A double blind, placebo-controlled pilot study of galantamine augmentation of antidepressant treatment in older adults with major depression. Reduced mania and depression in juvenile bipolar disorder associated with long-chain ω-3 polyunsaturated fatty acid supplementation Shortened onset of action of antidepressants in major depression using acetylsalicylic acid augmentation: a pilot open-label study Comparing augmentation with non-antidepressants over sticking to antidepressants after treatment failure in depression: a naturalistic study. A placebo-controlled comparison of lithium and triiodothyronine augmentation of tricyclic antidepressants in unipolar refractory depression. Omega-3 Fatty Acid Augmentation of Citalopram Treatment for Patients With Major Depressive Disorder Double-blind, placebo-controlled trial of the use of lithium to augment antidepressant medication in continuation treatment of unipolar major depression. Ultra-High-Frequency Left Prefrontal Transcranial Magnetic Stimulation as Augmentation in Severely Ill Patients with Depression: A Naturalistic Sham-Controlled, Double-Blind, Randomized Trial Augmenting antidepressants with deep transcranial magnetic stimulation (DTMS) in treatment-resistant major depression TREAD: TReatment with Exercise Augmentation for Depression: study rationale and design Pharmacological choices after one antidepressant fails: a survey of UK psychiatrists. Oxidative damage and major depression: the potential antioxidant action of selective serotonin re-uptake inhibitors Tricyclic antidepressants and tryptophan in unipolar depression. A double blind, randomized clinical trial assessing the efficacy and safety of augmenting standard antidepressant therapy with nimodipine in the treatment of 'vascular depression'. The efficacy of omega-3 supplementation for major depression: a randomized controlled trial. Serum concentrations of nerve growth factor and brain-derived neurotrophic factor in depressed patients before and after antidepressant treatment. Antidepressant effects of augmentative transcranial magnetic stimulation: randomised multicentre trial.
OBJECTIVE Depression in older adults is often associated with cognitive abnormalities and may predict later development of a primary cognitive disorder . This double-blind , r and omized , placebo-controlled pilot study was design ed to assess the safety and efficacy of galantamine augmentation of antidepressant treatment for depressive and cognitive symptoms in older adults with major depression . METHODS Thirty-eight , non-demented older adults ( age > 50 ) with major depression were r and omized to receive galantamine or placebo augmentation of st and ard antidepressant pharmacotherapy ( venlafaxine XR or citalopram ) .  Mood and cognitive status were monitored for 24 weeks using the 24-item Hamilton Rating Scale for Depression and the Repeatable Battery for the Assessment of Neuropsychological Status . RESULTS Both groups showed significant improvements in mood and cognition over 24 weeks , but no significant difference was found in change over time between groups . An exploratory post-hoc analysis suggested that patients r and omized to galantamine had lower depression scores compared to patients in the placebo group after 2 weeks of treatment . Dropout was high with more subjects r and omized to antidepressant plus galantamine  withdrawing early from the study . CONCLUSIONS This pilot study failed to demonstrate a benefit for galantamine augmentation of antidepressant medication in the treatment of depression in older adults . Future studies should explore strategies for reducing dropout in such longitudinal trials and more carefully assess time to response with cholinesterase inhibitor augmentation Long-chain ω-3 polyunsaturated fatty acid ( LCn-3PUFA ) supplementation may improve symptoms of depression in children and bipolar disorder ( BD ) in adults . No studies have examined the effectiveness of LCn-3PUFA supplementation in the treatment of mania and depression in juvenile BD ( JBD ) when given as an adjunct to st and ard pharmacological treatment . Eighteen children and adolescents with JBD received supplements containing 360 mg per day eicosapentaenoic acid ( EPA ) and 1560 mg per day docosahexaenoic acid ( DHA ) for 6 weeks in an open-label study . Intake and fasting red blood cell ( RBC ) LCn-3PUFA , mania , depression and global function were assessed before and after supplementation . RBC EPA and DHA were significantly higher following supplementation . Clinician ratings of mania and depression were significantly lower and global functioning significantly higher after supplementation . Parent ratings of internalizing and externalizing behaviours were also significantly lower following supplementation . A larger r and omized controlled trial appears warranted in this participant population Based on our pre clinical data showing a potential accelerating effect of acetylsalicylic acid ( ASA ) in combination