title: B vitamins to enhance treatment response to antidepressants in middle-aged and older adults: results from the B-VITAGE randomised, double-blind, placebo-controlled trial. Effects of Zinc Supplementation in Patients with Major Depression: A Randomized Clinical Trial Annual high-dose vitamin D3 and mental well-being: randomised controlled trial. Omega-3 fatty acids in major depressive disorder: A preliminary double-blind, placebo-controlled trial “Add-On”-therapy with an individualized preparation consisting of free amino acids for patients with a major depression Eicosapentaenoic acid versus docosahexaenoic acid in mild-to-moderate depression: A randomized, double-blind, placebo-controlled trial The treatment of depression in general practice: a comparison of L-tryptophan, amitriptyline, and a combination of L-tryptophan and amitriptyline with placebo. Omega-3 augmentation of sertraline in treatment of depression in patients with coronary heart disease: a randomized controlled trial. Preliminary randomized double-blind placebo-controlled trial of tryptophan combined with fluoxetine to treat major depressive disorder: antidepressant and hypnotic effects. S-Adenosyl-L-Methionine Augmentation in Patients with Stage II Treatment-Resistant Major Depressive Disorder: An Open Label, Fixed Dose, Single-Blind Study Omega-3 Fatty Acid Augmentation of Citalopram Treatment for Patients With Major Depressive Disorder Inflammation as a Predictive Biomarker for Response to Omega-3 Fatty Acids in Major Depressive Disorder: A Proof of Concept Study Enhancement of the antidepressant action of fluoxetine by folic acid: a randomised, placebo controlled trial. Tricyclic antidepressants and tryptophan in unipolar depression. L-methylfolate as adjunctive therapy for SSRI-resistant major depression: results of two randomized, double-blind, parallel-sequential trials. A randomized double-blind comparison of fluoxetine augmentation by high and low dosage folic acid in patients with depressive episodes. Eicosapentaenoic acid as an add-on to antidepressant medication for co-morbid major depression in patients with diabetes mellitus: a randomized, double-blind placebo-controlled study. Industry sponsorship and financial conflict of interest in the reporting of clinical trials in psychiatry. Double-Blind, Controlled, Crossover Trial of Inositol Versus Fluvoxamine for the Treatment of Panic Disorder Inositol addition does not improve depression in SSRI treatment failures Therapeutic effects of vitamin D as adjunctive therapy to fluoxetine in patients with major depressive disorder Effect of Folic Acid Combined with Fluoxetine in Patients with Major Depression on Plasma Homocysteine and Vitamin B12, and Serotonin Levels in Lymphocytes S-adenosyl methionine (SAMe) augmentation of serotonin reuptake inhibitors for antidepressant nonresponders with major depressive disorder: a double-blind, randomized clinical trial. Folinic acid (Leucovorin) as an adjunctive treatment for SSRI-refractory depression. Addition of omega-3 fatty acid to maintenance medication treatment for recurrent unipolar depressive disorder. Zinc supplementation augments efficacy of imipramine in treatment resistant patients: a double blind, placebo-controlled study. Total, Dietary, and Supplemental Vitamin C Intake and Risk of Incident Kidney Stones. S-Adenosyl-L-Methionine (SAMe) as an Adjunct for Resistant Major Depressive Disorder: An Open Trial Following Partial or Nonresponse to Selective Serotonin Reuptake Inhibitors or Venlafaxine Double-blind, controlled trial of inositol treatment of depression. Treatment of depression with L-5-hydroxytryptophan combined with chlorimipramine, a double-blind study. A dose-ranging study of the effects of ethyl-eicosapentaenoate in patients with ongoing depression despite apparently adequate treatment with standard drugs. Folate Augmentation of Treatment--Evaluation for Depression (FolATED): randomised trial and economic evaluation. Potentiation of a monoamine oxidase inhibitor by tryptophan. Combination of inositol and serotonin reuptake inhibitors in the treatment of depression Comparison of Therapeutic Effects of Omega-3 Fatty Acid Eicosapentaenoic Acid and Fluoxetine, Separately and in Combination, in Major Depressive Disorder
abstract: BACKGROUND Depression is common and the efficacy of antidepressants is suboptimal . High plasma homocysteine has been consistently associated with depression , and treatment with certain B vitamins demonstrably reduces its concentration . AIMS To determine whether vitamins B6 , B12 and folic acid enhance response to antidepressant treatment  over 52 weeks . METHOD R and omised , double-blind , placebo-controlled trial of citalopram ( 20 - 40 g ) together with 0.5 mg of vitamin B12 , 2 mg of folic acid and 25 mg of vitamin B6 for 52 weeks ( Australian and New Zeal and Clinical Trials Registry : 12609000256279 ) . Participants were community-dwelling adults aged 50 years or over with DSM-IV-TR major depression . We measured severity of symptoms with the Montgomery-Åsberg Depression Rating Scale ( MADRS ) . The primary outcome was remission of the depressive episode after 12 , 26 and 52 weeks . Secondary outcomes included reduction of MADRS scores over time and relapse of major depression after recovery by week 12 . Results In total , 153 people were r and omised ( 76 placebo , 77 vitamins ) .  Remission of symptoms was achieved by 78.1 and 79.4 % of participants treated with placebo and vitamins by week 12 ( P = 0.840 ) , by 76.5 and 85.3 % at week 26 and 75.8 and 85.5 % at week 52 ( effect of intervention over 52 weeks : odds ratio ( OR ) = 2.49 , 95 % CI 1.12 - 5.51 ) . Group differences in MADRS scores over time were not significant ( P = 0.739 ) . The risk of subsequent relapse among those who had achieved remission of symptoms at week 12 was lower in the vitamins than placebo group ( OR = 0.33 , 95 % CI 0.12 - 0.94 ) . CONCLUSIONS B vitamins did not increase the 12-week efficacy of antidepressant treatment , but enhanced and sustained antidepressant response over 1 year . Replication of these findings would m and ate that treatment guidelines adopt the adjunctive use of B vitamins as a safe and inexpensive strategy to manage major depression in middle-aged and older adults Objective Major depression is a mood disorder that causes changes in physical activity , appetite , sleep and weight . Regarding the role of zinc in the pathology of depression , the present study was aim ed to investigate the effects of zinc supplementation in the treatment of this disease . Methods This study was a double-blind r and omized clinical trial . Forty four patients with major depression were r and omly assigned to groups receiving zinc supplementation and placebo . Patients in Zinc group received daily supplementation with 25 mg zinc adjunct to antidepressant ; Selective Serotonin Reuptake Inhibitors ( SSRIs ) , while the patients in placebo group received placebo with antidepressants ( SSRIs ) for twelve weeks . Severity of depression was measured using the Beck Depression Inventory at baseline and was repeated at the sixth and twelfth weeks . ANOVA with repeated measure was used to