseline and after one-week alcohol withdrawal. METHODS Twenty-five alcoholic patients were admitted for alcohol detoxification treatment, and 22 healthy control subjects were also enrolled. We collected blood samples of the patient group on the first and seventh day of alcohol withdrawal, and measured serum BDNF level with sandwich enzyme-linked immunosorbent assay. The severity of withdrawal symptoms was evaluated by the Clinical Institute Withdrawal Assessment-Alcohol, Revised every eight hours. RESULTS Serum BDNF levels did not differ significantly between alcoholic patients and control subjects. But BDNF levels were found to be significantly increased one week after alcohol withdrawal (from 13.9 +/- 3.8 ng/ml to 15.4 +/- 3.8 ng/ml, P = 0.03). A significant positive correlation was found between baseline BDNF level and baseline withdrawal severity (r = 0.45, P = 0.03). CONCLUSIONS The present study suggests that elevated serum BDNF levels were found in early alcohol withdrawal, implying that BDNF may involve in neuroadaptation during the period.

Reduced production of interferon-gamma but not interleukin-10 in bipolar mania and subsequent remission

BACKGROUND Activation of inflammatory response system (IRS) is suggested by increased levels of plasma soluble interleukin-2 receptor (sIL-2R) in patients with bipolar mania. The reasons for changes in stimulated interferon-gamma (IFN-gamma) and interleukin-10 (IL-10) production in bipolar mania along with subsequent remission remain unclear. METHODS We measured phytohemagglutinin (PHA)-stimulated IFN-gamma and IL-10 production in 20 physically healthy inpatients aged between 18 and 45 years with bipolar mania (DSM-IV) using Young Mania Rating Scale (YMRS) scores > or = 26 and in subsequent remission (YMRS < or = 12), as well as in 15 age- and sex-matched healthy normal controls. RESULTS The mean values of IFN-gamma production in patients in acute mania and in subsequent remission were significantly lower than those of healthy controls (P=0.0004, P=0.0005, respectively). There was no significant difference in IL-10 production between bipolar patients in acute mania as well as in subsequent remission and healthy controls. In acute mania, the mean values of IFN-gamma and IL-10 production in medicated patients (n = 13) did not differ from those of drug-free patients (n = 7). Other clinical variables had no effect on IFN-gamma and IL-10 production. LIMITATION The uncontrolled medication, small sample size of the bipolar individuals, and some immune re-measurements prior to full remission periods, limit generalization from the data in this study. CONCLUSION Reduced production of IFN-gamma without alternation of IL-10 in bipolar mania and subsequent remission suggest that the immune modulation may vary in patients with different major psychiatric disorders.

Time course of the changes in antipsychotic-induced hyperprolactinemia following the switch to aripiprazole

Hyperprolactinemia is an important but neglected adverse effect of antipsychotic medication. All first generation antipsychotics and the second generation antipsychotics amisulpride and risperidone have been shown to cause marked elevation in serum prolactin levels, whereas most other second generation antipsychotics and aripiprazole appear to have little or no effect on serum prolactin levels. This study was aimed to assess the time course of changes in antipsychotic-induced hyperprolactinemia during the process of antipsychotic switching to aripiprazole. Twenty-three female schizophrenic subjects with risperidone- or sulpiride-induced symptomatic hyperprolactinemia were recruited into the study and 20 of them completed the trial. We added aripiprazole to the therapeutic dose first, then overlapped the preexisting antipsychotic treatment and aripiprazole, and finally tapered the preexisting antipsychotic treatment. Clinical status was assessed by using the Positive and Negative Syndrome Scale (PANSS) and the Clinical Global Impression Severity Scale (CGI-S). Assessment scales and serum prolactin levels were measured at baseline, during the combination treatment period, and four weeks after having completed discontinuation of the preexisting antipsychotic treatment. Switching antipsychotic drugs to aripiprazole was effective in reducing serum prolactin levels and restoring menstruation in schizophrenic patients who received prolactin-raising antipsychotics. Mean serum prolactin levels at baseline, during combination period, and after the switch were 97.0+/-69.0 ng/ml, 27.2+/-10.6 ng/ml (p<0.001, vs. baseline), and 12.2+/-5.3 ng/ml (p<0.001, vs. baseline), respectively. None of the study subjects experienced any serious adverse effects during the switching process. No significant changes were noted in the PANSS and CGI-S scores during the switching process. The prolactin-normalizing effects of aripiprazole are likely caused by the unique characteristics of the dopamine partial agonist with its high affinity for dopamine D2 receptors.