Effect of Vortioxetine vs. Escitalopram on Sexual Functioning in Adults with Well-Treated Major Depressive Disorder Experiencing SSRI-Induced Sexual Dysfunction. 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† Effects of selective serotonin reuptake and dual serotonergic-noradrenergic reuptake treatments on memory and mental processing speed in patients with major depressive disorder. World Federation of Societies of Biological Psychiatry (WFSBP) Guidelines for the Pharmacological Treatment of Anxiety, Obsessive-Compulsive and Post-Traumatic Stress Disorders – First Revision Efficacy and Tolerability of Reboxetine Compared with Citalopram: A Double-blind Study in Patients with Major Depressive Disorder Antidepressant Class, Age, and the Risk of Deliberate Self-Harm: A Propensity Score Matched Cohort Study of SSRI and SNRI Users in the USA The Alpha 2A-Adrenergic Receptor Gene Polymorphism Modifies Antidepressant Responses to Milnacipran (S)-(+)-mecamylamine (TC-5214): a neuronal nicotinic receptor modulator enters phase III trials as an adjunct treatment for Major Depressive Disorder (MDD). 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 A Review of Vilazodone, Serotonin, and Major Depressive Disorder Does pretreatment testing for serotonin transporter polymorphisms lead to earlier effects of drug treatment in patients with major depression? A decision-analytic model. GENetic and clinical Predictors Of treatment response in Depression: the GenPod randomised trial protocol Ziprasidone augmentation of selective serotonin reuptake inhibitors (SSRIs) for SSRI-resistant major depressive disorder. Brain-derived neurotrophic factor Val66Met polymorphism and 6-month antidepressant remission in depressed Caucasian patients. A randomized, double-blind, active-control study of sertraline versus venlafaxine XR in major depressive disorder. Are benzodiazepines still the medication of choice for patients with panic disorder with or without agoraphobia? Amygdala Reactivity to Emotional Faces in the Prediction of General and Medication-Specific Responses to Antidepressant Treatment in the Randomized iSPOT-D Trial Time to response in panic disorder in a naturalistic setting: combination therapy with alprazolam orally disintegrating tablets and serotonin reuptake inhibitors compared to serotonin reuptake inhibitors alone. The diagnosis and treatment of generalized anxiety disorder. Suicide rates in clinical trials of SSRIs, other antidepressants, and placebo: analysis of FDA reports. Clinical and Neurobiological Effects of Tianeptine and Paroxetine in Major Depression Differential prediction of first clinical response to serotonergic and noradrenergic antidepressants using the loudness dependence of auditory evoked potentials in patients with major depressive disorder.
INTRODUCTION Sexual dysfunction is common with serotonergic antidepressants , including selective serotonin reuptake inhibitors ( SSRIs ) and serotonin-norepinephrine reuptake inhibitors ( SNRIs ) , and does not resolve in most patients . Vortioxetine , an antidepressant with a multimodal mechanism of action , has shown low rates of sexual dysfunction in previous major depressive disorder ( MDD ) trials . AIM This study compared the effects of vortioxetine and escitalopram on sexual functioning in adults with well-treated MDD experiencing treatment-emergent sexual dysfunction ( TESD ) . METHODS Participants treated with , and responding to , citalopram , paroxetine , or sertraline were r and omized to switch to either vortioxetine ( 10/20 mg ; n = 225 ) or escitalopram ( 10/20 mg ; n = 222 ) for 8 weeks . Sexual function was assessed using the Changes in Sexual Functioning Question naire Short Form ( CSFQ-14 ) , and antidepressant efficacy was assessed using the Montgomery-Åsberg Depression Rating Scale ( MADRS ) , Clinical Global Impressions ( CGI ) scale , and Profile of Mood States brief form ( POMS-brief ) . Safety and tolerability were also assessed . MAIN OUTCOME MEASURES The primary endpoint was change from baseline in the CSFQ-14 total score after 8 weeks of treatment . The MADRS , CGI , and POMS-brief were used to assess antidepressant efficacy . Safety was assessed via adverse events , vital signs , electrocardiograms , laboratory values , weight , and physical examination findings . RESULTS Vortioxetine showed significantly greater improvements in CSFQ-14 total score ( 8.8 ± 0.64 , mean ± st and ard error ) vs. escitalopram ( 6.6 ± 0.64 ; P = 0.013 ) . Benefits vs. escitalopram were significant on four of five dimensions and all three phases of sexual functioning assessed by the CSFQ-14 ( P < 0.05 ) . Antidepressant efficacy continued in both groups , with similar , but slight , improvements in MADRS and CGI scores . Vortioxetine and escitalopram had similar clinical efficacy profiles in this study , with safety profiles similar to previous trials . Nausea ( n = 9 , 4.0 % ) was the most common treatment-emergent adverse event leading to discontinuation of vortioxetine . CONCLUSION Switching antidepressant therapy