compare and track the changes during the study . Results The mean score of Beck test decreased significantly in the zinc supplement group at the end of week 6 ( P < 0.01 ) and 12 ( P < 0.001 ) compared to the baseline . The mean score of Beck Depression Inventory reduced significantly compared to the placebo group at the end of 12th week ( P < 0.05 ) Conclusion The results of the present study indicate that zinc supplementation together with SSRIs antidepressant drug improves major depressive disorders more effectively in patients with placebo plus antidepressants ( SSRIs ) BACKGROUND Epidemiological evidence supports a relationship between vitamin D and mental well-being , although evidence from large-scale placebo-controlled intervention trials is lacking . AIMS To examine if vitamin D supplementation has a beneficial effect on mood in community-dwelling older women ; if a single annual large dose of vitamin D has a role in the prevention of depressive symptoms ; and if there is an association between serum 25-hydroxyvitamin D levels and mental health . METHOD A double-blind , r and omised , placebo-controlled trial of women aged 70 or older ( the Vital D Study : IS RCT N83409867 and ACTR12605000658617 ) . Participants were r and omly assigned to receive 500 000 IU vitamin D(3 ) ( cholecalciferol ) orally or placebo every autumn/winter for 3 - 5 consecutive years . The tools utilised at various time points were the General Health Question naire , the 12-item Short Form Health Survey , the Patient Global Impression-Improvement scale and the WHO Well-Being Index . Serum 25-hydroxyvitamin D levels were measured in a subset of 102 participants . RESULTS In this non- clinical population , no significant differences between the vitamin D and placebo groups were detected in any of the measured outcomes of mental health . Serum 25-hydroxyvitamin D levels in the vitamin D group were 41 % higher than the placebo group 12 months following their annual dose . Despite this difference , scores from the question naires did not differ . Furthermore , there was no interaction between those on antidepressant/anxiety medication at baseline and the treatment groups . CONCLUSIONS The lack of improvement in indices of mental well-being in the vitamin D group does not support the hypothesis that an annual high dose of vitamin D(3 ) is a practical intervention to prevent depressive symptoms in older community-dwelling women 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 The efficacy of a deficit oriented add-on therapy with free amino acids in depressive patients treated with the antidepressant Remeron ®  was evaluated . About 40 in- patients were investigated by a r and omised double-blind  placebo-controlled study during 4 weeks . Plasma levels of 20 amino acids and measures of depression , suicidal behaviour and aggression were surveyed on admission and after a 4 weeks ’ therapy with Remeron ® plus an individualized amino acid mixture or placebo . The preparation of the amino acid mixture was based on an aminogram and consisted of essential amino acids plus vitamins and trace elements as co-factors for the amino acid metabolism . Patients of the experimental group showed a significantly better improvement of depression and a higher responder rate than those of the placebo group . The results suggest that oral application of a deficit oriented amino acid mixture can improve the therapeutic outcome of an antidepressant . Furthermore , lacking side effects of the amino acids result ing also in a better patient compliance may improve the benefit/risk ratio Controversy exists as to whether eicosapentaenoic acid ( EPA ) or docosahexaenoic acid ( DHA ) or both are responsible for the efficacy of n-3 polyunsaturated fatty acids in depression . We conducted a single-center , r and omized , double-blind , placebo-controlled , multi-arm , parallel-group trial , comparing the efficacy of EPA versus DHA as adjuvants to maintenance medication treatments for mild-to-moderate depression . Eighty-one mild-to-moderately depressed out patients were r and omly assigned to receive either 1g/d of EPA or DHA or placebo ( coconut oil ) for 12 weeks . The primary outcome measure was the 17-item Hamilton Depression Rating Scale ( HDRS ) final score in the modified intention-to-treat population , which comprised of all r and omized patients with at least 1 post-r and omization observation ( n=62 ; 61.3 % female ; mean age 35.1 ± 1.2 years ) . Allocated treatments were well tolerated . Although there was no significant difference between groups at baseline , patients in the EPA group showed a significantly lower mean HDRS score at study endpoint compared with those in the DHA ( p<0.001 ) or placebo ( p=0.002 ) groups . Furthermore , response to treatment ( defined as a ≥ 50 % decrease from the baseline HDRS score ) was only observed in 6 patients receiving EPA , while no one in any of DHA or placebo groups responded to treatment . Overall , these data suggest greater efficacy of EPA compared to DHA or placebo as an adjunctive treatment in mild-to-moderate depression . However , further , r and omized controlled trials are needed to support these findings One hundred and fifteen patients from 5 general practice s participated in a 12-week , double-blind study comparing L-tryptophan , amitriptyline , L-tryptophan-amitriptyline combination and placebo in the treatment of depression . Analysis of total score on the Hamilton Depression Scale and a global rating of depression showed that all 3 active treatments were more effective than placebo . Significantly more patients were withdrawn as treatment failures in the placebo group compared with the active treatment groups . Side-effects necessitated withdrawal of more patients from the amitriptyline group than from the other active treatment groups , but this difference was not significant . Plasma amitriptyline and nortriptyline levels were similar in the amitriptyline and combined treatment groups . St and ard haematological and biochemical profiles did not alter significantly in any group , but mean heart rate was significantly increased in patients receiving amitriptyline . There was no change in free or total plasma tryptophan concentration with treatment or on remission of symptoms CONTEXT Studies of depressed psychiatric patients have shown that antidepressant efficacy can be increased by augmentation with omega-3 fatty acids . OBJECTIVE To determine whether omega-3 improves the response to sertraline  in patients with major depression and coronary heart disease ( CHD ) . DESIGN , SETTING , AND PARTICIPANTS R and omized controlled trial . Between May 2005 and December 2008 , 122 patients in St Louis , Missouri , with major depression and CHD were r and omized . INTERVENTIONS After a 2-week run-in period , all patients were given 50 mg/d of sertraline and r and omized in double-blind fashion to receive 2 g/d of omega-3 acid ethyl esters ( 930 mg of eicosapentaenoic acid [ EPA ] and 750 mg of docosahexaenoic acid [ DHA ] ) ( n=62 ) or to corn oil placebo capsules ( n=60 ) for 10 weeks . MAIN OUTCOME MEASURES Scores on the Beck Depression Inventory ( BDI-II ) and the Hamilton Rating