Treatments for Poststroke Motor Deficits and Mood Disorders: A Systematic Review for the 2019 U.S. Department of Veterans Affairs and U.S. Department of Defense Guidelines for Stroke Rehabilitation A Review of Vilazodone, Serotonin, and Major Depressive Disorder Efficacy outcomes from 3 clinical trials of edivoxetine as adjunctive treatment for patients with major depressive disorder who are partial responders to selective serotonin reuptake inhibitor treatment. Controlled withdrawal of selective serotonin reuptake inhibitor drugs in elderly patients in nursing homes with no indication of depression Ziprasidone augmentation of selective serotonin reuptake inhibitors (SSRIs) for SSRI-resistant major depressive disorder. Lack of sexual dysfunction with the selective noradrenaline reuptake inhibitor reboxetine during treatment for major depressive disorder A pragmatic 12-week, randomized trial of duloxetine versus generic selective serotonin-reuptake inhibitors in the treatment of adult outpatients in a moderate-to-severe depressive episode Effects of Zinc Supplementation in Patients with Major Depression: A Randomized Clinical Trial Placebo-controlled comparison of the selective serotonin reuptake inhibitors citalopram and sertraline Bupropion as an augmenting agent in patients of depression with partial response. Cardiac side‐effects of two selective serotonin reuptake inhibitors in middle- aged and elderly depressed patients A double-blind, placebo-controlled study of edivoxetine as an adjunctive treatment for patients with major depressive disorder who are partial responders to selective serotonin reuptake inhibitor treatment. A randomised, double-blind study in adults with major depressive disorder with an inadequate response to a single course of selective serotonin reuptake inhibitor or serotonin–noradrenaline reuptake inhibitor treatment switched to vortioxetine or agomelatine† Cost-effectiveness of selective serotonin reuptake inhibitors and routine specialist care with and without cognitive behavioural therapy in adolescents with major depression. The serotonin transporter polymorphism, 5HTTLPR, is associated with a faster response time to sertraline in an elderly population with major depressive disorder Efficacy and Tolerability of Reboxetine Compared with Citalopram: A Double-blind Study in Patients with Major Depressive Disorder L-methylfolate as adjunctive therapy for SSRI-resistant major depression: results of two randomized, double-blind, parallel-sequential trials. Further evidence of a combined effect of SERTPR and TPH on SSRIs response in mood disorders Effects of selective serotonin reuptake and dual serotonergic-noradrenergic reuptake treatments on memory and mental processing speed in patients with major depressive disorder. Fluoxetine treatment of patients with major depressive disorder who failed initial treatment with sertraline. IL-6 levels decrease with SSRI treatment in patients with major depression. Safety and Tolerability of Dexmecamylamine (TC-5214) Adjunct to Ongoing Antidepressant Therapy in Patients With Major Depressive Disorder and an Inadequate Response to Antidepressant Therapy: Results of a Long-Term Study Treatment of residual anxiety symptoms with adjunctive aripiprazole in depressed patients taking selective serotonin reuptake inhibitors.
Background Early rehabilitation after stroke is essential to help reduce disability . Purpose To summarize evidence on the benefits and harms of nonpharmacologic and pharmacologic treatments for motor deficits and mood disorders in adults who have had stroke . Data Sources English- language search es of multiple electronic data bases from April 2009 through July 2018 ; targeted search es to December 2018 for studies of selective serotonin reuptake inhibitors ( SSRIs ) or serotonin-norepinephrine reuptake inhibitors . Study Selection 19 systematic review s and 37 r and omized controlled trials addressing therapies for motor deficits or mood disorders in adults with stroke . Data Extraction One investigator abstract ed the data , and quality and GRADE assessment were checked by a second investigator . Data Synthesis Most interventions ( for example , SSRIs , mental practice , mirror therapy ) did not improve motor function . High- quality evidence did not support use of fluoxetine to improve motor function . Moderate- quality evidence supported use of cardiorespiratory training to improve maximum walking speed and repetitive task training or transcranial direct current stimulation to improve activities of daily living ( ADLs ) . Low- quality evidence supported use of robotic arm training to improve ADLs . Low- quality evidence indicated that antidepressants may reduce depression , whereas the frequency and severity of antidepressant-related adverse effects was unclear . Low- quality evidence suggested that cognitive behavioral therapy and exercise , including mind-body exercise , may reduce symptoms of depression and anxiety . Limitation Studies were of poor quality , interventions and comparators were heterogeneous , and evidence on harms was scarce . Conclusion Cardiorespiratory training , repetitive task training , and transcranial direct current stimulation may improve ADLs in adults with stroke .  