to vortioxetine may be beneficial for patients experiencing sexual dysfunction during antidepressant therapy with SSRIs 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 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 In this report , which is an up date of a guideline published in 2002 ( B and elow et al. 2002 , World J Biol Psychiatry 3:171 ) , recommendations for the pharmacological treatment of anxiety disorder , obsessive-compulsive disorder ( OCD ) and post-traumatic stress disorder ( PTSD ) are presented . Since the publication of the first version of this guideline , a substantial number of new r and omized controlled studies of anxiolytics have been published . In particular , more relapse prevention studies are now available that show sustained efficacy of anxiolytic drugs . The recommendations , developed by the World Federation of Societies of Biological Psychiatry ( WFSBP ) Task Force for the Pharmacological Treatment of Anxiety , Obsessive-Compulsive and Post-traumatic Stress Disorders , a consensus panel of 30 international experts , are now based on 510 published r and omized , placebo- or comparator-controlled clinical studies ( RCTs ) and 130 open studies and case reports . First-line treatments for these disorders are selective serotonin reuptake inhibitors ( SSRIs ) , serotonin-noradrenaline reuptake inhibitors ( SNRIs ) and the calcium channel modulator pregabalin . Tricyclic antidepressants ( TCAs ) are equally effective for some disorders , but many are less well tolerated than the SSRIs/SNRIs . In treatment-resistant cases , benzodiazepines may be used when the patient does not have a history of substance abuse disorders . Potential treatment options for patients unresponsive to st and ard treatments are described in this overview . Although these guidelines focus on medications , non-pharmacological were also considered . Cognitive behavioural therapy ( CBT ) and other variants of behaviour therapy have been sufficiently investigated in controlled studies in patients with anxiety disorders , OCD , and PTSD to support them being recommended either alone or in combination with the above medicines 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 ) Background The US Food and Drug Administration ’s meta-analyses of placebo-controlled antidepressant trials found approximately twice the rate of suicidal behaviors among children and adults aged 24 years and younger who were r and omized to receive antidepressant medication  than among those who were r and omized to placebo .  Rates of suicidal behavior were similar for subjects aged 25–64 years whether they received antidepressants or placebo , and subjects aged 65 years or older r and omized to antidepressants were found to have lower rates of suicidal behavior . The age-stratified FDA meta-analyses did not have adequate power to investigate rates of suicidal behaviors by antidepressant drug class . Objective Our objective was to assess the risk of deliberate self-harm associated with the two most commonly prescribed classes of antidepressant agents . Design Propensity score matched cohort study of incident users of antidepressant agents . Setting Population -based healthcare utilization data of US residents . Patients US residents aged 10–64 years with a recorded diagnosis of depression who initiated use of selective serotonin reuptake inhibitors ( SSRIs ) or serotonin norepinephrine reuptake inhibitors ( SNRIs ) between 1 January 1998 and 31 December 2010.Main Outcome Measures ICD-9 external cause of injury codes E950.x – E958.x ( deliberate self-harm ) . Results A total of 102,647 patients aged between 10 and 24 years , and 338,021 aged between 25 and 64 years , initiated therapy with antidepressants . Among 10–24 year olds , prior to propensity score matching , 75,675 initiated therapy with SSRIs and 5,344 initiated SNRIs . After matching , there were 5,344 SNRI users and 10,688 SSRI users . Among the older cohort , 36,037 SNRI users were matched to 72,028 SSRI users ( from an unmatched cohort of 225,952 SSRI initiators ) . Regardless of age cohort , patients initiating SSRIs and patients initiating SNRIs had similar rates of deliberate self-harm . Restriction to patients with no antidepressant use in the past 3 years did not alter our findings . Conclusions Our findings of similar rates of deliberate self-harm for depressed patients who initiate treatment with either an SSRI or an SNRI suggests that physicians who have decided that their patients would benefit from initiating antidepressant therapy need not weigh differential suicide risk when deciding which class of antidepressant to prescribe Objective : The alpha 2A-adrenergic receptor ( ADRA2A ) plays a central role in the regulation of systemic sympathetic activity . Recently , the functional defect of ADRA2A has been implicated as a cause of depression , attention deficit hyperactivity disorder , and Tourette syndrome . In this study , the effect of genetic variants of the ADRA2A gene on the response to selective serotonin reuptake inhibitors (SSRIs)/serotonin norepinephrine reuptake inhibitors ( SNRIs ) was examined in depressed patients . Method : Ninety-three Japanese depressed patients were recruited in the present study , assigned r and omly to paroxetine or milnacipran , and assessed by the Hamilton Rating Scale for Depression ( HAM-D ) scoring every 2 weeks before and after drug administration . The ADRA2A C-1297 G polymorphism was considered in the association analysis with the efficacy of antidepressants . Results : There were significant differences in the HAM-D percent score change over time ( P = 0.019 ) among C/C , C/G , and G/G of the ADRA2A C-1297 G polymorphism in the total subjects . The C allele carriers of the ADRA2A C-1297 G polymorphism showed a significantly better improvement than G/G subjects at weeks 2 , 4 , and over time ( P = 0.037 ) in the milnacipran group . Discussion : Our findings suggest that ADRA2A plays an important role in depression therapy . The level of ADRA2A expression could be associated with the efficacy of SSRIs/SNRIs , especially milnacipran , although the functional change brought about by C-1297 G polymorphism has not yet been fully identified in vivo and in vitro . Conclusions : The ADRA2A polymorphism could be a reasonable c and i date to predict the response to milnacipran . Our results are still preliminary , and a large sample size will be required to confirm our findings . However , to the best of our knowledge , this study is the first to suggest a possible association of ADRA2A variants with the SNRI response Major Depressive Disorder ( MDD ) is a common illness that affects > 40 million people worldwide , and antidepressants are one of the top 5 leading classes of pharmaceuticals with annual sales in excess of $ 20 billion ( 1,2 ) . The current st and ard of care focuses on serotonin−norepinephrine reuptake inhibitors ( SNRI ) and selective serotonin reuptake inhibitors ( SSRI ) ; however , patients often respond poorly . In fact , the National Institute of Mental Health conducted a large-scale STAR*D study and found that 63 % of patients did not achieve remission with the SSRI Citalopram ( 1,3−5 ) . Citalopram was originally developed in Lundbeck in the late 1980s and sold as a racemate . Lundbeck , in collaboration with Forest Laboratories , has recently released an up date d version called Escitalopram ( also known as Lexapro ) , which is the single (S)-enantiomer of the racemic Citalopram , which provided new patent life . In 2009 , Lexapro garnered ∼$2.7 billion in sales in the US ( Figure ​(Figure1)1 ) ( 2 ) . Figure 1 Structures of Citalopram , Escitalopram , and TC-5214 . An alternative hypothesis for depression emerged over 30 years ago and suggests that a cholinergic imbalance ( hypercholinergic tone ) is a major factor in depression , and both clinical and pre clinical studies have implicated neuronal nicotinic cholinergic receptors ( NNRs ) rather than muscarinic receptors ( 5 ) . On the basis of these data , AstraZeneca and Targacept have explored the role of NNR antagonism in depressive disorders and recently announced the initiation of a phase III trial of TC-5214 , (S)-(+)-mecamylamine , as an adjunct therapy with Citalopram . TC-5214 is a low molecular weight ( 167.3 as free base , 203.8 as the HCl salt ) , basic ( pKa = 11.5 ) compound , freely soluble in water . While TC-5214 displays modest selectivity among the NNRs , its antidepressive properties are presumed to be the result of inhibition of the α4β2 NNRs . Pre clinical ly , TC-5214 demonstrated robust efficacy in rodent models of depression ( forced swim and behavioral despair ) and anxiety ( social interaction and light/dark chamber ) . The (S)-enantiomer showed a superior preclincial safety profile compared to that of either the racemic compound or the (R)-enantiomer . Furthermore , TC-5214 was well tolerated in both acute and chronic toxicity tests , displayed no mutagenic potential , and possessed pharmacokinetic properties suitable for development ( 3−5 ) . In 2009 , Targacept conducted a double blind , placebo controlled phase IIb trial in MMD patients with TC-5214  , as an adjunct treatment with Citalopram demonstrated superiority to placebo in both primary and secondary outcome measures ( 3−5 ) . This positive outcome led to a license agreement in December of 2009 with AstraZeneca for the global development and commercialization of TC-5214 . On June 23 , 2010 , AstraZeneca and Targacept announced the enrollment of the first patients in the phase III trial of TC-4214 . Coined the Renaissance Program , the trial will include two fixed dose and two flexible dose phase III studies of TC-5214 as an adjunct treatment for patients with poor response to st and ard SSRI or SNRI therapy . Each fixed dose and flexible dose phase III study will employ an initial open label phase wherein patients diagnosed with MDD receive one of seven marketed SSRIs or SNRIs for eight weeks to assess therapeutic response . Patients that respond poorly will then be r and omized into a double blind , placebo controlled