Efficacy Of Omega-3 Fatty Acids Research Articles

Omega-3 fatty acids therapy for IgA nephropathy: a meta-analysis of randomized controlled trials

The efficacy of omega-3 fatty acids (O3FA) in IgA nephropathy remains a controversial issue. The aim of the current updated meta-analysis is to assess the efficacy of O3FA treatment for adult IgA nephropathy. We searched PubMed/MEDLINE, EMBASE and the Cochrane Central Register of Controlled Trials for randomized controlled trials that compared O3FA treatments with placebo or no treatment in adult IgA nephropathy. Outcomes of interest were effects on urine protein excretion (UPE) and renal function. Five RCTs (239 patients) were included for analysis. Compared with control groups, O3FA treatments did not show significant benefits for reducing UPE (standardized mean difference (SMD), -0.111; 95% confidence interval (CI), -0.369 - 0.147) or improving glomerular filtration rate (GFR) or estimated GFR (SMD, 0.177; 95% CI, -0.082 - 0.435), although the pooled results slightly favored O3FA. On the other hand, a lower risk of an increase of 50% or more in serum creatinine and ESRD were found in O3FA-treated IgA nephropathy patients (RR 0.189; 95% CI 0.068 - 0.524, p = 0.001; RR 0.236; 95% CI 0.094 - 0.594, p = 0.002), but the two outcomes were reported in only two trials. The current metaanalysis suggests that there are insufficient data to confirm the efficacy of O3FA treatments for proteinuria and renal function in IgA nephropathy. Further large scale trials are needed to shed more light on this issue.

Omega-3 Fatty Acids in the Prevention of Atrial Fibrillation Recurrences after Cardioversion: A Meta-analysis of Randomized Controlled Trials

Previous randomized studies have reported conflicting results on the efficacy of omega-3 fatty acids in preventing atrial fibrillation (AF) recurrences after cardioversion. A systematic review and meta-analysis of the role of omega-3 fatty acids in the prevention of atrial fibrillation recurrences after cardioversion was conducted. PubMed, Cochrane Library, Elsevier, Science Online database were searched up to the end of January 2012 to identify all of the studies in human subjects that reported the effects of omega-3 fatty acids on the prevention of atrial fibrillation recurrences after cardioversion. Overall, omega-3 fatty acids had no significant effect on the prevention of AF recurrences after cardioversion (OR: 0.63,95% CI 0.35-1.13; p=0.12). The heterogeneity among the studies was significant (p=0.01, I(2)=66%). Subgroup analysis showed that by administering omega-3 fatty acids at least 4 weeks prior to cardioversion and continuing thereafter, the recurrence rate of AF is significantly low (OR: 0.39, 95% CI 0.25-0.61; p<0.0001). In the subgroup administered omega-3 fatty acids at least 4 weeks prior to cardioversion and continued thereafter, the recurrence rate of AF was significantly low. More double-blind, randomized, placebo-controlled, multicenter studies with high quality and longer follow-up periods are needed to affirm our conclusion.

Effects of Omega-3 Fatty Acid for Sudden Cardiac Death Prevention in Patients with Cardiovascular Disease: A Contemporary Meta-Analysis of Randomized, Controlled Trials

Experimental and epidemiological studies suggest that omega-3 fatty acids have an antiarrhythmic effect. However, evidence from randomized controlled trials (RCTs) for prevention of sudden cardiac death (SCD) remains controversial. This study sought to evaluate the efficacy of omega-3 fatty acids for secondary prevention of SCD in patients with cardiovascular disease (CVD) in the era of guidelines-based therapy. We conducted a PubMed/EMBASE/CENTRAL search for RCTs evaluating omega-3 fatty acids for CVD secondary prevention with at least 6 months follow-up and with data on SCD. Primary outcome was SCD. Secondary outcomes were cardiovascular mortality and all-cause mortality. Ten randomized controlled trials were identified evaluating a total of 33,429 patients with CVD. In patients with guidelines-adjusted therapy, omega-3 fatty acids did not reduce the risk ratio (RR) of SCD (RR:0.96; 95% CI: 0.84-1.10). In patients with non- guidelines-adjusted therapy, omega-3 fatty acids reduced the RR of SCD (RR: 0.64; 95% CI: 0.51-0.80). Overall, RR for cardiac death and all-cause mortality were 0.81 (95% CI: 0.69-0.95) and 0.89 (95% CI: 0.79-1.01), respectively. In the era of guidelines-adjusted treatment for CVD secondary prevention, omega-3 fatty acids do not appear to reduce SCD.