Cognitive behavioral therapy , exercise , and SSRIs may reduce symptoms of poststroke depression , but use of SSRIs to prevent depression or improve motor function was not supported . Primary Funding Source U.S. Department of Veterans Affairs , Veterans Health Administration Objective : To review the mechanism of selective serotonin reuptake inhibitor (SSRI)–mediated serotonergic neurotransmission , focusing on serotonin 1A ( 5-HT1A ) autoreceptors , which are proposed to be involved in delaying therapeutic efficacy . Vilazodone was specifically design ed to function both as an SSRI and a partial agonist at 5-HT1A receptors . This combined mechanism is proposed to decrease time to efficacy , minimize sexual side effects , and provide concomitant anxiolytic properties . Data Sources : A PubMed search of all English- language articles from January 1990 to January 2013 was conducted using the search terms depression and 5-HT1A , depression and buspirone , depression and pindolol , and vilazodone . Study Selection : We found 47 articles and abstract s that were selected for inclusion on the basis of information about the pharmacology of 5-HT1A receptors and the clinical data on pindolol , buspirone , and vilazodone in depression . Data Extraction : This review summarizes current literature involving antidepressant activity , the role of 5-HT1A autoreceptors , and clinical trials involving serotonin reuptake inhibition in conjunction with 5-HT1A agonists and partial agonists , with a focus on vilazodone . Results : Vilazodone has demonstrated efficacy in 2 large , r and omized , double-blind , placebo-controlled trials in major depressive disorder . Results suggest that vilazodone has a low incidence of sexual side effects and is effective in patients with high levels of anxiety . A pooled analysis shows evidence of significant symptom reduction after only 1 week of therapy . Conclusions : If future studies corroborate the clinical benefits attributed to its mechanism of action , vilazodone may show potential advantages in terms of onset of action , sexual side effects , and anxiolytic activity in patients with major depressive disorder OBJECTIVE Three studies examined whether edivoxetine ( a highly selective norepinephrine reuptake inhibitor ) had efficacy as adjunctive therapy for patients with major depressive disorder ( DSM-IV-TR ) who were partial responders to selective serotonin reuptake inhibitor ( SSRI ) treatment of at least 6 weeks ' duration . METHOD Studies were 8-week r and omized , placebo-controlled trials with a 3-week double-blind placebo lead-in phase , conducted from December 16 , 2010 , to October 21 , 2013 . Patients entered the double-blind adjunctive treatment phase if they met r and omization criteria ( < 25 % improvement on  Montgomery-Asberg Depression Rating Scale  [  MADRS  ] and  MADRS total score ≥ 14 ) ; patients not r and omized remained on adjunctive placebo . Study 1 compared fixed-dose edivoxetine ( 12 or 18 mg daily ) + SSRI ( N = 231 and N = 230 , respectively ) with placebo + SSRI ( N = 240 ) ; study 2 compared flexible-dose edivoxetine ( 12 - 18 mg daily ) + SSRI ( N = 232 ) and fixed-dose edivoxetine ( 6 mg daily ) + SSRI ( N = 226 ) with placebo + SSRI ( N = 231 ) ; and study 3 compared flexible-dose edivoxetine ( 12 - 18 mg daily ) + SSRI ( N = 230 ) with placebo + SSRI ( N = 219 ) . The primary outcome was mean change from r and omization baseline to week 8 in MADRS total score , analyzed using repeated measures analysis . RESULTS Each trial failed to meet the primary and most of the secondary objectives . The least-squares mean changes in MADRS total score were as follows- study 1 : -8.5 ( edivoxetine 12 mg + SSRI ) , -8.7 ( edivoxetine 18 mg + SSRI ) , and -7.8 ( placebo + SSRI ) ; study 2 : -9.4 ( edivoxetine 12 - 18 mg + SSRI ) , -9.6 ( edivoxetine 6 mg + SSRI ) , and -9.4 ( placebo + SSRI ) ; and study 3 : -8.7 ( edivoxetine 12 - 18 mg + SSRI ) and -8.5 ( placebo + SSRI ) . CONCLUSIONS Adjunctive edivoxetine treatment for patients with major depressive disorder who were partial responders to SSRIs did not significantly improve efficacy outcomes . TRIALS REGISTRATION S Clinical Trials.gov identifiers : NCT01173601 , NCT01187407 , NCT01185340 Objective The aim of the investigation was to study the effects of withdrawing selective serotonin reuptake inhibitor ( SSRI ) drugs in nursing home patients , who had no documented diagnosis or symptoms of depression . Setting The setting of the study was in 11 nursing homes in the county of Stockholm , Sweden . Participants Participants were patients without dementia or history of depression who had received treatment with SSRI drugs for more than 6 months and who had no indications of anxiety disorder or major depression Design The included patients ( n=70 ) were r and omized to either the intervention group  ( withdrawal of SSRI ) or the control group  ( no change in treatment ) , 35 patients to each group . Main outcome measures The patients were subjected to assessment using the following instruments : Montgomery-Åsberg depression rating scale , global assessment for functioning , health index and a symptom assessment form . Assessment was made at the start of the study and at the 3-month and 6-month follow-ups . Results We found no significant difference between the intervention and control groups in any outcome measure . Conclusion Treatment with SSRI drugs in patients without clinical major depression or anxiety disorder is often unjustified and should be discontinued BACKGROUND Due to their favorable side-effect profile , atypical antipsychotic agents offer important therapeutic advantages in mood disorders .  Ziprasidone , an atypical antipsychotic agent with strong 5-HT(1A ) agonist activity , may be particularly useful when used in conjunction with st and ard antidepressants in treatment-resistant depression . The purpose of this study is to test this hypothesis in depressed out patients who have not experienced significant clinical improvement following an adequate trial of a selective serotonin reuptake inhibitor ( SSRI ) . METHOD Twenty patients with major depressive disorder ( MDD ) who had failed to experience a clinical response to an adequate trial of an SSRI were treated with open-label ziprasidone in addition to their SSRI for 6 weeks between February 2002 and December 2002 . MDD was diagnosed with the Structured Clinical Interview for DSM-IV Axis I disorders . Clinical response was defined as a 50 % or greater decrease in depressive symptoms during the course of the trial ( baseline to endpoint ) , as measured by the HAM-D-17 total score . RESULTS Thirteen of 20 patients ( 65.0 % ) completed the trial . Using a completer analysis , 8 patients ( 61.5 % ) were classified as responders . An intent-to-treat ( ITT ) analysis result ed in 10 responders ( 50.0 % ) . The overall proportion of remitters was 5 of 13 ( 38.5 % ) using a completer analysis and 5 of 20 ( 25.0 % ) using the ITT analysis . Ziprasidone administration appeared to be safe , with no clinical ly significant QTc prolongation or severe adverse events observed in any of the study participants . CONCLUSION These results suggest a possible augmentation role for ziprasidone when used in conjunction with SSRIs in SSRI-resistant MDD & NA ; Sexual side‐effects due to antidepressant treatment are an important consideration when selecting a treatment regimen and can influence patient compliance . Sexual function during treatment with the selective noradrenaline reuptake inhibitor reboxetine , the selective serotonin reuptake inhibitor ( SSRI ) fluoxetine and placebo has been assessed in a multicentre , r and omized , 8‐week , double‐blind study of 450 patients diagnosed with major depressive disorder .  Sexual function was measured by the Rush Sexual Inventory completed by male and female patients and administered at baseline , week 4 and week 8 . The results indicate that reboxetine was similar to placebo and superior to fluoxetine in its effect on overall sexual function . There was a greater degree of sexual satisfaction in the reboxetine group compared to fluoxetine ( P = 0.02 ) . The percentage of female patients able to achieve orgasm increased during the study period for women who received reboxetine and placebo , but decreased for those who received fluoxetine . These results suggest that reboxetine may be of particular benefit for patients at risk for sexual dysfunction with SSRIs Some evidence suggests that medications that modulate both serotonin and norepinephrine may be more effective than selective serotonin-reuptake inhibitors ( SSRIs ) in severe major depressive disorder ( MDD ) . This prospect i ve pragmatic trial tests this hypothesis . Patients with severe MDD were r and omly assigned to either duloxetine ( a serotonin and norepinephrine-reuptake inhibitor ) or physicians ’ choice of four generic SSRIs . Nonblinded , flexibly dosed treatment was used to mimic clinical practice . To address potential investigator bias , the patient-reported Quick Inventory of Depressive Symptomatology Self-Report ( QIDS-SR ) was used as the primary efficacy outcome measure . A total of 750 out patients ( 19.2 % , African descent ; 14.8 % , Hispanic ) were r and omized . The primary outcome , remission at week 12 by QIDS-SR , was numerically greater for duloxetine compared with SSRIs ( 36 vs. 32 % ) , but this difference was not statistically significant . Mean changes in secondary outcomes were significantly superior in favor of duloxetine for the Hamilton Depression Scale-17 item , the Brief Pain Inventory , and the Sheehan Disability Scale . Remission superiority on the QIDS-SR was not achieved . Significantly greater benefit for duloxetine compared with SSRIs was demonstrated on measures of pain and functioning . Study demographics suggest a more generalizable racial and ethnic population than is typical in r and omized