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The past decade has brought major new developments in the psychopharmacologic management of generalized anxiety disorder and social phobia . We examined medication-prescribing patterns for the treatment of these anxiety disorders for 12 years to assess changes in patients ' anti-anxiety psychotropic medication usage during that period of evolving practice guidelines . We examined psychotropic medication use in 305 patients with generalized anxiety disorder and 232 with social phobia enrolled in the Harvard/Brown Anxiety Disorders Research Project ( HARP ) , a prospect i ve , longitudinal study of anxiety disorders .  Psychotropic treatment patterns seem to have remained relatively stable over 12 years with benzodiazepines the medications most commonly used for both generalized anxiety disorder and social phobia . Comparatively , selective serotonin reuptake inhibitor ( SSRI ) and venlafaxine usage as st and -alone medications for these disorders remained low throughout the follow-up period . At the 12-year follow-up , 24 % of patients with generalized anxiety disorder and 30 % of patients with social phobia were utilizing neither an  SSRI/selective norepinephrine reuptake inhibitor ( SNRI ) nor a benzodiazepine . Treatment recommendations for use of SSRIs and venlafaxine in the management of generalized anxiety disorder and social phobia initially promulgated in 1998 had a modest impact on changes in psychopharmacologic practice 4 - 5 years later . Difficulties in the implementation of treatment guidelines are discussed OBJECTIVE The purpose of this study was to examine the use of benzodiazepines ( BZs ) and selective serotonin reuptake inhibitors/selective norepinephrine reuptake inhibitors ( SSRIs/SNRIs ) over nine years of follow-up in middle-aged and older adults with diagnoses of panic disorder with or without agoraphobia , social phobia , or generalized anxiety disorder . SETTING AND PARTICIPANTS Participants in this study were enrolled in the Harvard/Brown Anxiety Research Project ( HARP ) . HARP is a naturalistic , longitudinal , multisite study of adults with anxiety disorders who are recruited from psychiatric setting s. The analytic sample consisted of 51 participants with anxiety disorders who were 55 to 70 years old at baseline and a younger cohort of 211 participants added for comparative analysis . DESIGN The authors examined patterns of medication use ( BZs and SSRIs/SNRIs ) in participants with anxiety disorders as they aged , by assessing the proportion of participants taking these medications using generalized estimating equation modeling . MEASUREMENTS The present data were derived from the structured diagnostic interview administered at enrollment using a combination of the Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders , Third Edition-R Non-Affective Disorder , Patient Version , Research Diagnostic Criteria Schedule for Affective Disorders-Lifetime , and subsequent follow-up interviews over a nine-year period using the Longitudinal Interval Follow-up Evaluation-Pharmacia & Upjohn to assess the weekly course of disorders to indicate syndrome severity and document medication use by specific type and dose on a weekly basis . RESULTS Findings showed that rates of BZ use were high among both the older ( 53 % at baseline ) and the younger ( 57.4 % ) age groups and did not significantly decrease over time , after controlling for time in episode of their anxiety disorders . There was a statistically significant increase in  SSRI/SNRI use over time in both groups . At the beginning of the study , 18 % of the older group and 21 % of the younger group were using SSRIs/SNRIs ; however , at the end of the study , the rates increased to 35 % and 43 % , respectively . CONCLUSIONS Although there was an increase in  SSRI/SNRI use in older participants with anxiety disorders over the course of study , at nine years of follow-up , only 35 % of participants were utilizing SSRI/SNRI medication , while more than one-half of the same participants were continuing to use BZs . To the authors ' knowledge , there are no r and omized clinical trials that have addressed comparative efficacy and safety of BZs and SSRIs/SNRIs in this population . However , there is documented evidence of adverse effects of chronic BZ use and the risk of developing dependency in older population 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 Abstract . Rationale : The DSM-IV includes the specifier " generalized " to refer to social anxiety disorder ( social phobia ) patients if the fears include " most social situations " . The focus on interventions such as the selective serotonin reuptake inhibitors ( SSRIs ) for generalized social anxiety disorder arguably runs the risk that inadequate treatment will be provided to patients with the non-generalized or discrete subtypes . There are , however , few data to address whether more generalized and less generalized subgroups of social anxiety disorder differ in response to medication . Objective : To compare response of more generalized and less generalized social anxiety disorder to pharmacotherapy . Methods : Data from three r and omized placebo-controlled double-blind multicenter trials of the SSRI paroxetine in social anxiety disorder were pooled . Response on the Clinical Global Impression Global Improvement