Omega-3 fatty acids for major depressive disorder associated with the menopausal transition

We sought to obtain preliminary data regarding the efficacy of omega-3 fatty acids for major depressive disorder associated with the menopausal transition. Secondary outcomes were assessed for vasomotor symptoms (or hot flashes). After a single-blind placebo lead-in, participants received 8 weeks of treatment with open-label omega-3 fatty acid capsules (eicosapentaenoic acid and docosahexaenoic acid, 2 g/d). The Montgomery-Asberg Depression Rating Scale (MADRS) was the primary outcome measure. Hot flashes were monitored prospectively using daily diaries and the Hot Flash Related Daily Interference Scale. Blood samples for plasma pretreatment and posttreatment essential fatty acid assays were obtained. Because of the small sample size, data were analyzed using nonparametric techniques. Of 20 participants treated with omega-3 fatty acids, 19 (95%) completed the study. None discontinued because of adverse effects. The pretreatment and final mean MADRS scores were 24.2 and 10.7, respectively, reflecting a significant decrease in MADRS scores (P < 0.0001). The response rate was 70% (MADRS score decrease of ≥50%), and the remission rate was 45% (final MADRS score of ≤). Responders had significantly lower pretreatment docosahexaenoic acid levels than nonresponders did (P = 0.03). Hot flashes were present in 15 (75%) participants. Among those with hot flashes at baseline, the number of hot flashes per day improved significantly from baseline (P = 0.02) and Hot Flash Related Daily Interference Scale scores decreased significantly (P = 0.006). These data support further study of omega-3 fatty acids for major depressive disorder and hot flashes in women during the menopausal transition.

A Pilot Randomized Controlled Trial of Omega-3 Fatty Acids for Autism Spectrum Disorder

We conducted a pilot randomized controlled trial to determine the feasibility and initial safety and efficacy of omega-3 fatty acids (1.3 g/day) for the treatment of hyperactivity in 27 children ages 3–8 with autism spectrum disorder (ASD). After 12 weeks, hyperactivity, as measured by the Aberrant Behavior Checklist, improved 2.7 (±4.8) points in the omega-3 group compared to 0.3 (±7.2) points in the placebo group (p = 0.40; effect size = 0.38). Correlations were found between decreases in five fatty acid levels and decreases in hyperactivity, and the treatment was well tolerated. Although this pilot study did not find a statistically significant benefit from omega-3 fatty acids, the small sample size does not rule out small to moderate beneficial effects.

Omega-3 Fatty Acids for Autistic Spectrum Disorder: A Systematic Review

We conducted a systematic review to determine the safety and efficacy of omega-3 fatty acids for autistic spectrum disorder (ASD). Articles were identified by a search of MEDLINE, EMBASE, and the Cochrane Database using the terms autism or autistic and omega-3 fatty acids. The search identified 143 potential articles and six satisfied all inclusion criteria. One small randomized controlled trial (n = 13) noted non-significant improvements in hyperactivity and stereotypy. The remaining five studies were small (n = 30, 22, 19, 9, and 1) with four reporting improvements in a wide range of outcomes including language and learning skills, parental observations of general health and behavior, a clinician-administered symptom scale, and clinical observations of anxiety. Due to the limitations of evidence from uncontrolled studies and the presence of only one small randomized controlled trial, there is currently insufficient scientific evidence to determine if omega-3 fatty acids are safe or effective for ASD.

Review of Omega-3 Fatty Acids for the Treatment of Attention Deficit/Hyperactivity Disorder