clinical trials 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 Previous comparative studies of the selective serotonin reuptake inhibitors ( SSRIs ) have rarely included a placebo control group and have rarely demonstrated significant between-group differences . The study reported on here was a placebo-controlled comparison of the antidepressant effects of two SSRIs , citalopram and sertraline . METHODS Three hundred twenty-three patients with DSM-IV-defined major depressive disorder were r and omized to 24 weeks of double-blind treatment with citalopram ( 20 - 60 mg/day ) , sertraline ( 50 - 150 mg/day ) , or a placebo . The primary efficacy measure was the Hamilton Depression Rating Scale ( HAMD ) and the primary statistical analysis was an analysis of variance comparing the change from baseline to the last observation carried forward in each treatment group . RESULTS Both citalopram and sertraline produced significantly greater improvement than placebo on the HAMD , the Montgomery-Asberg Depression Rating Scale , and the Clinical Global Impression Scale . Significant improvement was observed at earlier timepoints in the citalopram group than the sertraline group ; however , sertraline treatment was associated with increased gastrointestinal side effects and a tendency toward early discontinuation , and analyses that excluded early dropouts revealed similar acute efficacy for the two active treatments . The Hamilton Anxiety Scale demonstrated a significant anxiolytic effect of citalopram , but not sertraline , relative to placebo . CONCLUSIONS This study confirms the antidepressant efficacy of two SSRIs , citalopram and sertraline . It is hypothesized that the more consistent evidence of antidepressant activity that was observed early in treatment in the citalopram group was related to more pronounced antianxiety effects and better tolerability upon initiation of therapy The objective of this study is to evaluate the effects of bupropion as an add-on therapy to selective serotonin reuptake inhibitor ( SSRI ) on patients of major depressive disorder with partial response . This prospect i ve , r and omized , controlled and single-blind study was conducted in sixty patients suffering from major depressive disorder as per Diagnostic and Statistical Manual (DSM)-IV TR criteria , who were having Hamilton depression rating scale ( HDRS ) score ≥16 after 4 weeks of treatment with SSRIs . Group A received SSRI plus placebo and group B received SSRI plus bupropion . Evaluation was performed based on changes in HDRS score , Montgomery and Asberg depression rating scale ( MADRS ) , Amritsar depressive inventory ( ADI ) and spontaneously reported adverse effects . There was a significant decrease in the HDRS , MADRS and ADI scores as compared to baseline in both groups . However , the mean decrease in depression score was more in group B than in group A. The percentage decrease of remitters was also significantly more in group B ( 60 % as per HDRS score and 63 % as per MADRS score ) , as compared to group A ( 24 % as per HDRS score and 27 % as per MADRS score ) ( p < 0.05 ) , at the end of treatment . In conclusion , bupropion add-on can act as augmenting agent in patients of depression with partial response to SSRIs Selective serotonin reuptake inhibitors ( SSRIs ) are the ‘ new ’ drugs of first choice for the treatment of depression in the older patient . Systematic studies on the effects of SSRIs on cardiac function are scarce , despite the high prevalence of cardiac disorders in the older depressed patient . This is a study which systematic ally assesed cardiac function by echo-cardiography in middle-aged and elderly depressed patients treated with SSRI . In a double-blind r and omized trial , 20 patients were assigned to receive fluvoxamine 20 mg/day or fluoxetine 100mg/day for 6 weeks . Cardiac function was assessed by left ventricle ejection fraction , aortic flow integral and early or passive/late or active mitral inflow , and electrocardiography . Neither SSRI significantly affected cardiac function . Compared with patients without a history of myocardial infa rct ion and /or hypertension , patients with such a history showed a significant improvement in left ventricular ejection fraction . Despite our small study sample , these data indicate that both fluoxetine and fluvoxamine do not affect cardiac function adversely BACKGROUND This phase 2 study examined the efficacy and tolerability of edivoxetine , a highly selective norepinephrine reuptake inhibitor , as an adjunctive treatment for patients with major depressive disorder ( MDD ) who have a partial response to selective serotonin reuptake inhibitor ( SSRI ) treatment . METHODS Study design consisted of double-blind , 10-week therapy of adjunctive edivoxetine ( 6 - 18 mg once daily ) or adjunctive placebo with SSRI .  