Scale for Depression ( HAM-D ) . RESULTS Adherence to the medication regimen was 97 % or more in both groups for both medications . There were no differences in weekly BDI-II scores ( treatment x time interaction = 0.02 ; 95 % confidence interval [ CI ] , -0.33 to 0.36 ; t(112 ) = 0.11 ; P = .91 ) , pre-post BDI-II scores  ( placebo , 14.8 vs omega-3 , 16.1 ; 95 % difference-in-means CI , -4.5 to 2.0 ; t(116 ) = -0.77 ; P = .44 ) , or HAM-D scores ( placebo , 9.4 vs omega-3 , 9.3 ; 95 % difference-in-means CI , -2.2 to 2.4 ; t(115 ) = 0.12 ; P = .90 ) . The groups did not differ on predefined indicators of depression remission ( BDI-II < or = 8 : placebo , 27.4 % vs omega-3 , 28.3 % ; odds ratio [ OR ] , 0.96 ; 95 % CI , 0.43 - 2.15 ; t(113 ) = -0.11 ; P = .91 ) or response ( > 50 % reduction in BDI-II from baseline : placebo , 49.0 % vs omega-3 , 47.7 % ; OR , 1.06 ; 95 % CI , 0.51 - 2.19 ; t(112 ) = 0.15 ; P = .88 ) . CONCLUSIONS Treatment of patients with CHD and major depression with sertraline and omega-3 fatty acids did not result in superior depression outcomes at 10 weeks , compared with sertraline and placebo . Whether higher doses of omega-3 or sertraline , a different ratio of EPA to DHA , longer treatment , or omega-3 monotherapy can improve depression in patients with CHD remains to be determined . TRIAL REGISTRATION clinical trials.gov Identifier : NCT00116857 OBJECTIVE Because the initial phase of treatment of depression with a selective serotonin reuptake inhibitor is often complicated by a delayed onset of action of the antidepressant or severe insomnia or both , we investigated whether tryptophan , an amino acid with both antidepressant-augmenting and hypnotic effects , would benefit patients with depression at the beginning of treatment with fluoxetine .  DESIGN R and omized , double-blind , placebo-controlled trial . PATIENTS Thirty individuals with major depressive disorder . INTERVENTIONS Treatment over 8 weeks with 20 mg of fluoxetine per day and either tryptophan ( 2 to 4 g per day ) or placebo . OUTCOME MEASURES Mood was assessed using the 29-item Hamilton Depression Rating Scale ( HDRS-29 ) and the Beck Depression Inventory ( BDI ) . Laboratory sleep studies were done at baseline and after 4 and 8 weeks of treatment using st and ard procedures . RESULTS During the first week of treatment , there was a significantly greater decrease in HDRS-29 depression scores , and a similar trend in BDI scores , in the tryptophan/fluoxetine group than in the placebo/fluoxetine group . No significant differences were noted at later time points . With respect to sleep measures , there was a significant group-by-time interaction for slow-wave sleep at week 4 . Further analysis revealed a significant decrease in slow-wave sleep after 4 weeks of treatment in the placebo/fluoxetine group , but not in the tryptophan/fluoxetine group . No cases of serotonin syndrome occurred , and the combination was well tolerated , although the 4 g per day dosage of tryptophan produced daytime drowsiness . CONCLUSIONS Combining 20 mg of fluoxetine with 2 g of tryptophan daily at the outset of treatment for major depressive disorder appears to be a safe protocol that may have both a rapid antidepressant effect and a protective effect on slow-wave sleep . Further large-scale studies are needed to confirm these initial findings We investigated the efficacy of S-Adenosyl-L-Methionine ( SAMe ) augmentation in patients with treatment-resistant depressive disorder ( TRD ) . Thirty-three out patients with major depressive episode who failed to respond to at least 8 weeks of treatment with two adequate and stable doses of antidepressants were treated openly with fixed dose of SAMe ( 800 mg ) for 8 weeks , added to existing medication . The primary outcome measure was the change from baseline in total score on Hamilton Rating Scale for Depression ( HAM-D ) . The Clinical Global Impression of Improvement ( CGI-I ) was rated at the endpoint . Patients with a reduction of 50 % or more on HAM-D total score and a CGI-I score of 1 or 2 at endpoint were considered responders ; remission was defined as a HAM-D score ≤7 . Secondary outcome measures included the Snaith-Hamilton Pleasure Scale ( SHAPS ) and the Sheehan Disability Scale ( SDS ) . At 8 weeks , a significant decrease in HAM-D score was observed with response achieved by 60 % of the patients and remission by 36 % . Also a statistically significant reduction in SHAPS and SDS was observed . Our findings indicate that SAMe augmentation may be effective and well tolerated in stage II TRD . However , limitations of the present study must be considered and further placebo-controlled trials are needed Objective The objective of this study was to explore the efficacy of combination therapy with citalopram plus omega-3 fatty acids versus citalopram plus placebo ( olive oil ) in the initial treatment of individuals with major depressive disorder ( MDD ) . We hypothesized that combination therapy would lead not only to greater efficacy but also to a more rapid onset of therapeutic response . Methods Forty-two subjects participated in this 9-week r and omized , masked , placebo-controlled study of combination therapy ( two 1 g capsules containing a blend of 900 mg of eicosapentaenoic acid , 200 mg of and docosahexaenoic acid , and 100 mg of other omega-3 fatty acids twice daily plus citalopram ) versus monotherapy ( two 1 g capsules of olive oil per day plus citalopram ) treatment of MDD . Results The combination therapy demonstrated significantly greater improvement in Hamilton Depression Rating scale scores over time ( F = 7.32 ; df 1,177 ; P = 0.008 ) beginning at week 4 ( t = −2.48 ; df 177 ; P = 0.014 ) . Conclusions Combination therapy was more effective than monotherapy in decreasing signs and symptoms of MDD during the 8 weeks of active treatment ; however , combination therapy did not seem to enhance the speed of the initial antidepressant response . These findings suggest that there may be an advantage to combining omega-3 fatty acids with a selective serotonin uptake inhibitor in the initial treatment of individuals with MDD . A larger definitive study is warranted This study explores whether inflammatory biomarkers act as moderators of clinical response to omega-3 ( n-3 ) fatty acids in subjects with major depressive disorder ( MDD ) . One hundred fifty-five subjects with Diagnostic and Statistical Manual of Mental Disorders , 4th Edition ( DSM-IV ) MDD , a baseline 17-item Hamilton Depression Rating Scale ( HAM-D-17 ) score ⩾15 and baseline biomarker data ( interleukin (IL)-1ra , IL-6 , high-sensitivity C-reactive protein ( hs-CRP ) , leptin and adiponectin ) were r and omized between 18 May 2006 and 30 June 2011 to 8 weeks of double-blind treatment with eicosapentaenoic acid (EPA)-enriched n-3 1060 mg day−1 , docosahexaenoic acid (DHA)-enriched n-3 900 mg day−1 or placebo . Outcomes were determined using mixed model repeated measures analysis for ‘ high ’ and ‘ low ’ inflammation groups based on individual and combined biomarkers . Results are presented in terms of st and ardized treatment effect size ( ES ) for change in HAM-D-17 from baseline to