Objective To review the efficacy of omega-3 fatty acids in the treatment of attention deficit/hyperactivity disorder (ADHD). Data Souces Literature was accessed via MEDLINE (1950–February 2009) and International Pharmaceutical Abstracts (1960–2009) using the medical subject heading terms omega-3 fatty acids and attention deficit disorder with hyperactivity. Additional references were found by searching bibliographic references of resulting citations. Study Selection and Data Extraction All English-language, placebo controlled publications identified were analyzed for significance. Studies relevant to the objective were used, including eight studies evaluating the use of omega-3 fatty acid in the treatment of children with symptoms of ADHD. Data Synthesis Omega-3 fatty acid supplementation has been found to have variable efficacy in the treatment of patients with ADHD. Of the eight studies evaluated, three demonstrated no significant improvements in any evaluation criteria, with five studies reporting positive effects in at least one outcome measure. All positive efficacy studies included concomitant supplementation with omega-6 fatty acids. No clinically significant adverse effects were identified in the reviewed studies. Conclusions Based on the available data, current fatty acid supplementation techniques do not appear to be a consistant method of controlling ADHD symptoms. Without better evidence to determine the true value of fatty acids in the treatment of ADHD, omega-3 fatty acid use should be isolated to adjuvant supplementation or used in patients unable or unwilling to take stimulant medications. If recommended, there does not appear to be clinically significant adverse events associated with omega-3 fatty acid supplementation and this would be a safe treatment modality.

Investigations Regarding Obesity Induction and Prevention through a Guided Diet

Obesity is associated with a high risk of develop ing diabetes and cardiovascular diseases. Therefore, management of body weight to prevent obesity remains as an important priority. The present investigation addresses the effects of Omega-3 PUFAs on body weight, blood composition and histological aspects in guinea pigs . We used 21 Guinea pigs, 12 weeks old, which were randomly assigned to control group, 0.5 % chol esterol in diet group and 0.5 % cholesterol in diet plus Omega-3 group. Guinea pigs fed with 0.5 % cholesterol in diet showed a significant increase in body weight and serum levels - total cholesterol (T C), triglycerides (TG) and LDL cholesterol (LDL- C) - when compared to control group (P=0.0039, P=0.00950, P=0.00001, P= 0.00134 respectively). They also develop severe hepatic steatosis. Adding Omega-3 in diet significant reduce body weight, serum levels - TC, TG and LDL-C and hepatic steatosis when compared to control group (P=0.04077, P= 0.01, P=0.00001, P=0.0995). In conclusion, concerning the efficacy of Omega-3 fatty acids to reduce body weight, hypertriglyceridemia and hepati c steatosis, their adding in diet have positive effects in obesity prevention.

Omega-3 fatty acids and supportive psychotherapy for perinatal depression: A randomized placebo-controlled study

Background Perinatal major depressive disorder (MDD), including antenatal and postpartum depression, is common and has serious consequences. This study was designed to investigate the feasibility, safety, and efficacy of omega-3 fatty acids for perinatal depression in addition to supportive psychotherapy. Methods Perinatal women with MDD were randomized to eicosapentaenoic (EPA) and docosahexaenoic acids (DHA), 1.9g/day, or placebo for 8weeks. A manualized supportive psychotherapy was provided to all subjects. Symptoms were assessed with the Hamilton Rating Scale for Depression (HAM-D) and Edinburgh Postnatal Depression Scale (EPDS) biweekly. Results Fifty-nine women enrolled; N = 51 had two data collection points that allowed for evaluation of efficacy. Omega-3 fatty acids were well tolerated. Participants in both groups experienced significant decreases in EPDS and HAM-D scores ( p < .0001) from baseline. We did not find a benefit of omega-3 fatty acids over placebo. Dietary omega-3 fatty acid intake was low among participants. Limitations The ability to detect an effect of omega-3 fatty acids may have been limited by sample size, study length, or dose. The benefits of supportive psychotherapy may have limited the ability to detect an effect of omega-3 fatty acids. Conclusions There was no significant difference between omega-3 fatty acids and placebo in this study in which all participants received supportive psychotherapy. The manualized supportive psychotherapy warrants further study. The low intake of dietary omega-3 fatty acids among participants is of concern, in consideration of the widely established health advantages in utero and in infants.