Inclusion /entry criteria included partial response to current SSRI by investigator opinion and a GRID 17-item Hamilton Rating Scale for Depression ( HAMD17 ) total score ≥16 . The primary efficacy measure was the Montgomery-Asberg Depression Rating Scale ( MADRS ) . Safety measures included treatment-emergent adverse events ( TEAE ) and vital signs . RESULTS For the primary evaluable population ( n=63 for adjunctive edivoxetine and n=68 for adjunctive placebo ) , the treatment groups did not differ significantly on the primary outcome of change from baseline to week 8 in the MADRS total score ; the effect size of edivoxetine treatment was 0.26 . Significant treatment differences , favoring adjunctive edivoxetine ( p≤.05 ) , were shown for improvements in role functioning and the functional impact of fatigue . For the adjunctive edivoxetine r and omized group ( N=111 ) , the most frequent TEAEs were hyperhidrosis ( 7.2 % ) , nausea ( 7.2 % ) , erectile dysfunction ( 6.3 % ) and testicular pain ( 6.3 % ) . Hemodynamic changes were observed in blood pressure and pulse rate between treatment groups . LIMITATIONS Study was underpowered for an alpha 2-sided 0.05 significance level for the primary outcome . CONCLUSIONS For patients with MDD who had a partial response to SSRIs  , adjunctive edivoxetine treatment was not statistically superior to adjunctive placebo on the primary outcome measure . However , pending further study , improved functioning and remission rate suggest a potential role for edivoxetine for patients with depression Objective This r and omised , double-blind , 12-week study compared efficacy and tolerability of flexible-dose treatment with vortioxetine ( 10–20 mg/day ) versus agomelatine ( 25–50 mg/day ) in major depressive disorder patients with inadequate response to selective serotonin reuptake inhibitor (SSRI)/serotonin – noradrenaline reuptake inhibitor ( SNRI ) monotherapy . Methods Patients were switched directly from SSRI/SNRI to vortioxetine or agomelatine . Primary endpoint was change from baseline to week 8 in the Montgomery – Åsberg Depression Rating Scale ( MADRS ) total score analysed by mixed model for repeated measurements , using a noninferiority test followed by a superiority test . Secondary endpoints included response and remission rates , anxiety symptoms ( Hamilton Anxiety Rating Scale ) , Clinical Global Impression , overall functioning ( Sheehan Disability Scale ) , health-related quality of life ( EuroQol 5 Dimensions ) , productivity ( work limitation question naire ) and family functioning ( Depression and Family Functioning Scale ) . Results Primary endpoint noninferiority was established and vortioxetine ( n = 252 ) was superior to agomelatine ( n = 241 ) by 2.2 MADRS points ( p < 0.01 ) . Vortioxetine was also significantly superior in response and remission rates at weeks 8 and 12 ; MADRS , Hamilton Anxiety Rating Scale , Clinical Global Impression , Sheehan Disability Scale and EuroQol 5 Dimensions scores at week 4 onwards ; work limitation question naire at week 8 and Depression and Family Functioning Scale at weeks 8 and 12 . Fewer patients withdrew because of adverse events with vortioxetine ( 5.9 % vs 9.5 % ) . Adverse events ( incidence ≥5 % ) were nausea , headache , dizziness and somnolence . Conclusions Vortioxetine was noninferior and significantly superior to agomelatine in major depressive disorder patients with previous inadequate response to a single course of SSRI/SNRI monotherapy . Vortioxetine was safe and well tolerated BACKGROUND Major depression is an important and costly problem among adolescents , yet evidence to support the provision of cost-effective treatments is lacking . AIMS To assess the short-term cost-effectiveness of combined selective serotonin reuptake inhibitors ( SSRIs ) and cognitive-behavioural therapy ( CBT ) together with clinical care compared with SSRIs and clinical care alone in adolescents with major depression . METHOD Pragmatic r and omised controlled trial in the UK .  Outcomes and costs were assessed at baseline , 12 and 28 weeks . RESULTS The trial comprised 208 adolescents , aged 11 - 17 years , with major or probable major depression who had not responded to a brief initial psychosocial intervention . There were no significant differences in outcome between the groups with and without CBT .  Costs were higher in the group with CBT , although not significantly so ( P=0.057 ) . Cost-effectiveness analysis and exploration of the associated uncertainty suggest there is less than a 30 % probability that CBT plus SSRIs is more cost-effective than SSRIs alone . CONCLUSIONS A combination of CBT plus SSRIs is not more cost-effective in the short-term than SSRIs alone for treating adolescents with major depression in receipt of routine specialist clinical care Rationale A common polymorphism ( 5HTTLPR ) within the promoter region of the serotonin transporter gene ( LSC6A4 ) has been shown to influence response time as well as overall response to selective serotonin reuptake inhibitors ( SSRIs ) in subjects with major depressive disorder . We hypothesized that a similar effect in response time to sertraline would be observed and that no effect on response time would be seen in a placebo arm . Objectives We