treatment week 8 . Although overall treatment group differences were negligible ( ES=−0.13 to + 0.04 ) , subjects with any ‘ high ’ inflammation improved more on EPA than placebo ( ES=−0.39 ) or DHA ( ES=−0.60 ) and less on DHA than placebo ( ES=+0.21 ) ; furthermore , EPA-placebo separation increased with increasing numbers of markers of high inflammation . Subjects r and omized to EPA with ‘ high ’ IL-1ra or hs-CRP or low adiponectin ( ‘ high ’ inflammation ) had medium ES decreases in HAM-D-17 scores vs subjects ‘ low ’ on these biomarkers . Subjects with ‘ high ’ hs-CRP , IL-6 or leptin were less placebo-responsive than subjects with low levels of these biomarkers ( medium to large ES differences ) . Employing multiple markers of inflammation facilitated identification of a more homogeneous cohort of subjects with MDD responding to EPA vs placebo in our cohort . Studies are needed to replicate and extend this proof-of-concept work BACKGROUND A consistent finding in major depression has been a low plasma and red cell folate which has also been linked to poor response to antidepressants . The present investigation was design ed to investigate whether the co-administration of folic acid would enhance the antidepressant action of fluoxetine . METHODS 127 patients were r and omly assigned to receive either 500 microg folic acid or an identical looking placebo in addition to 20 mg fluoxetine daily . All patients met the DSM-III-R criteria for major depression and had a baseline Hamilton Rating Scale ( 17 item version ) score for depression of 20 or more . Baseline and 10-week estimations of plasma folate and homocysteine were carried out . RESULTS Patients receiving folate showed a significant increase in plasma folate . This was less in men than in women . Plasma homocysteine was significantly decreased in women by 20.6 % , but there was no significant change in men . Overall there was a significantly greater improvement in the fluoxetine plus folic acid group . This was confined to women where the mean Hamilton Rating Scale score on completion was 6.8 ( S.D. 4 . 1 ) in the fluoxetine plus folate group , as compared to 11.7 ( S.D. 6 . 7 ) in the fluoxetine plus placebo group (P<0.001).A percentage of 93 . 9 of women , who received the folic acid supplement , showed a good response ( > 50 % reduction in score ) as compared to 61.1 % of women who received placebo supplement ( P<0.005 ) . Eight ( 12.9 % ) patients in the fluoxetine plus folic acid group reported symptoms possibly or probably related to medication , whereas in the fluoxetine plus placebo group 19 ( 29.7 % ) patients reported such symptoms ( P<0.05 ) . LIMITATIONS AND CONCLUSIONS Folic acid is a simple method of greatly improving the antidepressant action of fluoxetine and probably other antidepressants . Folic acid should be given in doses sufficient to decrease plasma homocysteine . Men require a higher dose of folic acid to achieve this than women , but more work is required to ascertain the optimum dose of folic acid Depressed patients ( unipolar ) were given one of the following combinations in an attempt to test aspects of the ' amine hypothesis ' and to find a preferential therapy : ( 1 ) clomipramine ; ( 2 ) clomipramine and tryptophan ; ( 3 ) desipramine and clomipramine , and ( 4 ) desipramine and tryptophan . Treatment ( 2 ) should have given optimal potentiation of 5-HT neurones and ( 3 ) and ( 4 ) should have acted similarly on both serotoninergic and adrenergic pathways . In no group was there any evidence of accelerated recovery , indicating that the process of conversion to normal mood may be more complex than suggested by most versions of the amine hypothesis OBJECTIVE The authors conducted two multicenter sequential parallel comparison design trials to investigate the effect of L-methylfolate augmentation in the treatment of major depressive disorder in patients who had a partial response or no response to selective serotonin reuptake inhibitors ( SSRIs ) .  METHOD In the first trial , 148 out patients with SSRI-resistant major depressive disorder were enrolled in a 60-day study divided into two 30-day periods . Patients were r and omly assigned , in a 2:3:3 ratio , to receive L-methylfolate for 60 days ( 7.5 mg/day for 30 days followed by 15 mg/day for 30 days ) , placebo for 30 days followed by L-methylfolate ( 7.5 mg/day ) for 30 days , or placebo for 60 days . SSRI dosages were kept constant throughout the study . In the second trial , with 75 patients , the design was identical to the first , except that the l-methylfolate dosage was 15 mg/day during both 30-day periods . RESULTS In the first trial , no significant difference was observed in outcomes between the treatment groups . In the second trial , adjunctive L-methylfolate at 15 mg/day showed significantly greater efficacy compared with continued SSRI therapy plus placebo on both primary outcome measures ( response rate and degree of change in depression symptom score ) and two secondary outcome measures of symptom severity . The number needed to treat for response was approximately six in favor of adjunctive L-methylfolate at 15 mg/day . L-Methylfolate was well tolerated , with rates of adverse events no different from those reported with placebo . CONCLUSIONS Adjunctive L-methylfolate at 15 mg/day may constitute an effective , safe , and relatively well tolerated treatment strategy for patients with major depressive disorder who have a partial response or no response to SSRIs BACKGROUND Though encouraging evidence exists for the use of folic acid as an augmenting agent to antidepressants , evidence regarding its optimal dosage is lacking . METHODS Forty-two female out- patients with moderate ( with or without somatic syndrome ) or severe depressive episodes ( without psychotic symptoms ) diagnosed as per ICD-10 criteria , were r and omized in a double-blind fashion to receive either 20 mg fluoxetine and a relatively low dose folic acid ( 1.5 mg/day ; n=23 ; Group I ) or 20 mg fluoxetine and high dose folic acid ( 5 mg/day ; n=19 ; Group II ) . Primary outcome measures were weekly changes of scores on Hamilton Depression Rating Scale ( HDRS ) and Beck Depression Inventory ( BDI ) for 6 weeks . RESULTS Group II patients showed greater improvement in both HDRS [ Mean ( SD ) baseline HDRS score=21 ( 2.3 ) for group I and 20.0 ( 1.4 ) for group-II ; time X group interaction effect : p=0.01 ] and BDI [ Mean ( SD ) baseline BDI score=25.1 ( 5.2 ) for group-1 and 23.1 ( 2.7 ) for group-II ; time X group interaction effect : p=0.01 ] . With regard to HDRS , 7 ( 36.8 % ) group II patients remitted compared to 2 ( 8.7 % ) group I patients ( p=0.03 ) ; 9 ( 47.4 % ) patients of group II responded when compared to 6 ( 26.1 % ) from group I ( p=0.15 ) . When BDI was considered , 5 ( 26.3 % ) group II patients remitted when compared to 2 ( 8.7 % ) from group I ( p=0.13 ) ; 10 patients ( 52.6 % ) from group II responded when compared to 5 ( 21.7 % ) from group I ( p=0.04 ) . No adverse effects were noted in either group . LIMITATIONS Lack of a placebo arm and small sample size . CONCLUSION Compared to folic acid 1.5 mg/day , augmentation with 5 mg/day may be more