second phase to receive a fixed or a flexible dose of TC-5214 or placebo , twice daily , while continuing the SSRI or SNRI therapy . A change from double blind baseline for TC-5214 on the Montgomery−Asberg Depression Rating Scale ( MADRS ) as compared to placebo is the primary outcome measure . The program will also include a double blind , placebo controlled study for long-term safety . The companies plan completion of the trial in time to file an IND with the FDA in late 2012 ( 3−5 ) . MMD is the leading cause of disability in the US for people 15−44 , and the burden for MDD in the US in 2000 was in excess of $ 83 billion ( 6 ) . When broken down , the workplace burden for lost time is ∼62 % , treatment costs account for ∼31 % , and suicide related costs average 7 % ( 6 ) . For those suffering from MDD with poor response to SSRIs and SNRIs , the phase III data is anxiously awaited 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 : 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 BACKGROUND An estimated 30 % to 40 % of patients with depression do not sufficiently respond to treatment with selective serotonin reuptake inhibitors ( SSRIs ) and the period in which treatment efficacy can be assessed is relatively long . Therefore , a test to identify potential nonresponders could be useful in the treatment of depression . Serotonin transporter gene ( SLC6A4 ) variations have been reported to account for differences in the way individuals respond to SSRI treatment . OBJECTIVE A decision-analytic model was used to assess whether pretreatment genetic testing for 5-HTTLPR , a polymorphism of the SLC6A4 genotype , could be an efficient tool in the treatment of depression . METHODS A theoretical clinical decision-analytic model was constructed to compare the current treatment strategy in The Netherl and s with an alternative strategy for the treatment of depression . Under treatment guidelines in The Netherl and s , all patients with depression receive SSRI treatment ( nontesting strategy ) . Under the alternative strategy , genetic testing would be performed to identify which class of antidepressant would be the best choice for initiation of treatment ( genetic testing strategy ) . Probabilities ( predicted results ) for this model were based on data from previous studies and the opinions of experts in the field of psychopharmacology . To test the robustness of the model , 6- and 12-week remission rates for patients treated with SSRIs were varied in a sensitivity analysis using a predetermined range that was established based on expert opinion . Threshold analyses were performed on the parameters of serotonin transporter genotype frequency and response and nonresponse rates for patients receiving SSRIs , serotonin-norepinephrine reuptake inhibitors ( SNRIs ) , and tricyclic antidepressants ( TCAs ) to determine the value for a variable at which it could be concluded that a change in treatment strategy would be preferred . RESULTS When genetic testing was performed before an antidepressant was prescribed , 64.6 % of patients were predicted to be in remission after 6 weeks of treatment compared with 60.0 % of patients who did not receive genetic testing . After 12 weeks , 79.5 % of patients in the testing group who received an SNRI as initial treatment and 83.2 % of those who received a TCA initially were predicted to be in remission compared with 76.7 % of patients in the nontesting group . Sensitivity analyses indicated that the model was robust to variation of probability estimates within their plausible ranges . However , these findings were based on a theoretic model and did not include cost assessment . Pretreatment genetic testing must be evaluated further in r and omized clinical trials and costs must be assessed before implementing this strategy in routine psychiatric practice can be recommended . CONCLUSIONS The findings of this study suggest that performing genetic testing before prescribing antidepressant treatment may lead to greater numbers of patients experiencing remission early in treatment Background The most effective pharmacological treatments for depression inhibit the transporters that reuptake serotonin ( Selective Serotonin Reuptake Inhibitors – SSRIs ) and noradrenaline ( Noradrenaline Reuptake Inhibitors – NaRIs ) into the presynaptic terminal . There is evidence to suggest that noradrenaline and serotonin enhancing drugs work through separate mechanisms to produce their clinical antidepressant action . Although most of the current evidence suggests there is little difference in overall efficacy between SSRIs and NaRIs , there are patients who respond to one class of compounds and not another . This suggests that treatment response could be predicted by genetic and /or clinical characteristics . Firstly , this study aims to investigate the influence of a polymorphism ( SLC6A4 ) in the 5HT transporter in altering response to SSRI medication . Secondly , the study will investigate whether those with more severe depression have a better response to NaRIs