item was analyzed using logistic regression , and change in total Liebowitz Social Anxiety Score was analyzed using analysis of variance , with both models incorporating treatment ( paroxetine vs placebo ) , subgroup ( more generalized vs less generalized ) , demographic , and clinical variables . Results : The prevalence of more generalized social anxiety disorder was higher in females than in males . However , there was no significant difference in terms of age or clinical characteristics ( duration of condition , baseline pulse , mean arterial blood pressure ) . At treatment endpoint there were significant treatment effects ( for paroxetine vs placebo ) , but no significant subgroup effects ( for more generalized vs less generalized ) . Conclusions : Although the current data base is limited insofar as few patients with discrete social anxiety disorder would have been included , it is helpful in addressing the value of medication for patients lying on the spectrum from generalized to non-generalized and discrete social anxiety disorder .  Paroxetine was effective in both more generalized and in less generalized social anxiety disorder OBJECTIVE Numerous studies have demonstrated the efficacy of serotonergic antidepres-sants , particularly the selective serotonin reuptake inhibitors ( SSRIs ) , in the treatment of social phobia . We evaluated the efficacy , safety , and tolerability of nefazodone , a 5-HT(2 ) antagonist , in patients with generalized social phobia ( GSP ) . METHOD One hundred five patients with GSP ( confirmed using the Structured Clinical Interview for DSM-IV ) from 4 Canadian outpatient anxiety clinics were assigned r and omly to nefazodone ( 300 - 600 mg/day , flexible dose ) or placebo for 14 weeks of double-blind treatment . Data were collected from October 12 , 1999 , through December 8 , 2001 . Primary efficacy outcomes were the Clinical Global Impressions-Improvement scale ( CGI-I ) score and the Liebowitz Social Anxiety Scale score . RESULTS In the intent-to-treat sample , 16 ( 31.4 % ) of 51 subjects taking nefazodone and 12 ( 23.5 % ) of 51 subjects taking placebo were rated as much or very much improved on the CGI-I at endpoint ( chi(2 ) = 0.79 , p = .38 ) . With the exception of the Social Phobia Scale , no significant differences were found in measures of social phobia when comparing the nefazodone and placebo groups . CONCLUSION These findings suggest that nefazodone is not an effective agent in the treatment of GSP . These data parallel some recent findings with the use of the SSRI fluoxetine in GSP . The lack of efficacy of 2 serotonergic antidepressants in GSP suggests that serotonin reuptake inhibition may not be the only mechanism of action required for efficacy to occur in the treatment of GSP 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 Previous studies have shown selective and non-selective monoamine oxidase inhibitors ( MAOIs ) to be effective in the treatment of social phobia . In this study we investigated the efficacy of selective serotonin reuptake inhibitors ( SSRIs ) in social phobia . Thirty patients with social phobia ( DSM-IIIR ) were treated with the SSRI fluvoxamine ( 150 mg daily ) using a 12-week double-blind placebo controlled design . A substantial improvement was observed in seven ( 46 % ) patients on fluvoxamine and in one ( 7 % ) on placebo . Statistically significant effects were seen on measures of social anxiety and general ( or anticipatory ) anxiety in patients treated with fluvoxamine compared with placebo . The level of phobic avoidance decreased also but the difference at endpoint between fluvoxamine and placebo failed to reach statistical significance . It is concluded that treatment with the SSRI fluvoxamine has beneficial effects in patients suffering from social phobia , suggesting that serotonergic mechanisms might be implicated in social anxiety CONTEXT The generalized type of social phobia ( social anxiety disorder ) is a severe and often disabling form of social anxiety that affects approximately 5 % of the general population . Earlier research has shown monoamine oxidase inhibitors or benzodiazepines to be effective in treating this condition , but neither has achieved widespread use . OBJECTIVE To compare the efficacy of paroxetine , a selective serotonin reuptake inhibitor , with placebo in adults with generalized social phobia . DESIGN Twelve-week , multicenter , r and omized , double-blind trial . SETTING Thirteen centers across the United States and 1 in Canada . PARTICIPANTS Between April 13 , 1995 , and February 28 , 1996 , 187 persons meeting Diagnostic and Statistical Manual of Mental Disorders , Fourth Edition criteria for generalized social phobia were r and omized ( and 183 returned for at least 1 efficacy assessment ) to treatment . INTERVENTION After a 1-week , single-blind , placebo , run-in period , patients received a double-blind , 11-week course of either paroxetine or matching-image placebo . The initial daily dosage of paroxetine ( or placebo ) was 20 mg with increases of 10 mg/d weekly ( flexible dosing to a maximum of 50 mg/d ) permitted after the second week of treatment . MAIN OUTCOME MEASURES Number of responders based on the Clinical Global Impression Global Improvement Item ( " much improved " or " very much improved " ) ; mean change from baseline on the Liebowitz Social Anxiety Scale