beneficial in female patients with depressive episodes taking fluoxetine 20 mg/day BACKGROUND Depression is common in individuals with diabetes . The present study is the first r and omized controlled trial to test the efficacy of omega-3 ethyl-eicosapentaenoic acid ( E-EPA ) as adjuvant to antidepressant medication in the treatment of depression in adults with diabetes mellitus . METHODS In the VU University Medical Center , we conducted a 12-week , placebo-controlled , double-blind , parallel-group intervention study of E-EPA ( 1g/day ) versus placebo in 25 diabetes patients meeting DSM-IV criteria for major depressive disorder , who were already using antidepressant medication . The primary outcome was severity of depressive symptoms , assessed by the Montgomery Asberg Depression Rating Scale ( MADRS ) at baseline and 12-week follow-up at two-weekly intervals . Blood sample s were collected at baseline and at 12-week follow-up to determine EPA levels in erythrocyte membranes . Data were analyzed with ANOVA for repeated measures . RESULTS Thirteen participants were r and omly assigned to  E-EPA ; 12 participants were given  placebo . At 12-week follow-up , erythrocyte membranes from patients receiving E-EPA contained tripled levels of EPA , while no changes were noted in participants receiving placebo . In both groups , depressive symptoms significantly decreased over time ( F=21.14 , p<0.001 ) , yet no significant differences were found between those treated with E-EPA versus placebo ( F=1.63 , p=0.17 ) . LIMITATIONS Although having sufficient study power , this study had a relatively small sample size . Small effects could not be detected , and dose-dependent effects could not be studied . CONCLUSIONS No evidence was found for the efficacy of adding E-EPA to antidepressants in reducing depressive symptoms in diabetic patients with co-morbid depression OBJECTIVE Financial conflict of interest has been reported to be prevalent in clinical trials in general medicine and associated with a greater likelihood of reporting results favorable to the intervention being studied . The extent and implication s of industry sponsorship and financial conflict of interest in psychiatric clinical trials have not been investigated , to the authors ' knowledge . METHOD The authors examined funding source and author financial conflict of interest in all clinical trials published in the American Journal of Psychiatry , the Archives of General Psychiatry , the Journal of Clinical Psychopharmacology , and the Journal of Clinical Psychiatry between 2001 and 2003 . RESULTS Among 397 clinical trials identified , 239 ( 60 % ) reported receiving funding from a pharmaceutical company or other interested party , and 187 studies ( 47 % ) included at least one author with a reported financial conflict of interest . Among the 162 r and omized , double-blind , placebo-controlled studies examined , those that reported conflict of interest were 4.9 times more likely to report positive results ; this association was significant only among the subset of pharmaceutical industry-funded studies . CONCLUSIONS Author conflict of interest appears to be prevalent among psychiatric clinical trials and to be associated with a greater likelihood of reporting a drug to be superior to placebo Only 70 % of patients respond to current treatments for panic disorder , and many discontinue drugs because of side effects . myo-Inositol , a natural isomer of glucose and a precursor for the second-messenger phosphatidyl-inositol system , has previously been found superior to placebo in the treatment of depression , panic disorder , and obsessive-compulsive disorder ( OCD ) , but a direct comparison with an established drug has never been performed . A double-blind , controlled , r and om-order crossover study was undertaken to compare the effect of inositol with that of fluvoxamine in panic disorder . Twenty patients completed 1 month of inositol  up to 18 g/day and 1 month of fluvoxamine up to 150 mg/day . Improvements on Hamilton Rating Scale for Anxiety scores , agoraphobia scores , and Clinical Global Impressions Scale scores were similar for both treatments . In the first month , inositol reduced the number of panic attacks per week ( mean and SD ) by 4.0 ( 2 ) compared with a reduction of 2.4 ( 2 ) with fluvoxamine ( p = 0.049 ) . Nausea and tiredness were more common with fluvoxamine ( p = 0.02 and p = 0.01 , respectively ) . Because inositol is a natural compound with few known side effects , it is attractive to patients who are ambivalent about taking psychiatric medication . Continuing reports of inositol ’s efficacy in the treatment of depression , panic disorder , and OCD should stimulate replication studies Summary . Some antidepressants , such as Lithium , can augment the antidepressant effect of serotonin selective uptake inhibitors ( SSRI ) in patients who have failed to respond to SSRI . Inositol has demonstrated antidepressant effects but in a controlled double blind augmentation trial did not improve depression in SSRI treatment failures Objective : To compare the therapeutic effects of vitamin D3 plus fluoxetine and fluoxetine alone in patients with major depressive disorder . Methods : In the present double-blind , r and omized , placebo-controlled trial , 42 patients with a diagnosis of major depressive disorder based on DSM-IV criteria were r and omly assigned into two groups to receive daily either 1500 IU vitamin D3 plus 20 mg fluoxetine or fluoxetine alone for 8 weeks . Depression severity was assessed at 2-week intervals using the 24-item Hamilton Depression Rating Scale ( HDRS ) as a primary outcome measure and the 21-item Beck Depression Inventory ( BDI ) as a secondary outcome measure . Serum 25(OH ) vitamin D was measured at baseline and after intervention . Results : Forty patients completed the trial . A two-way repeated- measures analysis of variance showed that depression severity based on HDRS and BDI decreased significantly after intervention , with a significant difference between the two groups . The vitamin D + fluoxetine combination was significantly better than fluoxetine alone from the fourth week of treatment . Conclusions : In the present 8-week trial , the vitamin D + fluoxetine combination was superior to fluoxetine alone in controlling depressive symptoms Objective ( s ) : Folic acid , a micronutrient supporting the natural defense system , may elevate antidepressant responses , although the lymphocyte serotonergic system has not been explored in folate-supplemented depressed patients . Methods : Twenty-seven patients were r and omly assigned to groups receiving fluoxetine ( 20 mg ) and folic acid ( 10 mg/day ) or fluoxetine and placebo for 6 weeks . Clinical outcome was assessed according to the Hamilton Depression Rating Scale ( HDRS ) at the beginning , during and at the end of treatment . Blood sample s were taken , plasma was separated , and lymphocytes were obtained by density gradient centrifugation with Ficoll/Hypaque and differential adhesion to plastic dishes . Fifteen healthy subjects served as controls .  