A Meta-Analytic Review of Double-Blind, Placebo-Controlled Trials of Antidepressant Efficacy of Omega-3 Fatty Acids

Evidence has indicated an association between depression and low dietary intake of omega-3 polyunsaturated fatty acids (PUFAs). However, clinical trials examining the therapeutic benefit of omega-3 PUFAs in depression showed inconsistent results. The goal of this study is to systematically evaluate the antidepressant efficacy of omega-3 PUFAs by using meta-analytic method. MEDLINE, Embase, and PsycINFO databases were searched from 1966 through August 2006 using the key words (depression OR depressive disorder OR mood disorder) AND (omega-3 OR EPA OR DHA OR poly-unsaturated fatty acid OR fish oil). The search was limited to literature in English and clinical trials. Ten double-blind, placebo-controlled studies in patients with mood disorders receiving omega-3 PUFAs with the treatment period lasting 4 weeks or longer were included. Effect size (ES) of each individual study was derived by computing the standardized mean difference. A random-effects model was used to pool the ESs of all included studies. When pooling the results of 10 included studies (N = 329), we found a significant antidepressant effect of omega-3 PUFAs (ES = 0.61, p = .003). Likewise, omega-3 PUFAs significantly improved depression in patients with clearly defined depression (ES = 0.69, p = .002) or with bipolar disorder (ES = 0.69, p = .0009). The dosage of eicosapentaenoic acid (EPA) did not change the antidepressant efficacy significantly. However, significant heterogeneity among these studies and publication bias were noted. Although our meta-analysis showed significant antidepressant efficacy of omega-3 PUFAs, it is still premature to validate this finding due to publication bias and heterogeneity. More large-scale, well-controlled trials are needed to find out the favorable target subjects, therapeutic dose of EPA, and the composition of omega-3 PUFAs in treating depression.

A randomized controlled trial to assess the efficacy of omega-3 fatty acids as a treatment for depression during the perinatal period.

A randomized controlled trial to assess the efficacy of omega-3 fatty acids as a treatment for depression during the perinatal period.

Acute Heart Failure—Basic Pathomechanism and New Drug Targets

In view of the high incidence of heart failure and sudden cardiac death, efforts in the development of compounds which target-specific mechanisms such as a reduced expression of SERCA2, the Ca2+ pump of sarcoplasmic reticulum, of hypertrophied cardiomyocytes of pressure-overloaded or infarcted hearts should be strengthened. Lead compounds for correcting a dysregulated gene expression are the carnitine palmitoyltransferase-1 (CPT-1) inhibitors etomoxir and oxfenicine. Since bypassing the CPT-1 inhibition by a medium-chain fatty acid diet had a lesser effect on myosin V1 proportion than on lipid droplet number, one has to infer also other mechanisms such as PPARalpha activation (FOXIB/PPARalpha). In view of the intricate interrelationship between depressed pump function and malignant arrhythmias, stimulation of endogenous antiarrhythmogenic mechanisms linked to an enhanced production of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) could potentially provide alternatives to the administration of 1 g EPA and DHA ethyl esters (minimum 84% EPA + DHA) for secondary prevention of myocardial infarction. The apparently greater efficacy of omega-3 fatty acids in post-myocardial infarction patients (GISSI-Prevention study) compared with ICD patients (SOFA study) can be attributed to the greater ischemia-induced release of membrane-bound EPA and DHA and a better compliance (one vs. four capsules daily).

Efficacy of Omega-3 Fatty Acids in Children and Adults with IgA Nephropathy Is Dosage- and Size-Dependent

Previous studies that have evaluated fish oil preparations in patients with IgA nephropathy (IgAN) have produced a wide range of conclusions. Proposed explanations for these discordant results have not provided a unifying hypothesis. Results from two clinical trials were analyzed to examine whether there is a dosage-dependent effect of Omacor, a purified preparation of omega-3 fatty acids, in patients with IgAN. Whether changes in the level of proteinuria and plasma phospholipid fatty acid profiles were dependent on the dose of Omacor factored by body size was determined. In a post hoc analysis of the first trial results, correlations were found between (1) phospholipid eicosapentaenoic acid (EPA)/arachidonic acid (AA) and docosahexaenoic acid (DHA)/AA ratios and the dosage of Omacor, expressed as milligrams per kilogram of body weight (r = 0.78, P < 0.001 for EPA/AA; r = 0.86, P < 0.001 for DHA/AA), (2) phospholipid EPA/AA and DHA/AA levels and percentage change in urine protein/creatinine ratio after 21 to 24 mo of therapy (r = -0.50, P = 0.02 for EPA/AA; r = -0.52, P = 0.01 for DHA/AA), and (3) dosage of Omacor per kilogram of body weight and change in proteinuria after 21 to 24 mo (r = -0.50, P = 0.02). A similar relationship was observed between urine protein/creatinine ratio and dosage of Omacor per kilogram of body weight in trial 2 (r = -0.38, P < 0.001). It is concluded from these data that the effect of Omacor on proteinuria in patients with IgAN is dosage dependent and is associated with a dosage-dependent effect of Omacor on plasma phospholipid EPA and DHA levels.