total score . RESULTS Fifty ( 55.0 % ) of 91 persons taking paroxetine and 22 ( 23.9 % ) of 92 persons taking placebo were much improved or very much improved at the end of treatment ( odds ratio [ OR ] , 3.88 ; 95 % confidence interval [ CI ] , 2.81 - 5.36 ) . Mean Liebowitz Social Anxiety Scale total scores were reduced by 39.1 % ( the mean baseline score of 78.0 declined by a mean of 30.5 points at follow-up ) in the paroxetine group compared with 17.4 % ( the mean baseline score of 83.5 declined 14.5 points at follow-up ) in the placebo group , a difference of 21.7 % ( 95 % CI , 8.7%-34.7 % ) favoring paroxetine . CONCLUSIONS Paroxetine is an effective treatment for patients with generalized social phobia . Short-term ( ie , 11-week ) treatment results in substantial and clinical ly meaningful reductions in symptoms and disability . Future research should test whether these may be further reduced by extended treatment or supplementation with specific educational-cognitive-behavioral techniques 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 The purpose of this study was to determine the efficacy of fluvoxamine for the treatment of social phobia ( social anxiety disorder ) . METHOD In a 12-week multicenter , double-blind , r and omized , placebo-controlled trial , 92 patients with social phobia were treated with the selective serotonin reuptake inhibitor fluvoxamine ;  91.3 % of the patients had the generalized subtype of the disorder . The primary criterion for response was a rating of " much improved " or " very much improved " on the Clinical Global Impression of Improvement scale . Secondary response criteria were changes on three specialized rating scales for social phobia symptoms : the Brief Social Phobia Scale , the Social Phobia Inventory , and the Liebowitz Social Anxiety Scale . Psychosocial impairment was assessed in three domains ( disruption of work , social life , and home/family life ) by using the Sheehan Disability Scale . RESULTS The mean daily dose of fluvoxamine was 202 mg ( SD = 86 ) . At study end or with the last observation carried forward , within the evaluable subjects ( N = 86 ) there was a significantly higher proportion of responders in the fluvoxamine group ( 42.9 % , N = 18 ) than in the placebo group ( 22.7 % , N = 10 ) . Similarly , fluvoxamine was superior to placebo on all social phobia rating scales at week 8 and beyond . Fluvoxamine also result ed in significantly greater decreases in measures of psychosocial disability than did placebo . Overall , fluvoxamine was well tolerated and safe . CONCLUSIONS These findings indicate that fluvoxamine is efficacious in the pharmacologic management of serious forms of social phobia BACKGROUND Selective serotonin reuptake inhibitors ( SSRIs ) are the current gold st and ard in the pharmacologic treatment of generalized social phobia . SSRIs are only effective in approximately 50 % of individuals with generalized social phobia and can be associated with significant side effects . Based on the successful use of the anticonvulsants gabapentin and pregabalin in treating generalized social phobia , we conducted an open trial examining the efficacy of the glutamatergic and GABAergic anticonvulsant topiramate in the treatment of generalized social phobia . METHOD Twenty-three adult out patients with DSM-IV social phobia , generalized type , were entered into a 16-week open trial of topiramate , starting at 25 mg/day , and gradually titrated up to a maximum dose of 400 mg/day . RESULTS Twelve of 23 patients completed the trial . In the intent-to-treat ( ITT ) analysis , 11 ( 47.8 % ) of 23 were responders by a Clinical Global Impressions Improvement ( CGI-I ) scale rating of " much " or " very much " improved . The mean drop in the Liebowitz Social Anxiety Scale ( LSAS ) score for the ITT group was 29.4 % . The change in LSAS score from baseline to endpoint was significant for the ITT group ( F = 3.44 , df = 4,110 ; p = .01 ) . In the completers group , 9 ( 75.0 % ) of 12 were responders by CGI-I at 16 weeks , with a mean drop in LSAS score of 45.1 % . The rate of remission in the ITT sample , using a definition of an LSAS score of < /= 30 , gave a remission rate of 26.1 % ( 6/23 ) . CONCLUSION This study suggests that topiramate may be effective in the treatment of generalized social phobia . These results also suggest the possibility that the neurotransmitters glutamate and GABA may be involved in the neurobiology of generalized social phobia OBJECTIVE The authors evaluated the efficacy , safety , and tolerability of sertraline , a selective serotonin reuptake inhibitor , in the treatment of generalized social phobia . METHOD Adult out patients with generalized social phobia ( N=204 ) from 10 Canadian centers were r and omly assigned to receive sertraline or placebo in a 2:1 ratio for a 20-week double-blind study following a 1-week , single-blind , placebo run-in . The initial dose of sertraline was 50 mg/day with increases of 50 mg/day every 3 weeks permitted after the fourth week of treatment ( dosing was flexible up to a maximum of 200 mg/day ) . Primary efficacy assessment s were the percentage of patients rated much or very much improved on the Clinical Global Impression ( CGI ) improvement item and the mean changes from baseline to study endpoint in total score on the social phobia subscale of the Marks Fear Question