with fluoxetine in an animal model of depression , we examined the effect of ASA augmentation therapy on selective reuptake inhibitors ( SSRI ) in major depressed non-responder patients . Twenty-four non-responder patients having received at least 4 weeks of an adequate SSRI treatment were included in a pilot open-label study . Participants were treated openly during 4 weeks with 160 mg/day ASA in addition to their current antidepressant treatment . The combination SSRI – ASA was associated with a response rate of 52.4 % . Remission was achieved in 43 % of the total sample and 82 % of the responder sample . In the responder group , a significant improvement was observed within week 1 ( mean Hamilton Depression Rating Scale-21 items at day 0=29.3±4.5 , at day 7=14.0±4.1 ; P<0.0001 ) and remained sustained until day 28 . Despite limitations due to the open nature of this study , our preliminary results confirm our pre clinical findings and are in favour of an accelerating effect  of ASA in combination with SSRIs in the treatment of major depression . Potential physiological and biochemical mechanisms may involve an anti-inflammatory and /or neurotrophic effect INTRODUCTION Non-response to an antidepressant monotherapy in unipolar depression is quite common . Therefore strategies for subsequent treatment steps are necessary . However , there is a lack of direct comparisons of these different strategies . In this naturalistic study we compared the outcome to different strategies after failure of the primary antidepressant treatment . METHODS Failure of primary antidepressant monotherapy occurred in 135 patients . 98 of these patients have been administered 4 treatment strategies of the physicians ' choice : lithium augmentation ( Li-Augm ) , switching to another antidepressant ( AD-Switch ) , combination of 2 antidepressants ( AD-Comb ) or augmentation with second generation antipsychotic ( SGA-Augm ) . Primary outcome measure was the 17-item Hamilton rating scale for depression ( HRSD ) . RESULTS Patients who received Li-Augm or augmentation with SGAs showed significantly greater improvement in HRSD and BDI compared to patients with antidepressant switch or antidepressant combination . Remission rates for Li-Augm and SGA-Augm were 89.3 % and 86.2 % compared to 40.7 % for AD-Switch and 42.9 % for AD-Comb . DISCUSSION Changing to another pharmacological class ( Li-Augm or augmentation with SGAs ) showed better treatment results than sticking to the class of antidepressants ( AD-Switch and AD-Comb ) after primary failure in response to antidepressant monotherapy in unipolar depression . The lack of r and omization and absence of a non-response definition are design flaws . Controlled studies are required to confirm the findings of this trial OBJECTIVE To directly compare the efficacy of lithium carbonate and liothyronine sodium ( triiodothyronine ) in the augmentation of therapeutic response in antidepressant nonresponders . DESIGN A r and omized , double-blind , placebo-controlled study of 2 weeks ' duration . SETTING The Mood Disorders Program , Clarke Institute of Psychiatry and the University of Toronto , Ontario . PATIENTS Fifty out patients , males and females , with unipolar , nonpsychotic major depression who had failed to respond to treatment with desipramine hydrochloride or imipramine hydrochloride .  RESULTS Both liothyronine and lithium were more effective than placebo in reducing scores on the Hamilton Rating Scale for Depression . However , the antidepressant augmenting effect of these two compounds did not differ from each other . When response was defined as a 50 % or more reduction in the Hamilton Rating Scale for Depression scores and a final score less than 10 , we found that 10 of 17 subjects responded to liothyronine , nine of 17 responded to lithium and three of 16 responded to placebo . CONCLUSIONS Our study suggests that both lithium and liothyronine may be considered as alternatives in augmenting antidepressant response in patients who do not respond to treatment with a tricyclic antidepressant 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 OBJECTIVE Use of lithium to augment antidepressant medication has been shown to be beneficial in the acute treatment of depression . The authors examined the efficacy of lithium augmentation in the continuation treatment of unipolar major depressive disorder . METHOD Thirty patients with a refractory major depressive episode who had responded to acute lithium augmentation during an open 6-week study participated in a r and omized , parallel-group , double-blind , placebo-controlled trial of lithium augmentation during continuation treatment . After a 2 - 4-week stabilization period following remission , patients were r and omly assigned to receive either lithium or placebo for a 4-month period . Antidepressant medication was continued throughout the study . RESULTS Relapses ( including one suicide ) occurred in seven ( 47 % ) of the 15 patients who received placebo in addition to antidepressants . None ( 0 % ) of the 14 patients who received lithium augmentation with antidepressants suffered a relapse during the double-blind phase of the study . Five of the seven relapsing patients in the placebo group developed a depressive episode , and the other two experienced a manic episode . CONCLUSIONS Lithium augmentation in the continuation phase of treatment of unipolar major depressive disorder effectively protects patients against a relapse .  