tested the hypothesis that subjects homozygous for the long allele at the 5HTTLPR polymorphism would respond more rapidly to sertraline than subjects carrying one or two copies of the short allele . Methods HAM-D and CGI-I responses to sertraline and placebo were measured weekly in the context of an 8-week , placebo-controlled study in elderly depressed subjects . Genotyping of the 5HTTLPR polymorphism was performed to test for correlations with response at each week in the  sertraline  and  placebo groups ( n=206 ) . Results Subjects homozygous for the long allele of 5HTTLPR showed a significant increase in response at week 1 and week 2 , as assessed by the CGI-I scale compared with subjects carrying one or two copies of the short allele ( P=0.01 at both weeks ) . No significant difference was observed in the placebo group . Conclusions These results suggest that genetic variation in the serotonin transporter gene effects the response time to sertraline and provides complementing evidence to previous reports that this polymorphism affects response time to other SSRIs The objective of this study was to compare efficacy and tolerability of the selective noradrenalin reuptake inhibitor reboxetine with the selective serotonin reuptake inhibitor citalopram , in the treatment of major depressive disorder ( MDD ) . In total , 357 out patients with MDD were r and omized to treatment with reboxetine 8 - 10 mg or citalopram 20 - 40 mg per day during 24 weeks . Primary end-point was change from baseline in the Hamilton Depression Rating Scale ( HAM-D , 21 items ) . Sexual function/dysfunction was measured by the Sexual Function scale ( SF ) . Observed case analysis showed that both treatments yielded a gradual reduction of HAM-D scores : reboxetine with -21.4 and citalopram with -22.1 points ( NS ) . LOCF analysis showed a greater reduction of the HAM-D scores with citalopram compared with reboxetine ( -19.6 vs. -17.8 ; P = 0.034 ) . The response rate was 90.3 % for reboxetine and 92.7 % for citalopram ( NS ) . The most common side effect in the reboxetine group was dry mouth , and in the citalopram group sexual dysfunction . At week 24 , anorgasmia was reported by 5.9 % of the sexually active women in the reboxetine group vs 39 % in the citalopram group . The  dropout number  was 91 in the  reboxetine group , and 54 in the citalopram group . To summarize , both treatments gave a satisfactory antidepressant effect . The side effect profile differed between the groups , with a notably high prevalence of sexual dysfunctions in the citalopram group . The high number of dropouts in the reboxetine group , is considered as a result of the non-titration starting dose of 8 mg reboxetine per day , which gave a high incidence of early side-effects .  Depressive disorders including major depression ( MDD ) is very common , with a lifetime prevalence of at least 15 % in men and 25 % in women.1,2 Depression can be treated effectively by a range of antidepressant agents . Recent review s have suggested that the selective serotonin reuptake inhibitors ( SSRIs ) offer equal efficacy to the older antidepressant agents , such as tricyclic antidepressants , with the advantage of greater tolerability.3 - 5 Other review ers have reported that non-SSRI antidepressants , such as clomipramine , have been found to be significantly more effective than fluoxetine for the treatment of patients with severe depression.6  Reboxetine ( reboxetine mesylate , Edronax ; Pfizer , New York ) is a highly selective noradrenaline reuptake inhibitor , and the efficacy of reboxetine has been independently demonstrated in multiple r and omized , double-blind , placebo-controlled studies .7 - 9 In addition to improvements in depressive symptoms , treatment-associated improvements in social behavior ( measured using the Social Adaptation Self-evaluation Scale [SASS]),10 were noticed in one of these studies .8 In this study , reboxetine was statistically and clinical ly superior to both placebo and fluoxetine in improving social functioning . The primary objective of the current study was to assess efficacy and tolerability of reboxetine  in comparison with those of citalopram ( Cipramil ; H. Lundbeck , Copenhagen , Denmark ) in patients with MDD .  Citalopram is a highly SSRI . The antidepressant mechanism is presumed to be a result of stimulation of serotonergic neurotransmission in the central nervous system as a consequence of higher serotonin levels result ing from inhibition of the serotonin transporter . The therapeutic efficacy of citalopram in patients with MDD has been investigated in several placebo-controlled studies and in long-term and extension studies .11 The underlying rationale for this comparison was to study 2 different drug profiles , 1 drug being pure " adrenergic " and the other pure " serotonergic . " A secondary objective was to analyze the correlation between the types of depression ( ie , degree of melancholia and the efficacy of the 2 drugs ) 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 We reported an