The evidence for efficacy of omega-3 fatty acids in preventing or slowing the progression of retinitis pigmentosa: a systematic review

Background: Studies in preterm and term human infants have suggested that a dietary supply of omega-3 fatty acids is essential for optimal visual development. Several basic science studies support the hypothesis that omega-3 fatty acids may be useful therapeutic agents for pathologies of the retina and lens. As part of a systematic review of the effect of omega-3 fatty acids on eye health, the purpose of this study was to conduct a systematic review of the scientific-medical literature to appraise and synthesize the evidence for the effects of omega-3 fatty acids in preventing the development or progression of retinitis pigmentosa. Methods: A comprehensive search was undertaken in MEDLINE, PREMEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, Global Health, and Dissertation Abstracts. Unpublished literature was sought through manual searches of reference lists of included studies and key review articles and from the files of content experts. Searches were not restricted by language of publication, publication type, or study design. Eligibility criteria were applied to screen eligible studies on two levels. Data extraction and quality assessment were performed. Results: Six studies published between 1995 and 2004 met eligibility criteria in investigating the question of the possible value of omega-3 fatty acids in slowing the progression of retinitis pigmentosa. Meta-analysis was not performed because there was not enough available information for formal quantitative analysis. Interpretation: There are trends in improvement of some retinitis pigmentosa outcomes with omega-3 fatty acids in the higher quality studies. Clinical research is preliminary in this field, however. Accordingly, definitive answers will require significantly more observational and interventional clinical research.

Costs of the standard rheumatology care in active rheumatoid arthritis patients seen in a tertiary care center in Mexico City

To assess the costs of standard care in patients with active rheumatoid arthritis (RA) seen in a tertiary care center in México City in the context of a clinical trial. To analyze the relationship between costs and utility units obtained by the patients in this scenario. This economic evaluation was performed during a clinical trial with a 48-week followup in a tertiary care center in México City. The trial compared the efficacy of omega-3 fatty acids versus placebo in patients with active RA who also received standard rheumatology care. The costs of medical consultations, complementary tests and drugs were assessed. Other direct costs were also measured. Hypothetical scenarios with fewer medical consultations and complementary tests than those in the clinical trial were also analyzed. Utilities were assessed by the Health Utility Index. A cost-utility ratio was calculated using the baseline utilities score as comparator. A descriptive statistical analysis was performed. Ninety RA patients (83 women [92%], age [X ± SD] 43.2 ± 14.2 years with disease duration of 3.3 ± 4.6 years) were included. Data from 88 patients were analyzed. The total direct costs were 152,704.11 US$ 2005 divided into medical attention (78,386.43 US$ 2005, 51.33%), drugs (39,339.5 US$ 2005, 25.76%) and other direct costs (34,978.18 US$ 2005. 22.91%). In scenarios with fewer medical consultations and complementary tests than those in the clinical trial, the total direct costs ranged from 39,507.4 to 103,880.6 US$ 2005. Patients improved by a mean of 0.18 utility units on a 0-1 scale equivalent to 0.18 quality adjusted lifeyears (QALYs). The cost-utility ratios ranged from 2,494.1 to 9,640.38 US$ 2005 per QALY in the scenarios analyzed. The direct costs of the standard care of RA in the scenarios analyzed are substantial in the social and economic context of Mexico. The cost per gained QALY is high.

An open trial of Omega-3 fatty acids for depression in pregnancy.

In this flexible-dose, open-label trial, we examined the efficacy of omega-3 fatty acids for the treatment of depression during pregnancy. Fifteen pregnant women with major depressive episodes participated. Subjects initially received two capsules per day [0.93 g of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA)]; the dose could be increased by one capsule per day every 2 weeks to a maximal dose of 2.8 g. Subjects were assessed with the Edinburgh Postnatal Depression Scale (EPDS) and Hamilton Rating Scale for Depression (HRSD). Average duration of participation in this treatment trial was 8.3 weeks (SD ± 7.1). Average final dose of EPA + DHA in this flexible dose trial was 1.9 g per day (±0.5). The mean reduction in EPDS scores was 40.9% (SD ± 21.9); the mean decrease in HRSD score was 34.1% (SD ± 27.1). This open trial provides data to support the need for randomized controlled dose-finding trials of omega-3 fatty acids in major depressive episodes during pregnancy.