Plasma folate , homocysteine and vitamin B12 , and serotonin concentration in lymphocytes were determined by HPLC . The HDRS score was significantly lower in patients receiving fluoxetine and folic acid compared with those receiving fluoxetine and placebo after 6 weeks of treatment ( 7.43 ± 1.65 vs. 11.43 ± 1.31 , respectively ; p = 0.04 ) . Plasma homocysteine statistically significant decreased after folic acid ( p = 0.02 ) , but no significant changes were observed in vitamin B12 . Results : Serotonin was significantly reduced after fluoxetine either with folate ( p = 0.03 ) or placebo ( p = 0.01 ) probably by the effect of transporter blockade . 5-Hydroxyindoleacetic acid was lower in lymphocytes of patients receiving folate ( p = 0.04 ) , indicating a reduced turnover rate , thus accumulating serotonin in the cells . A significant negative correlation was noted between homocysteine and folate . No significant correlations were present among biochemical parameters and depression severity . Conclusion : Modifications due to treatment with fluoxetine and folic acid may alter lymphocyte function in depression probably indirectly by reducing homocysteine levels and directly on lymphocytes by modifying the serotonergic system OBJECTIVE Despite the progressive increase in the number of antidepressants , many patients with major depressive disorder continue to be symptomatic . Clearly , there is an urgent need to develop better tolerated and more effective treatments for this disorder . The use of S-adenosyl methionine ( SAMe ) , a naturally occurring molecule that serves as a methyl donor in human cellular metabolism , as adjunctive treatment for antidepressant nonresponders with major depressive disorder represents one such effort toward novel pharmacotherapy development . METHOD Participants were 73 serotonin reuptake inhibitor ( SRI ) nonresponders with major depressive disorder enrolled in a 6-week , double-blind , r and omized trial of adjunctive oral SAMe ( target dose : 800 mg/twice daily ) . Patients continued to receive their SRI treatment at a stable dose throughout the 6-week trial . The primary outcome measure for the study was the response rates according to the 17-item Hamilton Depression Rating Scale ( HAM-D ) . RESULTS The HAM-D response and remission rates were higher for patients treated with adjunctive SAMe ( 36.1 % and 25.8 % , respectively ) than adjunctive placebo ( 17.6 % versus 11.7 % , respectively ) . The number needed to treat for response and remission was approximately one in six and one in seven , respectively . There was no statistically significant difference in the proportion of SAMe- versus placebo-treated patients who discontinued the trial for any reason ( 20.6 % versus 29.5 % , respectively ) , due to adverse events ( 5.1 % versus 8.8 % , respectively ) , or due to inefficacy ( 5.1 % versus 11.7 % , respectively ) . CONCLUSIONS These preliminary results suggest that SAMe can be an effective , well-tolerated , and safe adjunctive treatment strategy for SRI nonresponders with major depressive disorder and warrant replication Low folate is associated with poorer response to selective serotonin reuptake inhibitors ( SSRIs ) in major depressive disorder ( MDD ) . Folate supplementation in MDD has been studied in other setting s with promising results . The objective of this study was to assess the efficacy of methylfolate as an adjunctive treatment among adults with MDD and inadequate response to an SSRI . Twenty-two adults ( 59 % female ; mean age 45.2 + /- 11.0 years ) with DSM-IV MDD , partial or nonresponse to an SSRI after at least 4 weeks of treatment , and a 17-item Hamilton Depression Rating Scale ( HAM-D-17 ) score > or = 12 were enrolled in this 8-week prospect i ve open trial . Exclusion criteria included current use of anticonvulsants or psychotropics other than an SSRI , or B12 deficiency .  Leucovorin ( folinic acid ) , which is metabolized to methylfolate , was added to SSRIs at 15 - 30 mg/day .  Folate levels rose from 28 + /- 19 ng/mL to 301 + /- 203 ng/mL ( p < 0.001 ) . HAM-D-17 scores among the 16 completers decreased from 19.1 + /- 3.9 to 12.8 + /- 7.0 ( p < 0.01 ) . However only 31 % of completers and 27 % of the intent-to-treat ( ITT ) sample achieved response ( > or = 50 % reduction in HAM-D-17 scores ) , and only 19 % of completers and 18 % of the ITT sample achieved remission ( HAM-D-17 < or = 7 ) . Leucovorin appears to be modestly effective as an adjunct among SSRI-refractory depressed individuals with normal folate levels . The application of leucovorin as an adjunct in the setting of refractory depression deserves further study OBJECTIVE Studies have reported that countries with high rates of fish oil consumption have low rates of depressive disorder . The authors studied a specific omega-3 fatty acid , the ethyl ester of eicosapentaenoic acid ( E-EPA ) , as an adjunct to treatment for depressive episodes occurring in patients with recurrent unipolar depressive disorder who were receiving maintenance antidepressant therapy . METHOD Twenty patients with a current diagnosis of major depressive disorder participated in a 4-week , parallel-group , double-blind addition of either placebo or E-EPA to ongoing antidepressant therapy .  Seventeen of the patients were women , and three were men . RESULTS Highly significant benefits of the addition of the omega-3 fatty acid compared with placebo were found by week 3 of treatment . CONCLUSIONS It is not possible to distinguish whether E-EPA augments antidepressant action in the manner of lithium or has independent antidepressant properties of its own BACKGROUND One of the main problems in the therapy of depression is the limited efficacy of antidepressants and the limited utility of augmentation strategies . Zinc , a non competitive NMDA receptor antagonist exhibits pre clinical antidepressant efficacy . Moreover , a preliminary clinical report suggests augmentation of antidepressant therapy by zinc in depression . METHODS A placebo-controlled , double blind study of zinc supplementation in imipramine therapy was conducted in sixty , 18 - 55-year old , unipolar depressed patients fulfilling the DSM-IV criteria for major depression without psychotic symptoms . After a one week washout period , patients were r and omized into two groups treated with imipramine ( approximately 140 mg/day ) and receiving once daily either placebo ( n=30 ) or zinc supplementation ( n=30 , 25 mgZn/day ) for 12 weeks . RESULTS No significant differences in CGI , BDI , HADRS and MADRS scores were demonstrated between zinc-supplemented and placebo-supplemented antidepressant treatment non-resistant patients . However , zinc supplementation significantly reduced depression scores and facilitated the treatment outcome in antidepressant treatment resistant patients . CONCLUSION Zinc supplementation augments the efficacy and speed of onset of therapeutic response to imipramine treatment , particularly in patients previously nonresponsive to antidepressant pharmacotherapies . These data suggest the participation of disturbed zinc/glutamatergic transmission in the pathophysiology of drug resistance BACKGROUND Previous studies of  vitamin C  and kidney stones were conducted mostly in men and either