independent association of the short variant of the serotonin transporter gene‐linked polymorphic region ( SERTPR ) and tryptophan hydroxylase ( TPH ) genes with antidepressant response to  selective serotonin reuptake inhibitors ( SSRIs ) . The aim of the present study was to confirm the effect of the SERTPR and TPH gene variants on the  SSRIs antidepressant activity in a new sample of major and bipolar depressives . Two hundred and twenty one in patients ( major depressives = 128 , bipolar disorder = 93 ) were treated with SSRIs ( fluvoxamine or paroxetine ) for 6 weeks ; the severity of depressive symptoms was weekly assessed with the Hamilton Rating Scale for Depression ( HAMD ) . SERTPR and TPH variants were determined using PCR‐based techniques , 220 subjects genotyped for SERTPR and 221 for TPH that were never included in previous studies . SERTPR*s/s variant association with a poor response to SSRI treatment was confirmed , even if with less significant P values ( P = 0.034 ) , independently from clinical variables ; pooling the present sample with previous ones we observed a highly significant effect ( P < 0.000001 ) . TPH*A/A variants showed higher HAMD scores throughout the trial but with only a trend in the same direction of our previous study in terms of a worse response of A/A genotypes . Thus , the previous positive association was not fully replicated for TPH . The present independent replication confirms SERTPR variants as a liability factor for antidepressant efficacy while the TPH effect is not unequivocal . © 2004 Wiley‐Liss , Patients with major depressive disorder ( MDD ) usually suffer from altered cognitive functions of episodic memory , working memory , mental processing speed and motor response . Diverse studies suggest that different antidepressant agents may improve cognitive functions in patients with MDD . The aim of this work is to study the effects of serotonergic reuptake inhibitors ( SSRIs ) and serotonergic-noradrenergic reuptake inhibitors ( SNRIs ) treatments to improve the performance on memory tasks and mental processing speed in MDD . Seventy-three subjects meeting criteria for major depressive disorder were assessed with the Hamilton depression rating scale and a neuropsychological battery . The subjects were medicated with escitalopram ( n=36 ) or duloxetine ( n=37 ) for 24 weeks . At the end of the trial , the subjects were assessed again with the same neuropsychological battery used prior to the treatment . Both treatments improved importantly the episodic memory and to a lesser extent , working memory , mental processing speed and motor performance . Our results suggest that cognition is partially independent from improvement in clinical symptoms . Both groups achieved remission rates in the HAM-D-17 after 24 weeks of treatment , but SNRI was superior to SSRI  at improving episodic and working memory . Our work indicates that the superiority of SNRI over the SSRI  at episodic memory improvement is clinical ly relevant BACKGROUND This study was conducted to determine if patients with major depressive disorder who had previously failed treatment with one serotonin selective reuptake inhibitor ( SSRI ) would respond to a different SSRI . METHOD Adult out patients ( N = 106 ) with DSM-III-R major depressive disorder and a history of either intolerance ( N = 34 ) or nonresponse ( N = 72 ) to treatment with sertraline  were treated with fluoxetine ( mean dose = 37.2 mg/day ) in a st and ardized , open-label , 6-week clinical trial . Outcome was assessed at each visit using the Hamilton Rating Scale for Depression ( HAM-D ) , the Clinical Global Impressions ( CGI-Improvement and CGI-Severity ) scales , and the Patient 's Global Improvement ( PGI ) scale . RESULTS Ninety-one patients ( 86 % ) completed the study . Sixty-seven patients ( 63 % ) responded to fluoxetine ( i.e. , experienced > or = 50 % reduction in HAM-D28 total score at endpoint versus baseline ) . In addition , clinical ly and statistically significant improvements were noted on all measures of depressive symptoms and global functioning . There was a nonsignificant trend for patients with a history of less vigorous sertraline trials to respond more favorably to fluoxetine . Fluoxetine therapy was generally well tolerated , and there were only slight differences in adverse events reported by patients who had been intolerant to sertraline versus those who were nonresponders . CONCLUSION These findings indicate that fluoxetine and sertraline , two widely used SSRIs , are not interchangeable . Patients who either have had trouble tolerating or have not responded to sertraline may do well on fluoxetine treatment OBJECTIVE Some evidence indicates that an immune response with an increased production of proinflammatory cytokines often accompanies major depression . The objective of this study was to examine the serum levels of IL-6 in patients with major depression and the changes occurring in IL-6 levels during treatment with selective serotonin reuptake inhibitors ( SSRI ) . METHOD Twenty-three