Patients who respond to lithium augmentation  should be maintained on lithium augmentation for a minimum of 6 months or even longer Background and Aim : Repetitive transcranial magnetic stimulation ( rTMS ) is supposed to be not as effective in severe depression as it is in medium depression . We evaluated the treatment response to an ultra-high-frequency ( UHF ; 30 Hz ) approach , which was used to maximize the rTMS efficacy in severely ill patients . Methods : 43 severely depressed patients were included in the r and omized , double-blind study and received either rTMS with 30 Hz over the left dorsolateral prefrontal cortex or sham condition for 3 weeks as an add-on therapy to stable antidepressant medication .  Hamilton Depression Rating Scale ( HDRS ) and cognitive performance were evaluated before and after the intervention . Results : In the active UHF group , the HRDS score was reduced by about 7.2 , whereas the sham condition showed a smaller reduction of the HDRS score with 3.9 . However , lithium as a covariant was responsible for the outcome difference , not the group of stimulation . No adverse events were reported . Comparing the differences of both groups in the pre- and post- study performance in a trail-making test , a group effect for the UHF group that was not influenced by the lithium intake was observed . Conclusion : A 30-Hz left prefrontal rTMS in severely depressed patients was safe and no adverse events occurred . Due to a strong effect of lithium as a covariate , we could not demonstrate favorable antidepressant effects of the UHF stimulation compared to sham . However , we found an improvement of processing speed performance in the UHF group , which covaried with improvement of psychomotor retardation Abstract Objectives . Deep transcranial magnetic stimulation ( DTMS ) has been shown to be efficacious and relatively safe for major depressive disorder ( MDD ) . However , its clinical utility as an augmenting strategy for treatment-resistant depression ( TRD ) remains unexplored . Methods . In an open label trial , 17 out patients with severe TRD received 4 weeks of daily high frequency DTMS over the left dorsolateral prefrontal cortex . Depressive and anxious symptoms , suicidality and quality of life ( QOL ) were measured at baseline ( i.e. , in the week prior to the start of the DTMS treatment ) and at week 5 ( i.e. , in the week following the end of the DTMS treatment ) . Primary outcome measures were rates of response and remission at week 5 using an intention-to-treat approach . Results . Response and remission rates at week 5 were 70.6 and 41.2 % , respectively . Also , depression , anxiety , and suicidality ratings were significantly improved by week 5 ( with Hedges ’ g estimates ranging from 0.6 to 1.72 ) , as well as four of the five QOL domain scores ( i.e. , global , psychological , environmental and social ) . Finally , two patients dropped out of the study at week 1 because of significant scalp discomfort during stimulation . Conclusions . Our study suggests that DTMS , when used as an augmenting strategy for antidepressants in severe TRD , is efficacious , safe and relatively well tolerated . However , controlled studies with larger sample s are needed to confirm and exp and our preliminary findings Background Despite recent advancements in the pharmacological treatment of major depressive disorder ( MDD ) , over half of patients who receive treatment with antidepressant medication do not achieve full remission of symptoms . There is evidence that exercise can reduce depressive symptomatology when used as a treatment for MDD . However , no r and omized controlled trials have evaluated exercise as an augmentation strategy for patients with carefully diagnosed MDD who remain symptomatic following an adequate acute phase trial of antidepressant therapy . Purpose TReatment with Exercise Augmentation for Depression  ( TREAD ) is an NIMH-funded , r and omized , controlled trial design ed to assess the relative efficacy of two doses of aerobic exercise to augment selective serotonin reuptake inhibitor ( SSRI ) treatment of MDD . Methods The TREAD study includes 12 weeks of acute phase treatment with a 12-week post-treatment follow-up . In addition to looking at change in depressive symptoms as a primary outcome , it also includes comprehensive assessment of psychosocial function and treatment adherence . Results This paper review s the rationale and design of TREAD and illustrates