reported disparate results for supplemental and dietary vitamin C or did not examine dietary vitamin C. STUDY DESIGN Prospect i ve cohort analysis . SETTING & PARTICIPANTS 156,735 women in the Nurses ' Health Study ( NHS ) I and II and 40,536 men in the Health Professionals Follow-up Study ( HPFS ) . PREDICTOR  Total , dietary , and supplemental vitamin C intake  , adjusted for age , body mass index , thiazide use , and dietary factors . OUTCOMES Incident kidney stones . RESULTS During a median follow-up of 11.3 to 11.7 years , 6,245 incident kidney stones were identified . After multivariable adjustment ,  total vitamin C intake ( < 90 [ reference ] , 90 - 249 , 250 - 499 , 500 - 999 , and ≥1,000mg/d ) was not significantly associated with risk for kidney stones among women , but was among men ( HRs of 1.00 [ reference ] , 1.19 [ 95 % CI , 0.99 - 1.46 ] , 1.15 [ 95 % CI , 0.93 - 1.42 ] , 1.29 [ 95 % CI , 1.04 - 1.60 ] , and 1.43 [ 95 % CI , 1.15 - 1.79 ] , respectively ; P for trend = 0.005 ) . Median total vitamin C intake for the 500- to 999-mg/d category was ∼700mg/d . Supplemental vitamin C intake ( no use [ reference ] , < 500 , 500 - 999 , and ≥1,000mg/d ) was not significantly associated with risk for kidney stones among women , but was among men ( HR , 1.19 [ 95 % CI , 1.01 - 1.40 ] for ≥1,000mg/d ; P for trend =  0.001 ) . Dietary vitamin C intake was not associated with stones among men or women , although few participants had dietary intakes > 700mg/d . LIMITATIONS Nutrient intakes derived from food-frequency question naires , lack of data on stone composition for all cases . CONCLUSIONS Total and supplemental vitamin C intake was significantly associated with higher risk for incident kidney stones in men , but not in women Background : The purpose of this open trial was to evaluate the safety , tolerability , and efficacy of oral S-adenosyl-l-methionine as an antidepressant adjunct among partial and nonresponders to serotonin reuptake inhibitors or venlafaxine . Method : Thirty antidepressant-treated adult out patients with persisting major depressive disorder received 800 to 1600 mg of S-adenosyl-l-methionine tosylate over a 6-week trial . Results : Intent-to-treat analyses based on the Hamilton Depression Rating Scale revealed a response rate of 50 % and a remission rate of 43 % following augmentation with S-adenosyl-l-methionine .  Gastrointestinal symptoms and headaches were the most common side effects . Conclusion : Augmentation of selective serotonin reuptake inhibitors or venlafaxine with S-adenosyl-l-methionine warrants a placebo-controlled trial in resistant depression OBJECTIVE CSF levels of inositol have been reported to be lower than normal in depressed subjects . The authors administered inositol to depressed patients in a double-blind , controlled trial . METHOD Under double-blind conditions , 12 g/day of  inositol ( N = 13 ) or placebo ( N = 15 ) was administered to depressed patients for 4 weeks . RESULTS The overall improvement in scores on the Hamilton Depression Rating Scale was significantly greater for inositol than for placebo at week 4 . No changes were noted in hematology or in kidney or liver function . CONCLUSIONS This may be the first use of the precursor strategy for a second messenger rather than a neurotransmitter in treating depression . Although inositol had a significant antidepressant effect in this study , replication is crucial A double-blind clinical trial was carried out involving 26 hospitalized , depressed patients who were r and omized into two groups . Patients in each group received chlorimipramine ( 50 mg/day ) , combined with L-5-HTP ( 300 mg/day ) in Group A , and with placebo in Group B. The trial lasted 28 days . Two Group B patients dropped out . All the patients were evaluated by HRSD each week , and by ZDSI and CGI at the beginning and end of treatment . Several statistical analyses of the mean HRSD scores of each item presenting initial positive response and of ZDSI scores for both reactive and endogenous depression were performed , using Student 's t-test . To evaluate the efficacy of the chlorimipramine + L-5-HTP combination versus control therapy the Mann-Whitney test was applied to the reduction in HRSD scores , showing 0.05 significance . The results for both types of pathology were quantitatively and qualitatively more positive for Group A than for Group B. Cluster analysis of HRSD item scores alone and between this scale and ZDSI , according to Carrol 's correlation method for the symptoms of the cluster ( mood , anxiety and somatic symptoms ) , was carried out to confirm the above results BACKGROUND In depressed patients , low blood levels of eicosapentaenoic acid are seen . We tested the antidepressive effect of ethyl-eicosapentaenoate in these patients . METHODS We included 70 patients with persistant depression despite ongoing treatment with an adequate dose of a st and ard antidepressant .  Patients were r and omized on a double-blind basis to placebo or ethyl-eicosapentaenoate at dosages of 1 , 2 , or 4 g/d for 12 weeks in addition to unchanged background medication . Patients underwent assessment using the 17-item Hamilton Depression Rating Scale , the Montgomery-Asberg Depression Rating Scale , and the Beck Depression Inventory . RESULTS Forty-six ( 88 % ) of 52 patients receiving ethyl-eicosapentaenoate and 14 ( 78 % ) of 18 patients receiving placebo completed the 12-week study with no serious adverse events . The 1-g/d group showed a significantly better outcome than the placebo group on all 3 rating scales . In the intention-to-treat group , 5 ( 29 % ) of 17 patients receiving placebo and 9 ( 53 % ) of 17 patients receiving 1 g/d of ethyl-eicosapentaenoate achieved a 50 % reduction on the Hamilton Depression Rating Scale score . In the per- protocol group , the corresponding figures were 3 ( 25 % ) of 12 patients for placebo and 9 ( 69 % ) of 13 patients for the 1-g/d group . The 2-g/d group showed little evidence of efficacy , whereas the 4-g/d group showed nonsignificant trends toward improvement . All of the individual items on all 3 rating scales improved with the 1-g/d dosage of ethyl-eicosapentaenoate vs placebo , with strong beneficial effects on items rating depression , anxiety , sleep , lassitude , libido , and suicidality . CONCLUSION Treatment with ethyl-eicosapentaenoate at a dosage of 1 g/d was effective in treating  depression in patients who remained depressed despite adequate st and ard therapy BACKGROUND Folate deficiency is associated with depression . Despite the biological plausibility of a causal link , the evidence that adding folate enhances antidepressant treatment is weak . OBJECTIVES ( 1 ) Estimate the clinical effectiveness and cost-effectiveness of folic acid as adjunct to antidepressant medication ( ADM ) . ( 2 ) Explore whether baseline folate and homocysteine predict response to treatment . ( 3 ) Investigate whether response to treatment depends on genetic polymorphisms related to folate metabolism . DESIGN FolATED ( Folate Augmentation of Treatment - Evaluation for Depression ) was a double-blind and placebo-controlled , but otherwise pragmatic , r and omised trial including