patients with a DSM-IV diagnosis of major depressive disorder and 23 healthy matched controls were included in the study . The severity of depression was measured with the Hamilton rating scale for depression . Blood sample s for IL-6 levels were obtained at baseline and at week 6 of treatment and IL-6 concentrations were evaluated using a solid phase s and wich enzyme immunoassay . All patients were treated with an SSRI . RESULTS The IL-6 levels showed no statistically significant difference between the patients and the controls at baseline . However , IL-6 levels after treatment with SSRIs were significantly lower compared with the baseline IL-6 levels of both the patients and the controls . CONCLUSION The results of this study suggest that proinflammatory cytokines show some changes during the course of treatment of major depression . These findings might also be considered as supporting the hypothesis of a modulatory role of antidepressants on the immune system Abstract Safety and tolerability are important considerations when selecting patients ’ treatment for major depressive disorder . We report the long-term safety and tolerability of the nicotinic channel modulator dexmecamylamine ( TC-5214 ) , adjunct to selective serotonin reuptake inhibitors (SSRIs)/serotonin-norepinephrine reuptake inhibitors ( SNRIs ) in patients with major depressive disorder and who had an inadequate response to antidepressants . This 52-week , double-blind , placebo-controlled study explored the long-term safety and tolerability of dexmecamylamine .  Patients were r and omized 3:1 to receive flexibly dosed dexmecamylamine 1 to 4 mg adjunct to SSRI/SNRI or placebo plus SSRI/SNRI . The patient population comprised inadequate responders from 2 Phase III acute  dexmecamylamine  studies ( NCT01157078 [ study 002 ] , NCT01153347 [ study 004 ] ) and de novo patients who responded inadequately during a 6-week open-label antidepressant treatment period preceding r and omization .  Safety and tolerability were assessed by monitoring adverse events , vital signs , and physical and laboratory parameters . Descriptive statistical analyses were performed on most efficacy-related end points . Sustained efficacy was analyzed using logistic regression . Overall , 813 patients were r and omized ( 610 received dexmecamylamine , 203 received placebo ) . In total , 82.4 % and 84.6 % of patients , respectively , experienced an adverse event . Adverse events occurring more frequently with dexmecamylamine vs placebo were constipation ( 19.6 % vs 6.0 % ) , dizziness ( 12.0 % vs 7.0 % ) , and dry mouth ( 9.7 % vs 5.0 % ) . Back pain ( 2.8 % vs 8.5 % ) , weight increase ( 4.4 % vs 7.0 % ) , and fatigue ( 5.6 % vs 7.5 % ) occurred more frequently in placebo-treated patients . No notable differences were observed between dexmecamylamine and placebo for any secondary end point . In this long-term study , safety and tolerability of dexmecamylamine were consistent with that reported in acute Phase III studies of dexmecamylamine BACKGROUND Depression and anxiety are common disorders and have substantially overlapping symptom complexes . Not surprisingly , treatment approaches are similar for both conditions with the selective serotonin reuptake inhibitors ( SSRIs ) as the initial therapy of choice . However , after first line treatments have been deployed , residual symptoms are often problematic . Augmentation strategies to address these difficulties are an area of active investigation . This study assessed aripiprazole as adjunctive therapy to SSRIs for patients with persistent anxiety symptoms complicating a depression or anxiety disorder . METHODS Ten patients who had been receiving SSRIs for at least 6 weeks , but still had clinical ly significant anxiety symptoms , were enrolled in an open label , flexibly-dosed study of adjunctive aripiprazole . Clinical status was assessed with the Hamilton Anxiety Rating Scale ( HAM-A ) , Montgomery Asberg Rating Scale ( MADRS ) , and Sheehan Disability Scale ( SDS ) . RESULTS Eighty percent of the subjects had a greater than 50 % reduction of symptoms on these outcome measures by week 2 of therapy , and continued with further decrements in symptoms throughout the course of the study . CONCLUSIONS The results of this trial provide preliminary evidence that aripiprazole may be an effective adjunctive treatment in individuals on SSRIs with residual symptoms of anxiety or depression . More rigorous double-blind studies are warranted to confirm and eluci date the potential role of aripiprazole in these conditions
SSRIs significantly increase the risk of both serious and non-serious adverse events .
The potential small beneficial effects seem to be outweighed by harmful effects .
Background The evidence on selective serotonin reuptake inhibitors ( SSRIs ) for major depressive disorder is unclear .
Methods Our objective was to conduct a systematic review assessing the effects of SSRIs versus placebo , ‘ active ’ placebo , or no intervention in adult participants with major depressive disorder .