how we address several key issues in contemporary patient-oriented research on MDD : 1 ) the use of augmentation strategies in the treatment of depressive disorders in general , 2 ) the use of non-pharmacological strategies in the treatment of depressive disorders , 3 ) the considerations of design ing a well-controlled trial using two active treatment groups , and 4 ) the implementation of an adherence program for the use of exercise as a treatment strategy . Conclusions The TREAD study is uniquely design ed to overcome sources of potential bias and threats to internal and external validity that have limited prior research on the mental health effects of exercise . The study is facilitated by the development of a multidisciplinary research team that includes experts in both depression treatment and exercise physiology , as well as other related fields BACKGROUND At least 30 % of depressed patients fail to respond to adequate first-line anti-depressant medication . Several pharmacological strategies have been suggested to treat such refractory depression . There has been no survey of United Kingdom psychiatrists ' treatment preferences for refractory depression . This study was carried out to determine both experience and preference of various strategies for management of refractory depression . METHOD A total of 300 fellows , members and inceptors of the Royal College of Psychiatrists were r and omly selected and approached by postal question naire . They were asked to comment on management of a detailed clinical vignette of a case of depression with initial treatment failure . RESULTS The response rate was 63 % ( n = 175 ) . The most popular treatment choices were increasing dosage of tricyclic medication and change of medication of SSRI . The most rarely selected were augmentation with triiodothyronine ( T3 ) and augmentation with tryptophan or MAOIs .  Treatment choice was significantly influenced by previous experience . A large number ( 39 % ) of psychiatrists were not confident in treating refractory depression . CONCLUSION Surprisingly few psychiatrists chose to use the best proven pharmacological treatments such as augmentation with lithium or T3 . In view of this and the considerable proportion of psychiatrists lacking confidence in the management of refractory depression , this topic deserves priority as a topic for continuing professional development ( CPD ) courses Abstract There is evidence of derangement of oxidant and antioxidant defense systems in depression . The present study examined the effects of fluoxetine and citalopram , st and ard selective serotonin re-uptake inhibitors , on lipid peroxidation , superoxide dismutase ( SOD ) activity and ascorbic acid concentrations . For this , a prospect i ve open-labeled , r and omized design was utilized . Patients with major depression ( n = 62 ) were compared with age- and sex-matched healthy volunteers ( n = 40 ) . There was a significant increase in serum SOD , serum MDA and decrease in plasma ascorbic acid levels in patients of major depression as compared to control subjects . The trend reversed significantly after treatment with fluoxetine and citalopram . Results indicate a greater reduction in oxidative stress with citalopram than fluoxetine . The Hamilton Rating Scale for Depression ( HRSD ) score also improved with fluoxetine and citalopram treatment . These findings indicate that major depression is associated with increased levels of serum SOD , serum MDA and decreased levels of plasma ascorbic acid . Treatment with fluoxetine and citalopram reversed these biochemical parameters . This study can be used as a predictor of drug response by fluoxetine and citalopram in major depression 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 BACKGROUND ' Vascular depression ' may be caused by cerebrovascular disease . Calcium channel blockers , which are putative treatments for cerebrovascular disease , might be expected to improve depression reduction and to prevent recurrence of depression in this patient population . This clinical trial was design ed to test these hypotheses . DESIGN This was a controlled , double blind , r and omized clinical trial in which 84 patients with vascular depression ( Alexopoulos criteria ) were treated with antidepressants at st and ard doses . Patients were also r and omized to  nimodipine  ( n = 40 ) or an inactive comparator , vitamin C ( n = 44 ) . Treatment outcomes were assessed using the Hamilton depression rating scale ( HDRS ) regularly up to 300 days after treatment initiation . RESULTS As expected , depression reduction was successful in most patients . In addition , those treated with nimodipine plus an antidepressant had greater improvements in depression overall in repeated measures ANCOVA ( F(1,81 ) = 8.64 , p = 0.004 ) . As well a greater proportion of nimodipine-treated participants ( 45 versus 25 % ) exhibited a full remission ( HDRS < or = 10 ) ( chi(2)(df , 1 ) = 3.71 , p = 0.054 ) . Among