cost-utility analysis . To yield 80 % power of detecting st and ardised difference on the Beck Depression Inventory version 2 ( BDI-II ) of 0.3 between groups ( a ' small ' effect ) ,  FolATED trialists sought to analyse 358 participants . To allow for an estimated loss of 21 % of participants over three time points , we planned to r and omise 453 . SETTING S Clinical - Three centres in Wales - North East Wales , North West Wales and Swansea . Trial management - North Wales Organisation for R and omised Trials in Health in Bangor University . Biochemical analysis - University Hospital of Wales , Cardiff . Genetic analysis - University of Liverpool . PARTICIPANTS Four hundred and seventy-five adult patients presenting to primary or secondary care with confirmed moderate to severe depression for which they were taking or about to start ADM , and able to consent and complete assessment s , but not ( 1 ) folate deficient , vitamin B12 deficient , or taking folic acid or anticonvulsants ; ( 2 ) misusing drugs or alcohol , or suffering from psychosis , bipolar disorder , malignancy or other unstable or terminal illness ; ( 3 ) ( planning to become ) pregnant ; or ( 4 ) participating in other clinical research . INTERVENTIONS Once a day for 12 weeks experimental participants added 5 mg of folic acid to their ADM , and control participants added an indistinguishable placebo . All participants followed pragmatic management plans initiated by a trial psychiatrist and maintained by their general medical practitioners . MAIN OUTCOME MEASURES Assessed at baseline , and 4 , 12 and 25 weeks thereafter , and analysed by ' area under curve ' ( main ) ; by analysis of covariance at each time point ( secondary ) ; and by multi-level repeated measures ( sensitivity analysis ): Mental health - BDI-II ( primary ) , Clinical Global Impression ( CGI ) , Montgomery-Åsberg Depression Rating Scale ( MADRS ) , UKU side effects scale , and Mini International Neuropsychiatric Interview ( MINI ) suicidality subscale ; General health - UK 12-item Short Form Health Survey ( SF-12 ) , European Quality of Life scale - 5 Dimensions ( EQ-5D ) ; Biochemistry - serum folate , B12 , homocysteine ; Adherence - Morisky Question naire ; Economics - re source use . RESULTS Folic acid did not significantly improve any of these measures . For example it gained a mean of just 2.9 quality -adjusted life-days [ 95 % confidence interval ( CI ) from -12.7 to 7.0 days ] and saved a mean of just £ 48 ( 95 % CI from -£292 to £ 389 ) . In contrast it significantly reduced mental health scores on the SF-12 by 3.0 % ( 95 % CI from -5.2 % to -0.8 % ) . CONCLUSIONS The FolATED trial generated no evidence that folic acid was clinical ly effective or cost-effective in augmenting ADM . This negative finding is consistent with improving underst and ing of the one-carbon folate pathway suggesting that methylfolate is a better c and i date for augmenting ADM . Hence the findings of FolATED undermine treatment guidelines that advocate folic acid for treating depression , and suggest future trials of methylfolate to augment ADM . TRIAL REGISTRATION Current Controlled Trials IS RCT N37558856 . FUNDING This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment ; Vol . 18 , No. 48 . See the HTA programme website for further project information Abstract This double blind study investigated the reported potentiation of an MAO inhibitor by tryptophan . Twenty seriously depressed patients were placed on phenelzine sulfate . Half of these patients received supplements of tryptophan while the remainder received a placebo . Those receiving the tryptophan supplements showed significantly more improvement as measured by a modified version of the Hamilton scale . The possible pathways for the mediation of this tryptophan effect are discussed BACKGROUND Inositol has been reported to be an effective treatment in depression , and we hypothesized that inositol addition might enhance or speed up response to  serotonin selective reuptake inhibitors ( SSRI ) . METHODS Twenty-seven depressed patients completed a double-blind controlled 4-week trial of SSRI plus placebo or SSRI plus inositol .  Hamilton Depression Rating Scale was used as an assessment tool at baseline , and 1 , 2 , 3 , and 4 weeks . RESULTS No significant difference was found between the two treatment groups . CONCLUSIONS Previous studies combining different effective antidepressant therapies similarly found no evidence for additive effects [ e.g. , monoamine oxidase inhibitors ( MAOI ) plus tricyclic antidepressants ( TCA ) , TCA plus lithium ] . By contrast , augmentation by lithium or MAOI after a failed course of antidepressant treatment is effective and should be studied with inositol Objective : To compare therapeutic effects of eicosapentaenoic acid ( EPA ) , fluoxetine and a combination of them in major depression . Method : Sixty out patients with a diagnosis of major depressive disorder based on DSM-IV criteria and a score ≥15 in the 17-item Hamilton Depression Rating Scale ( HDRS )  were r and omly allocated to receive daily either 1000 mg EPA or 20 mg fluoxetine , or their combination for 8 weeks . Double dummy technique was used to double blind the study . Patients were assessed at 2 week intervals . Change in HDRS was the primary outcome measure . Results : Analysis of covariance for HDRS at week 8 across treatment groups was performed in 48 patients who completed at least 4 weeks of the study , with the last observation carried forward . Treatment , age of onset and baseline HDRS had a significant effect on HDRS at week 8 . EPA + fluoxetine combination was significantly better than fluoxetine or EPA alone from the fourth week of treatment . Fluoxetine and EPA appear to be equally effective in controlling depressive symptoms . Response rates ( ≥50 % decrease in baseline HDRS ) were 50 % , 56 % and 81 % in the fluoxetine , EPA and combination groups , respectively . Conclusions : In the present 8 week trial EPA and fluoxetine had equal therapeutic effects in major depressive disorder . EPA + fluoxetine combination was superior to either of them alone
target: Mixed results were found for zinc , folic acid , vitamin C , and tryptophan , with nonsignificant results for inositol .
  No major adverse effects were noted in the studies ( aside from minor digestive disturbance ) .
  A meta- analysis of adjunctive omega-3 versus placebo revealed a significant and moderate to strong effect in favor of omega-3 .
  Conversely , a meta- analysis of folic acid revealed a nonsignificant difference from placebo .
  Current evidence supports adjunctive use of SAMe , methylfolate , omega-3 , and vitamin D with antidepressants to reduce depressive symptoms
background: OBJECTIVE There is burgeoning interest in augmentation strategies for improving inadequate response to antidepressants .
  The adjunctive use of st and ardized pharmaceutical- grade nutrients , known as nutraceuticals , has the potential to modulate several neurochemical pathways implicated in depression .
  While many studies have been conducted in this area , to date no specialized systematic review ( or meta- analysis ) has been conducted .