than SSRIs . Methods / design The GenPod trial is a multi-centre r and omised controlled trial . GPs referred patients aged between 18–74 years presenting with a new episode of depression , who did not have any medical contraindications to antidepressant medication and who had no history of psychosis or alcohol/substance abuse . Patients were interviewed to ascertain their suitability for the study . Eligible participants ( with a primary diagnosis of depression according to ICD10 criteria and a Beck Depression Inventory ( BDI ) score > 14 ) were r and omised to receive one of two antidepressant treatments , either the SSRI Citalopram or the NaRI Reboxetine , stratified according to severity . The final number r and omised to the trial was 601 . Follow-up assessment s took place at 2 , 6 and 12 weeks following r and omisation . Primary outcome was measured at 6 weeks by the BDI . Outcomes will be analysed on an intention-to-treat basis and will use multiple regression models to compare treatments . Discussion The results of the trial will provide information about targeting antidepressant treatment for individual patients ; in turn this may increase prescribing efficacy , thereby speeding recovery and reducing the cost to the NHS . It will also help to underst and the different roles that noradrenaline and serotonin might play in the biology of depression . The trial is expected to report in the autumn of 2008.Trial Registration IS RCT N 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 BACKGROUND Whether the Brain Derived Neurotrophic Factor ( BDNF ) Val66Met polymorphism can predict antidepressant drug efficacy in depressed patients remains unclear , suggesting that it may depend on antidepressant classes . We assessed the impact of Val66Met polymorphism on antidepressant response and remission depending on antidepressant classes . METHODS In a 6-month prospect i ve , real-world setting , treatment study , 345 Caucasian depressed patients requiring a new or different drug treatment with a selective serotonin reuptake inhibitor ( SSRI ) , a serotonin and noradrenalin reuptake inhibitor ( SNRI ) or a tricyclic antidepressant ( TCA )  , were genotyped and assessed for response and remission . RESULTS 231 ( 67 % ) patients were homozygous for the Val66 allele ( Val/Val ) and 114 ( 33 % ) were carriers of Met allele ( Met ) . 152 ( 44.1 % ) patients were treated with SSRI , the others with SNRI/TCA . Both response and remission were explained by interactions between the Val66Met polymorphism and antidepressant drug classes ( multivariate models adjusted for propensity-scores : p=0.02 and p=0.03 respectively ) . With SSRI , Val/Val patients had a higher response rate 3 months post-treatment than Met patients ( 68.1 % versus 44 % ; adjusted-OR : 3.04 , IC95 % [ 1.05 ; 9.37 ] , p=0.04 ) . With SNRI/TCA , Val/Val patients had a lower remission rate 6 months post-treatment than Met patients ( 33.3 % versus 60.9 % , adjusted-OR : 0.27 , IC95 % [ 0.09 ; 0.76 ] , p=0.02 ) . LIMITATIONS Limited sample size . CONCLUSIONS This study argues for a personalized prescription of antidepressants in Caucasian patients with major depressive disorder , based on the BDNF Val66Met polymorphism : SSRI should be preferred for Val/Val patients and SNRI/TCA for Met patients . Further studies are required to confirm these data OBJECTIVE Sertraline may produce dual neurotransmitter effects similar to the serotonin-norepinephrine reuptake inhibitors ( SNRIs ) ; however , it has been tested against an SNRI in only 1 previous study , and never at an optimal dose . The objective of the current multisite study was to compare relatively higher doses of sertraline ( i.e. , 150 mg/day ) and venlafaxine extended release ( XR ) ( 225 mg/day ) in out patients with major depressive disorder . METHOD Subjects with DSM-IV major depressive disorder were r and omly assigned to 8 weeks of double-blind treatment with sertraline ( N = 82 ) or venlafaxine XR ( N = 78 ) . The study ran from January 2002 through January 2003 . The primary outcome measure was the Quality of Life Enjoyment and Satisfaction Question naire ; secondary outcome variables included the 17-item Hamilton Rating Scale for Depression . RESULTS Both treatments led to significant improvement in depressive symptoms and quality -of-life measures . No significant differences were noted between treatment groups for final scores on the primary or secondary measures . The treatment groups did not differ significantly in the percentage of responders  ( sertraline = 55 % , venlafaxine XR = 65 % ; intent-to-treat [ ITT ] sample ) or remitters ( sertra-line = 38 % , venlafaxine XR = 49 % ; ITT sample ) , although the proportions are similar to those found in earlier selective serotonin reuptake inhibitor ( SSRI ) vs. venlafaxine meta-analyses . In patients who achieved the maximum dose of drug and maintained it for 3 weeks , response rates were similar to those found at lower doses ( sertraline = 59 % , venlafaxine XR = 70 % ) ; however , remission rates for this sample were