naire and total score on the Brief Social Phobia Scale . RESULTS In intent-to-treat endpoint analyses of 203 of the patients , significantly more of the 134 patients given sertraline  ( N=71 [ 53 % ] ) than of the 69 patients receiving placebo  ( N=20 [ 29 % ] ) were considered responders according to their CGI improvement scores at the end of treatment . The mean reductions in the social phobia subscale of the Marks Fear Question naire and in the total score on the Brief Social Phobia Scale were 32.6 % and 34.3 % in the sertraline group and 10.8 % and 18.6 % in the placebo group , respectively . Analysis of covariance showed superiority of sertraline over placebo on all primary and secondary efficacy measures . Sertraline was well tolerated : 103 ( 76 % ) of the 135 sertraline-treated patients and 54 ( 78 % ) of the 69 placebo-treated patients completed the study . CONCLUSIONS Sertraline is an effective treatment for patients with generalized social phobia BACKGROUND Tricyclic antidepressants and selective serotonin reuptake inhibitors ( SSRIs ) as well as benzodiazepines have been shown to be effective for the treatment of panic disorder . The introduction of SSRIs has enabled a greater underst and ing of the role of serotonin in the etiology of panic disorder ; however , the role of norepinephrine has been more challenging to ascertain . The aim of this study was to determine the efficacy and tolerability of reboxetine , a novel selective norepinephrine reuptake inhibitor , in patients with panic disorder with and without agoraphobia . METHOD Eighty-two patients ( aged 18 - 65 years ) with DSM-III-R panic disorder , with or without agoraphobia , were r and omly assigned to receive 6 to 8 mg/day of reboxetine ( 42 patients ) or placebo ( 40 patients ) for 8 weeks in this placebo-controlled , parallel-group , double-blind clinical trial . RESULTS Of the 82 patients enrolled in the trial , 75 were considered in the analysis ( 37 patients in the reboxetine group and 38 patients in the placebo group ) . At last assessment , there was a significant reduction in the mean number of panic attacks ( range , 9.3 - 1.2 ) and phobic symptoms ( range , 8.1 - 3.2 ) in the reboxetine group compared with the placebo group ( ranges , 8.5 - 5.8 and 7.7 - 5.2 , respectively ; p < .05 ) . Improvement in Hamilton Rating Scale for Depression , Hopkins Symptom Checklist-90 , and Sheehan Disability Scale scores were also greater in the reboxetine group compared with the placebo group . Adverse events reported more frequently with reboxetine than placebo included dry mouth ( 36 % vs. 16 % ) , constipation ( 27 % vs. 22 % ) , and insomnia ( 26 % vs. 22 % ) . CONCLUSION Reboxetine was effective and well tolerated in the treatment of panic disorder The efficacy of irreversible and reversible monoamine oxidase inhibitors ( MAOIs ) in the treatment of social phobia ( SP ) is well established . Recently , selective serotonin reuptake inhibitors ( SSRIs ) have been used more frequently . In the present study , the efficacy and side-effect profile of citalopram , an SSRI , and moclobemide , the only MAOI used in Turkey , were compared . The 71 patients diagnosed with SP according to DSM-III-R were r and omly assigned to two subgroups ; citalopram ( n = 36 ) or moclobemide ( n = 35 ) . The study was an 8-week , r and omized , open-label , rater-blinded , parallel-group trial . All patients were assessed by Hamilton anxiety rating ( HAM-A ) , Liebowitz social anxiety ( LSAS ) , clinical global impression-severity of illness ( CGI-SI ) and clinical global impression-improvement ( CGI-I ) scales . There was a similar percentage of responders ( citalopram 75 % , n = 27 and moclobemide 74.3 % , n = 26 ) , with a > 50 % or greater reduction in LSAS total score and ratings of " very much " or " much improved " on the CGI-I. None of the patients withdrew from the study . The results of the present study suggest that citalopram has shown promising results in patients with SP Depressive disorders are a major health care issue and one of the foremost causes of disability in adults around the world , result ing in significant costs to society and health care systems ( 1 ) . The estimated economic burden associated with depression was $ 83.1 billion in 2000 and is probably higher today ( 2 ) . Depressive disorders include major depressive disorder ( MDD ) ; dysthymia ; and subsyndromal depression , including minor depression . Major depressive disorder is the most prevalent depressive disorder , with an estimated lifetime prevalence of 16 % in the United States ( 3 ) . An average of 8 million ambulatory care visits per year result in a primary diagnosis of MDD ( 4 ) . The American Psychiatric Association ( 5 ) defines MDD as depressed mood or loss of pleasure or interest along with other symptoms , including significant change in weight or appetite , insomnia or hypersomnia , psychomotor agitation or retardation nearly every day , fatigue or loss of energy , feelings of worthlessness or excessive or inappropriate guilt , indecisiveness or decreased ability to concentrate , and recurrent thoughts of death or suicide , that last for at least 2 weeks and affect normal functioning . Dysthymia is less severe , but symptoms last for 2 or more years . In contrast , subsyndromal depression is associated with less severe symptoms of depression that do