Th-P15:169 Efficacy of omega-3 fatty acids in lowering lipoprotein(A) levels: A preliminary study

Th-P15:169 Efficacy of omega-3 fatty acids in lowering lipoprotein(A) levels: A preliminary study

Randomized dose‐ranging pilot trial of omega‐3 fatty acids for postpartum depression

Postpartum depression (PPD) affects 10-15% of mothers. Omega-3 fatty acids are an intriguing potential treatment for PPD. The efficacy of omega-3 fatty acids for PPD was assessed in an 8-week dose-ranging trial. Subjects were randomized to 0.5 g/day (n = 6), 1.4 g/day (n = 3), or 2.8 g/day (n = 7). Across groups, pretreatment Edinburgh Postnatal Depression Scale (EPDS) and Hamilton Rating Scale for Depression (HRSD) mean scores were 18.1 and 19.1 respectively; post-treatment mean scores were 9.3 and 10.0. Percent decreases on the EPDS and HRSD were 51.5% and 48.8%, respectively; changes from baseline were significant within each group and when combining groups. Groups did not significantly differ in pre- or post-test scores, or change in scores. The treatment was well tolerated. This study was limited by small sample size and lack of placebo group. However, these results support further study of omega-3 fatty acids as a treatment for PPD.

Fish oils in the care of coronary heart disease patients: a meta-analysis of randomized controlled trials.

What is the place of fish oils in the care of coronary heart disease (CHD) patients? As several clinical trials have already addressed this question without giving definitive answers, we did a meta-analysis of trials regarding the efficacy of omega-3 fatty acids in preventing cardiovascular mortality and morbidity. We searched the MEDLINE (1966-2003), EMBASE databases, proceedings abstracts and references of reviewed articles. Randomized controlled trials (RCTs) of the efficacy of omega-3 fatty acids among adults with recent or acute myocardial infarction (MI), or angina were selected. Two reviewers abstracted data independently. Five relevant outcomes, mortality from all causes, fatal and non-fatal MI, non-fatal stroke and angina, were measured. Data were synthesized using a fixed effect model. Ten RCTs with 14,727 patients were included. No significant heterogeneity was detected. Daily intake of omega-3 fatty acids for a mean duration of 37 months decreased all causes of mortality by 16% (relative risk 0.84, 95% confidence interval [0.76; 0.94]) and the incidence of death due to MI by 24% (0.76, [0.66; 0.88]). No significant effect was found for the other outcomes. Because of the suboptimal quality of the studies included into the meta-analysis and the absence of data in patients receiving statins, these results do not justify adding fish oils systematically to the heavy pharmaceutical assortment already recommended in CHD patients.

An overview of recent findings of the Stanley Foundation Bipolar Network (Part I).

Selected recent findings of the Stanley Foundation Bipolar Network are briefly reviewed and their clinical implications discussed. Daily prospective ratings on the NIMH-LCM indicate a high degree of residual depressive morbidity (three times that of hypomania or mania) despite active psychopharmacological treatment with a variety of modalities including mood stabilizers, antidepressants, and benzodiazepines, as well as antipsychotics as necessary. The rates of switching into brief to full hypomania or mania during the use of antidepressants is described, and new data suggesting the potential utility of continuing antidepressants in the small group of patients showing an initial acute and persistent response is noted. Bipolar patients with a history of major environmental adversities in childhood have a more severe course of illness and an increased incidence of suicide attempts compared with those without. Preliminary open data suggest useful antidepressant effects of the atypical antipsychotic quetiapine, while a double-blind randomized controlled study failed to show efficacy of omega-3 fatty acids (6 g of eicosapentaenoic acid compared with placebo for 4 months) in the treatment of either acute depression or rapid cycling. The high prevalence of overweight and increased incidence of antithyroid antibodies in patients with bipolar illness is highlighted. Together, these findings suggest a very high degree of comorbidity and treatment resistance in outpatients with bipolar illness treated in academic settings and the need to develop not only new treatment approaches, but also much earlier illness recognition, diagnosis, and intervention in an attempt to reverse or prevent this illness burden.