comparable for both drug groups ( sertraline = 48 % , venlafaxine XR = 50 % ) . CONCLUSIONS The efficacies of sertraline and venlafaxine XR were comparable . Although response and remission rates did not differ statistically , the rates were analogous to those reported in previous meta-analyses . However , at clinical ly relevant higher doses , the remission rates were very similar . CLINICAL TRIALS REGISTRATION Clinical Trials.gov identifier NCT00179283 OBJECTIVE Recently , pharmacological treatment guidelines for panic disorder have changed as newer treatment options have become available . The authors examined how the use of psychotropic drugs has shifted over the course of 10 years to determine if prescribing patterns have changed to reflect these revised treatment guidelines . METHOD A total of 443 patients with panic disorder were enrolled in the Harvard/Brown Anxiety Research Project , a prospect i ve longitudinal study of anxiety disorders . These patients were interviewed over the course of 10 years to examine their use of psychotropic medications . RESULTS Despite efforts aim ed at increasing the use of selective serotonin reuptake inhibitors ( SSRIs ) in patients with panic disorder ( e.g. , APA 's practice guideline for panic disorder , Food and Drug Administration approval of particular SSRIs for the treatment of panic disorder ) , only a modest increase in their use was found . Treatment patterns for psychotropic drugs  appear to have remained stable over the past decade , with benzodiazepines being the most commonly used medication for panic disorder . In comparison , SSRI use throughout the follow-up period has remained low . Patients using an SSRI did not have a more favorable clinical course than those using a benzodiazepine , nor were there significantly better rates of remission in patients using SSRIs and benzodiazepines concomitantly . CONCLUSIONS These results highlight a gap between pharmacological treatment guidelines and actual delivery of care in that recommendations to use SSRIs to treat panic disorder are not being followed . Factors potentially associated with promoting and ignoring treatment recommendations are discussed Although the cost of poor treatment outcomes of depression is staggering , we do not yet have clinical ly useful methods for selecting the most effective antidepressant for each depressed person . Emotional brain activation is altered in major depressive disorder ( MDD ) and implicated in treatment response . Identifying which aspects of emotional brain activation are predictive of general and specific responses to antidepressants may help clinicians and patients when making treatment decisions . We examined whether amygdala activation probed by emotion stimuli is a general or differential predictor of response to three commonly prescribed antidepressants , using functional magnetic resonance imaging ( fMRI ) . A test – retest design was used to assess patients with MDD in an academic setting as part of the International Study to Predict Optimized Treatment in Depression . A total of 80 MDD out patients were scanned prior to treatment and 8 weeks after r and omization to the selective serotonin reuptake inhibitors escitalopram and sertraline and the serotonin – norepinephrine reuptake inhibitor , venlafaxine-extended release ( XR ) . A total of 34 matched controls were scanned at the same timepoints . We quantified the blood oxygen level-dependent signal of the amygdala during subliminal and supraliminal viewing of facial expressions of emotion . Response to treatment was defined by ⩾50 % symptom improvement on the 17-item Hamilton Depression Rating Scale . Pre-treatment amygdala hypo-reactivity to subliminal happy and threat was a general predictor of treatment response , regardless of medication type ( Cohen ’s d effect size 0.63 to 0.77 ; classification accuracy , 75 % ) . Responders showed hypo-reactivity compared to controls at baseline , and an increase toward ‘ normalization ’ post-treatment . Pre-treatment amygdala reactivity to subliminal sadness was a differential moderator of non-response to venlafaxine-XR ( Cohen ’s d effect size 1.5 ; classification accuracy , 81 % ) . Non-responders to venlafaxine-XR  showed pre-treatment hyper-reactivity , which progressed to hypo-reactivity rather than normalization post-treatment , and hypo-reactivity post-treatment was abnormal compared to controls . Impaired amygdala activation has not previously been highlighted in the general vs differential prediction of antidepressant outcomes . Amygdala hypo-reactivity to emotions signaling reward and threat predicts the general capacity to respond to antidepressants . Amygdala hyper-reactivity to sad emotion is involved in a specific non-response to a serotonin – norepinephrine reuptake inhibitor . The findings suggest amygdala probes may help inform the personal selection of antidepressant treatments OBJECTIVE This study evaluated time to response in the treatment of panic disorder with a selective serotonin reuptake inhibitor ( SSRI ) or