not qualify for MDD or dysthymia diagnoses . The treatment of depression can be characterized by 3 phases ( Figure 1 ) : acute ( 6 to 12 weeks ) , continuation ( 4 to 9 months ) , and maintenance ( 1 year ) ( 7 ) . Relapse is defined as the return of depressive symptoms during the acute or continuation phases and is therefore considered part of the same depressive episode , whereas recurrence is defined as the return of depressive symptoms during the maintenance phase and is considered a new , distinct episode . Response to treatment ( typically defined as 50 % reduction in measured severity ) can be quantified using various tools , such as the Patient Health Question naire-9 ( PHQ-9 ) ( 7 ) or the Hamilton Depression Rating Scale ( HAM-D ) ( 8) . Figure 1 . Phases of treatment of major depression . Adapted from reference 6 . TX = treatment . Various treatment approaches can be used to manage MDD , such as psychotherapy , complementary and alternative medicine ( CAM ) , exercise , and pharmacotherapy . The psychological interventions used to treat depression include acceptance and commitment therapy , cognitive therapy , cognitive behavioral therapy ( CBT ) , interpersonal therapy , and psychodynamic therapies ( Table 1 ) . The CAM treatments include acupuncture , meditation , -3 fatty acids , S-adenosyl-l-methionine ( SAMe ) , St. John 's wort , and yoga . Exercise includes a broad range of activities that can be done for varying duration s , in classes , individually , or in informal groups . For pharmacologic therapy , the scope of this guideline is limited to second-generation antidepressants ( SGAs ) ( selective serotonin reuptake inhibitors , serotonin norepinephrine reuptake inhibitors , and selective serotonin norepinephrine reuptake inhibitors ) . First-generation antidepressants ( tricyclic antidepressants and monoamine oxidase inhibitors ) are very rarely used because SGAs have lower toxicity in overdose than first-generation antidepressants and similar efficacy . Table 1 . Common Psychological Interventions to Treat Depression Guideline Focus and Target Population The purpose of this guideline from the American College of Physicians ( ACP ) is to summarize and grade the evidence on the comparative effectiveness and safety of nonpharmacologic treatments and SGAs ( including serotonin reuptake inhibitors , serotonin norepinephrine reuptake inhibitors , bupropion , mirtazapine , nefazodone , and trazodone ) , alone or in combination , for MDD . The target audience for this guideline includes all clinicians , and the target patient population includes all adults with MDD . These recommendations are based on a background evidence article ( 9 ) and a systematic evidence review sponsored by the Agency for Healthcare Research and Quality ( AHRQ ) ( 6 ) . Methods Systematic Review of the Evidence The systematic evidence review was conducted by the AHRQ 's RTI InternationalUniversity of North Carolina at Chapel Hill Evidence -based Practice Center ( 6 ) . Additional method ological details can be found in the Appendix ) , accompanying background evidence article ( 9 ) , and full report ( 6 ) . Review ers search ed several data bases for studies published in English , German , or Italian from 1 January 1990 through September 2015 . Studies on efficacy were limited to r and omized , controlled trials and systematic review s and meta-analyses , although evidence on harms included observational studies . Review ers combined data when possible using meta- analysis and assessed the risk of bias and quality of studies according to established methods . The study population included adult out patients ( aged 18 years ) with MDD during either an initial or a second treatment attempt who did not remit after an initial adequate trial with an SGA . The review evaluated the following classes of interventions : depression-focused psychotherapy , CAM , exercise , and SGAs . Outcomes assessed included benefits in response ( often defined as 50 % improvement in HAM-D scores ) , remission ( often defined as a HAM-D score 7 ) , speed of response , speed of remission , relapse , quality of life , functional capacity ( as assessed by various scales ) , reduction of suicidality , or reduction of hospitalization . Harms assessed included overall adverse events , withdrawals because of adverse events , serious adverse events , and specific adverse events . Quality of life , functional status , suicidality , and hospitalizations were rarely reported . Grading the Evidence and Developing Recommendations This guideline was developed by the ACP Clinical Guidelines Committee according to the ACP guideline development process , which has been described ( 10 ) . The Clinical Guidelines Committee used the evidence tables in the accompanying systematic review and full report ( 9 ) when reporting the evidence and grade d the recommendations using ACP 's guideline grading system ( Table 2 ) . Table 2 . The American College of Physicians ' Guideline Grading System * Peer Review The AHRQ evidence review was sent to invited peer review ers and posted on the AHRQ Web site for public comments . The guideline was peer- review ed through the journal and was posted online for comments from ACP Governors and Regents . Comparative Benefits of Pharmacologic Versus Nonpharmacologic Treatment Options for Initial Management Refer to Appendix Table 