those experiencing a substantial response in the first 60 days ( 50 % reduction in HDRS ) , fewer patients on nimodipine ( 7.4 % ) had a recurrence of major depression when compared to those on antidepressant alone ( 32 % ) ( chi(2)(df , 1 ) = 3.59 , p = 0.058 ) . CONCLUSIONS In treating vascular depression , augmentation of antidepressant therapy with a calcium-channel blocker leads to greater depression reduction and lower rates of recurrence . These findings support the argument that cerebrovascular disease is involved in the pathogenesis and recurrence of depression in these patients OBJECTIVE To document the short-term efficacy of omega-3 supplementation in reducing depressive symptoms in patients experiencing a major depressive episode ( MDE ) . METHOD Inclusive , double-blind , r and omized , controlled , 8-week , parallel-group trial , conducted October 17 , 2005 through January 30 , 2009 in 8 Canadian academic and psychiatric clinics . Adult out patients ( N = 432 ) with MDE ( Mini-International Neuropsychiatric Interview , version 5.0.0 , criteria ) lasting at least 4 weeks , including 40.3 % taking antidepressants at baseline , were r and omly assigned to 8 weeks of 1,050 mg/d of eicosapentaenoic acid ( EPA ) and 150 mg/d of docosahexaenoic acid ( DHA ) or matched sunflower oil placebo ( 2 % fish oil ) . The primary outcome was the self-report Inventory of Depressive Symptomatology ( IDS-SR(30 ) ) ; the secondary outcome was the clinician-rated Montgomery-Åsberg Depression Rating Scale ( MADRS ) . RESULTS The adjusted mean difference between treatment and placebo was 1.32 points ( 95 % CI , -0.20 to 2.84 ; P = .088 ) on the IDS-SR(30 ) and 0.97 points ( 95 % CI , -0.012 to 1.95 ; P = .053 ) on the MADRS . Planned subgroup analyses revealed a significant interaction of comorbid anxiety disorders and study group ( P = .035 ) . For patients without comorbid anxiety disorders ( n = 204 ) , omega-3 supplementation was superior to placebo , with an adjusted mean difference of 3.17 points on the IDS-SR(30 ) ( 95 % CI , 0.89 to 5.45 ; P = .007 ) and 1.93 points ( 95 % CI , 0.50 to 3.36 ; P = .008 ) on the MADRS . CONCLUSIONS In this heterogeneous sample of patients with MDE , there was only a trend toward superiority of omega-3 supplementation over placebo in reducing depressive symptoms . However , there was a clear benefit of omega-3 supplementation among patients with MDE without comorbid anxiety disorders . TRIAL REGISTRATION controlled-trials.com Identifier : IS RCT N47431149 INTRODUCTION Stress , glucocorticoids and anti-depressant treatment have been found to modulate the expression of brain-derived neurotrophic factor ( BDNF ) and nerve growth factor ( NGF ) . Recent research suggests that serum BDNF concentration is reduced in depression and that successful antidepressant treatment leads to an increase in serum BDNF concentration . METHODS We studied depressed patients receiving a st and ardized antidepressant treatment with either 150 mg amitriptyline ( n=20 ) or 40 mg paroxetine ( n=20 ) for 36 days in a prospect i ve design . Changes in the concentrations of serum neurotrophins and salivary cortisol in response to antidepressant treatment were assessed . RESULTS Independent of clinical efficacy there was a significant ' treatment ' by ' medication ' interaction effect on BDNF serum concentrations that indicated a decline of BDNF by 12 % in paroxetine-treated patients while there was an increase by 13 % in amitriptyline-treated patients . Neither antidepressant altered NGF concentrations . The changes in cortisol and neurotrophin concentrations were not related . DISCUSSION Changes in BDNF serum concentrations as a result of antidepressant therapy depend on the antidepressant instead of being a general characteristic of response to antidepressant treatment BACKGROUND Repetitive transcranial magnetic stimulation ( rTMS ) has been proposed as a new treatment option for depression . Previous studies were performed with low sample sizes in single centres and reported heterogeneous results . AIMS To investigate the efficacy of rTMS as augmentative treatment in depression . METHOD In a r and omised , double-blind , sham-controlled multicentre trial 127 patients with moderate to severe depressive episodes were r and omly assigned to real or sham stimulation for 3 weeks in addition to simultaneously initiated antidepressant medication . RESULTS We found no difference in the responder rates of the real and the sham treatment groups ( 31 % in each ) or in the decrease of the scores on the depression rating scales . CONCLUSIONS The data do not support previous reports from smaller sample s indicating an augmenting or accelerating antidepressant effect of rTMS . Further exploration of the possible efficacy of other stimulation protocol s or within selected sub- population s of patients is necessary
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
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 .