serotonin norepinephrine reuptake inhibitor ( SNRI ) combined with alprazolam orally disintegrating tablets ( ODT ) , or SSRI/SNRI alone . DESIGN Subjects were r and omized to eight weeks open-label treatment with alprazolam ODT ( 4 weeks treatment followed by 3 - 4 week taper ) combined with an SSRI or SNRI , or treatment with SSRI/SNRI alone . SETTING The study was conducted under naturalistic conditions at 62 primary care and 34 psychiatric practice s. PARTICIPANTS Male or female subjects ≥18 years of age diagnosed with panic disorder , with or without agoraphobia . MEASUREMENTS The primary efficacy measure was time to response , defined as ≥50-percent decrease from baseline Hamilton Rating Scale for Anxiety ( HAM-A ) total score . Secondary measures included change from baseline in HAM-A scores and the Clinical Global Impression of Improvement ( CGI-I ) and Patient Global Impression ( PGI ) scales . RESULTS The intent-to-treat ( ITT ) population comprised 245 subjects . There was no statistical difference between treatment groups in time to response in the ITT population ; however , a prospect ively defined per protocol analysis revealed a statistically significant earlier onset of effect in subjects receiving SSRI/SNRI plus alprazolam ODT ( P<0.05 ) . Mean change from baseline in HAM-A total score and clinician and patient measures of global improvement also showed statistically significant early advantages for combination therapy compared with SSRI/SNRI monotherapy . CONCLUSION Combined treatment of panic disorder with alprazolam ODT and an SSRI/SNRI may be associated with more rapid improvement in anxiety symptoms compared with an SSRI/SNRI alone BACKGROUND Generalized anxiety disorder  ( GAD ) is a common and serious disease with a lifetime prevalence of 4.3 % to 5.9 % . It is underdiagnosed in primary care . METHODS Recommendations on the treatment of GAD are given on the basis of all available findings from pertinent r and omized trials , retrieved by a selective search of the literature . RESULTS Among psychotherapeutic techniques , various kinds of cognitive behavioral therapy ( CBT ) have been found useful in controlled trials . The drugs of first choice include selective serotonin reuptake inhibitors ( SSRIs ) , serotonin-norepinephine reuptake inhibitors ( SNRIs ) , and the calcium-channel modulator pregabalin . Tricyclic antidepressants are also effective but have more adverse effects than SSRIs . Although benzodiazepines are effective anxiolytic agents for short-term use , they should not be given over the long term because of the danger of addiction . Buspirone , an azapirone , was found to be effective in a small number of trials , but the findings across trials are inconsistent . The response rate of GAD to CBT in published studies lies between 47 % and 75 % , while its response rate to drug treatment lies between 44 % and 81 % . CONCLUSION The treatment of GAD with CBT and drugs is evidence -based and has a good chance of improving the manifestations of the disorder OBJECTIVE Previous reports suggesting that selective serotonin reuptake inhibitor ( SSRI ) use is associated with increased suicidal risk have not assessed completed suicides . The authors analyzed reports from r and omized controlled trials to compare suicide rates among depressed patients assigned to an SSRI , other antidepressants , or placebo .  METHOD Food and Drug Administration ( FDA ) summary reports of the controlled clinical trials for nine modern FDA -approved antidepressants provided data for comparing rates of suicide . RESULTS Of 48,277 depressed patients participating in the trials , 77 committed suicide . Based on patient exposure years , similar suicide rates were seen among those r and omly assigned to an SSRI ( 0.59 % , 95 % confidence interval [CI]=0.31%-0.87 % ) , a st and ard comparison antidepressant ( 0.76 % , 95 % CI=0.49%-1.03 % ) , or placebo ( 0.45 % , 95 % CI=0.01%-0.89 % ) . CONCLUSIONS These findings fail to support either an overall difference in suicide risk between  antidepressant- and placebo-treated depressed subjects in controlled trials or a difference between SSRIs and either other types of antidepressants or placebo Selective serotonin reuptake inhibitors ( SSRIs ) are widely used as effective pharmacological agents to treat depressive disorders . In contrast to the SSRIs , which block the presynaptic serotonin ( 5-HT ) transporter and by this route increase the concentration of serotonin in the synaptic cleft , the antidepressant tianeptine enhances the presynaptic neuronal reuptake of 5-HT and thus decreases serotonergic neurotransmission . Both SSRIs and tianeptine are clinical ly effective ; however , their opposite modes of action challenge the prevailing concepts on the need of enhancement of serotonergic neurotransmission . To better underst and the differences between these two opposite pharmacological modes of action , we compared the changes induced by tianeptine and paroxetine on psychopathology , the hypothalamic-pituitary-adrenocortical ( HPA ) system , and cognitive functions in a double-blind , r and omized , controlled trial including 44 depressed in patients over a period of 42 days .  