1 and the accompanying systematic review ( 9 ) for additional details of the evidence . Appendix Table 1 . First-Line Treatment for MDD : SGAs Versus Nonpharmacologic Therapies * SGA Versus Psychological Interventions SGA Versus CBT Monotherapy . Moderate- quality evidence from 5 trials ( 1115 ) showed no difference in response when comparing SGAs ( fluoxetine , fluvoxamine , paroxetine , or sertraline ) with CBT in patients with MDD after 8 to 52 weeks of treatment . Low- quality evidence from 3 trials ( 11 , 14 , 15 ) showed no difference between remission rates ( fluoxetine , fluvoxamine , and paroxetine ) and functional capacity ( 14 ) ( fluvoxamine and paroxetine ) for SGAs compared with CBT . Combination Therapy . Low- quality evidence from 2 trials ( 14 , 16 ) showed no difference in response or remission when comparing monotherapy using SGAs ( escitalopram , fluvoxamine , or paroxetine ) with combination therapy using SGAs plus CBT ( problem-solving therapy or telephone-based CBT ) in patients with MDD after 12 to 52 weeks of treatment . Low- quality evidence from 2 trials ( 14 , 16 ) assessed function , and 1 trial showed that patients who received the combination therapy reported more improvement on 3 of 5 work-functioning measures than those who received SGA monotherapy , although clinical ly important differences on these measures are uncertain . SGA Versus Interpersonal Therapy Monotherapy . Low- quality evidence showed no difference in response ( 1 trial ; escitalopram ) ( 17 ) or remission ( 2 trials ; citalopram , escitalopram , or sertraline ) ( 17 , 18 ) for SGAs compared with interpersonal therapy for patients with MDD after 12 weeks of treatment . Combination Therapy . Low- quality evidence from 1 trial ( 19 ) showed increased remission for SGA monotherapy compared with SGA combined with interpersonal therapy ( with nefazodone ) in patients with MDD after 12 weeks of treatment . SGA Versus Psychodynamic Therapies Monotherapy . Low- quality evidence from 1 trial ( 20 ) showed no difference in remission for fluoxetine compared with psychodynamic monotherapy in patients with MDD after 16 weeks of treatment . Low- quality evidence from 2 trials ( 20 , 21 ) showed few differences in functional capacity between the treatments . Combination Therapy . Low- quality evidence from 1 trial ( 21 ) showed no difference in functional capacity for SGA monotherapy compared with SGA plus psychodynamic combination therapy . SGA Versus CAM Interventions SGA Versus Acupuncture Monotherapy . Low- quality evidence from 2 trials ( 22 , 23 ) showed no difference in treatment response when comparing fluoxetine with acupuncture monotherapy for patients with MDD after 6 weeks of treatment . Combination Therapy . Low- quality evidence from 2 trials ( 24 , 25 ) showed that combination therapy of SGAs with acupuncture improved treatment response compared with monotherapy with SGAs ( fluoxetine or paroxetine ) in patients with MDD after 6 weeks of treatment . However , low- quality evidence from 1 trial ( 24 ) showed no difference in remission when comparing paroxetine monotherapy with paroxetine plus acupuncture combination therapy . SGA Versus -3 Fatty Acids Monotherapy . Low- quality evidence from network meta- analysis showed that SGAs ( fluoxetine ) were associated with a greater response than -3 fatty acids in patients with MDD .  SGA Versus SAMe Monotherapy . Low- quality evidence from network meta- analysis showed no difference in response between treatment with escitalopram OBJECTIVES New treatment options for dementia and its behavioral disturbances have become available since publication of The Expert Consensus Guidelines on the Treatment of Agitation in Older Persons with Dementia in 1998 . While only 2 cholinesterase inhibitors , donepezil and tacrine , were available in 1998 , 3 new cognitive-enhancing agents have been introduced since that time as well as several new atypical antipsychotics and antidepressants . However , there are still limited data from controlled studies to guide clinicians in choosing among these agents and sequencing and combining treatments . We therefore conducted a new survey study of expert opinion on the treatment of cognitive impairment and behavioral disturbances associated with dementia . METHODS Based on a literature review , a 61- question survey was developed with 1,225 options . Most options were scored using a modified version of the R AND 9-point scale for rating appropriateness of medical decisions . For other options , the experts were asked to write in answers . The survey was sent to 50 North American experts on dementia , 100 % of whom completed it . In analyzing responses to items rated on the 9-point scale , consensus was defined as a nonr and om distribution of scores by chi-square " goodness-of-fit " test . Based on the 95 % confidence interval around the mean , we assigned a categorical rank ( first line/preferred , second line/alternate , third line/usually inappropriate ) to each option . Guidelines indicating preferred treatment strategies were then developed for selected clinical situations . RESULTS For patients at risk for dementia , the experts recommended control of hypertension and diabetes . They also recommended aspirin and would consider a lipid-lowering agent in patients at risk for vascular dementia . Cholinesterase inhibitors were an option for patients with mild cognitive impairment ( i.e. , at risk for Alzheimer 's dementia [ AD ] ) . To slow cognitive impairment in mild/moderate AD , the experts recommended a cholinesterase inhibitor alone or combined with vitamin E. Donepezil and  galantamine  were the preferred cholinesterase inhibitors . The experts recommended combining a cholinesterase inhibitor with a N-methyl-D-aspartate ( NMDA ) antagonist ( e.g. , memantine ) if a patient with mild/moderate dementia has an inadequate response to monotherapy . Control of hypertension and diabetes was the treatment of choice , in patients with mild/moderate vascular or mixed AD/vascular dementia , with aspirin another first-line option . Cholinesterase inhibitors were also a first-line option for mild/moderate mixed AD/vascular dementia . Among nonpharmacological interventions for mild/moderate dementia , the experts recommended caregiver education , supportive therapy for caregivers , referral to day treatment , exercise programs , and respite care . For moderate/severe AD or mixed AD/vascular dementia , the experts recommended combining an NMDA antagonist with a cholinesterase inhibitor . For moderate/severe vascular or mixed AD/vascular dementia , they recommended control of hypertension and diabetes . The experts ' ratings underscore the importance of nonpharmacological strategies aim ed at reducing caregiver burden in more severe dementia . Management of agitation and other behavioral disturbances was another focus of this study . The experts recommended using an atypical antipsychotic for agitation associated with delirium , psychosis , aggression , or anger . They would also consider divalproex to manage anger with a risk of physical aggression . Selective serotonin reuptake inhibitors were recommended for the treatment of depression or anxiety in patients with dementia . Benzodiazepines or atypical antipsychotics were viewed as short-term options for acute anxiety .  Trazodone was recommended for insomnia . The experts also gave recommendations concerning dosage levels , duration of treatment , and choice of medications for patients with different complicating conditions . CONCLUSIONS The experts reached high levels of consensus on key steps in treating dementia and associated behavioral disturbances . Within the limits of expert opinion and with the expectation that new research data will take precedence , these guidelines may provide direction for clinicians offering care to patients with dementia 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 The objective of the study was to examine the efficacy of fluoxetine in  social phobia . Sixty subjects were r and omly assigned to 14 weeks of double-blind therapy with either fluoxetine or placebo . Dose was fixed at 20 mg for fluoxetine during the first 8 weeks of double-blind treatment ; during the final 6 weeks , the dose could be increased every two weeks by 20 mg to a maximum of 60 mg/day . An intentto-treat analysis was used . A significant change from baseline to endpoint was found for both fluoxetine and placebo on the Liebowitz Social Anxiety Scale . However , no significant difference was found between fluoxetine and placebo . The change for fluoxetine was somewhat lower than that found with other selective serotonin reuptake inhibitors , whereas the placebo response was greater .  Fluoxetine failed to separate from placebo in this trial . It is unknown whether a larger dose for longer duration would have yielded separation from placebo . A higher than usual  placebo response rate was found Abstract Objective . Anxiety disorders are frequently under-diagnosed conditions in primary care , although they can be managed effectively by general practitioners . Methods . This paper is a short and practical summary of the World Federation of Biological Psychiatry ( WFSBP ) guidelines for the pharmacological treatment of anxiety disorders , obsessive – compulsive disorder ( OCD ) and posttraumatic stress disorder ( PTSD ) for the treatment in primary care . The recommendations were developed by a task force of 30 international experts in the field and are based on r and omized controlled studies . Results . First-line pharmacological treatments for these disorders are  selective serotonin reuptake inhibitors  ( for all disorders ) ,  serotonin-norepinephrine reuptake inhibitors  ( for some ) and  pregabalin  ( for generalized anxiety disorder only ) . A combination of  medication and cognitive behavior/exposure therapy  was shown to be a clinical ly desired treatment strategy . Conclusions . This short version of an evidence -based guideline may improve treatment of anxiety disorders , OCD , and PTSD in primary care The augmentation of serotonin reuptake inhibitors ( SRIs ) with atypical antipsychotics for the management of  treatment-resistant obsessive-compulsive disorder ( OCD ) is gaining increasing acceptance . Quetiapine is a novel antipsychotic which is well tolerated , and which may therefore be particularly useful in this context . Charts of all patients treated in our OCD clinic with the combination of an SRI and quetiapine  were review ed . Demographic details and clinical symptoms on the Yale-Brown Obsessive-Compulsive Scale and the Clinical Global Impressions Scale ( CGI ) were tabulated before and after augmentation . Eight OCD patients who had proven resistance to