Depressive symptomatology significantly improved in all efficacy measures , with no significant differences between tianeptine and paroxetine . There was a trend toward better response to the SSRI among women . Assessment of the HPA system showed marked hyperactivity before the beginning of treatment , which then normalized in most of the patients , without significant differences between the two antidepressants . Cognitive assessment s showed no significant differences between the two drugs investigated . The results of the current study suggest that the initial effect , i.e. , enhancement or decrease of 5-HT release , is only indirectly responsible for antidepressant efficacy , and they support the notion that downstream adaptations within and between nerve cells are crucial . The normalization of the HPA system as a common mode of action of different antidepressants seems to be of special interest OBJECTIVE Predictors of treatment response to serotonergic versus nonserotonergic , e.g. , noradrenergic , antidepressants are of considerable clinical relevance as they could help to reduce the occurrence of patients ' receiving weeks or even months of unsuccessful treatment . Several studies show that the response to selective serotonin reuptake inhibitors can be successfully predicted by using the loudness dependence of auditory evoked potentials ( LDAEP ) , which denotes change in the amplitudes in response to different stimulus intensities and is to date one of the best vali date d indicators of the central serotonergic system . The aim of the current r and omized prospect i ve study was to investigate whether or not LDAEP also allows the differential prediction of treatment response to serotonergic versus noradrenergic antidepressants . METHOD Electrophysiologic recordings were performed on 48 subjects between 1999 and 2001 . After exclusions due to artifacts , the study sample consisted of 35 unmedicated in patients with a DSM-IV or ICD-10 diagnosis of major depressive disorder ( mean + /- SD age = 42.5 + /- 10.8 years ; 13 male , 22 female ; mean + /- SD score of 28.9 + /- 5.7 on the Hamilton Rating Scale for Depression [ HAM-D ] , the primary measure for psychopathology ) . The patients were then treated for 4 weeks with either the selective serotonin reuptake inhibitor citalopram or the noradrenaline reuptake inhibitor reboxetine . RESULTS Analysis of variance ( F = 5.05 , df = 1,31 ; p = .03 ) revealed that responders ( 50 % improvement in HAM-D score ) to the citalopram treatment were characterized by a strong LDAEP at baseline , and responders to reboxetine were characterized by a weak LDAEP at baseline . Non-responders to citalopram or reboxetine showed the inverse LDAEP characteristics , respectively . CONCLUSION This study is one of the first to demonstrate differential prediction of response to different classes of antidepressants . Patients at the beginning of an antidepressant treatment who show an initially strong LDAEP have a greater probability of responding to a serotonin-agonist antidepressant , whereas patients with a weak LDAEP will probably benefit more from a nonserotonergic , e.g. , noradrenergic , antidepressant . If these results were replicated in a larger sample , this simple electroencephalographic method could be more broadly used in clinical practice to support clinicians in replacing the trial and error method with a more targeted and individualized approach to antidepressant treatment
EXPERT OPINION Results of placebo-controlled trials suggest efficacy and an overall safety profile comparable to existing first-line antidepressants .
The most common side effects are nausea , vomiting and constipation .
Results of several studies indicate that vortioxetine may have therapeutic effects on cognition ( e.g. , memory and executive functioning ) that exceed that of st and ard antidepressants .
The authors suggest that vortioxetine is currently a good second-line antidepressant option and shows promise , pending additional long-term data , to become a first-line antidepressant option
INTRODUCTION Vortioxetine is a structurally novel medication that has recently been approved for treatment of major depressive disorder ( MDD ) .
This medication is a serotonin reuptake inhibitor that also has a number of other potentially relevant effects on serotoninergic receptors , which may differentiate the drug 's effects from those of current first-line antidepressants , such as selective serotonin reuptake inhibitors ( SSRIs ) and serotonin norepinephrine reuptake inhibitors ( SNRIs ) .
AREAS COVERED This article will review the basic clinical pharmacology of vortioxetine , summarize the major clinical trials that were performed prior to approval by the US Food and Drug Administration ( FDA ) , discuss relevant post-marketing studies of this drug , and offer expert commentary on the significance of this new agent in clinical practice .