treatment with SRIs  had received quetiapine augmentation . Four of these eight patients were responders ( CGI of 1 or 2 ) within 4 weeks . In the treatment-responders , the medication was well tolerated . Although limited by the retrospective design and lack of controls , these data are consistent with the growing literature suggesting that approximately one-half of OCD patients resistant to treatment with SRIs  may respond to augmentation with an atypical antipsychotic . Quetiapine , a relatively well tolerated agent , deserves further controlled study in this context Abstract : Venlafaxine extended release ( ER ) is a dual serotonin-norepinephrine reuptake inhibitor previously shown to be effective in the treatment of major depressive disorder and generalized anxiety disorder . This placebo-controlled , multicenter , r and omized , double-blind trial examined the efficacy and safety of venlafaxine ER in out patients with generalized social anxiety disorder . Two hundred seventy-two out patients were r and omly assigned to receive either a flexible dose of venlafaxine ER ( 75 to 225 mg/d ) or placebo for 12 weeks . Venlafaxine ER was statistically significantly more effective than placebo as demonstrated by the Liebowitz Social Anxiety Scale total scores at weeks 4 to 12 . Scores of both the Clinical Global Impression-Severity and Clinical Global Impression-Improvement scales showed that venlafaxine ER was significantly more effective than placebo at weeks 4 to 12 . In addition , more venlafaxine ER-treated patients achieved CGI-Improvement scores of 1 or 2 than placebo-treated patients at weeks 4 to 12 , demonstrating a greater percentage of responders to venlafaxine ER treatment . Assessment using the fear/anxiety and avoidance subscales of the Liebowitz Social Anxiety Scale and the Social Phobia Inventory Scale also showed venlafaxine ER to be more effective than placebo at weeks 4 to 12 and 6 to 12 , respectively . The Sheehan Disability Inventory showed that patients in the venlafaxine ER-treated group had significantly better outcomes in social life at weeks 4 and 12 , and in work at week 12 . Adverse events were similar to those reported in studies of venlafaxine ER in depression and generalized anxiety disorder .  Venlafaxine ER was safe , well tolerated , and efficacious in the short-term treatment of generalized social anxiety disorder 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 Introduction Pharmacotherapy and cognitive behavioural therapy ( CBT ) are consistently effective as first-line treatments for  social anxiety disorders ( SADs ) . Nevertheless , pharmacotherapy is often the first choice in clinical practice . In many countries , the first line of pharmacotherapy involves the administration of a selective serotonin reuptake inhibitor ( SSRI ) . Although a significant proportion of patients with SAD fail to respond to the initial SSRI administration , there is no st and ard approach to the management of SSRI-resistant SAD . This paper describes the study protocol for a r and omised controlled trial to evaluate the clinical effectiveness of CBT as a next-step strategy , concomitant with conventional treatment , for patients with SSRI-resistant SAD . Methods and analysis This Prospect i ve R and omized Open Blinded End-point study is design ed with two parallel groups , with dynamic allocation at the individual level . The interventions for the two groups are conventional treatment , alone , and CBT combined with conventional treatment , for 16 weeks . The primary end-point of SAD severity will be assessed by an independent assessor using the Liebowitz Social Anxiety Scale , and secondary end-points include severity of other social anxieties , depressive severity and functional impairment . All measures will be assessed at weeks 0 ( baseline ) , 8 ( halfway point ) and 16 ( postintervention ) and the outcomes will be analysed based on the intent-to-treat . Statistical analyses are planned for the study design stage so that field material s can be appropriately design ed . Ethics and dissemination This study will be conducted at the academic outpatient clinic of Chiba University Hospital . Ethics approval was granted by the Institutional Review Board of Chiba University Hospital . All participants will be required to provide written informed consent . The trial will be implemented and reported in accordance with the recommendations of CONSORT . Clinical Trial Registration Number UMIN000007552 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 Social phobia , also known as social anxiety disorder , is a highly prevalent disorder with significant morbidity . Patients with social phobia frequently develop co-morbid psychiatric disorders such as depression and substance abuse , and the disorder impacts significantly on social and occupational functioning . It has been suggested that the selective serotonin reuptake inhibitors ( SSRIs ) are useful in the management of this disorder , but few controlled trials have been undertaken in this regard . There are also few data on the pharmacotherapy of social phobia in South Africa . METHODS A double-blind r and omised placebo-controlled multi-site flexible-dose trial of paroxetine was undertaken over 12 weeks among patients with a primary diagnosis of social phobia . Primary response measures were the Global Improvement item on the Clinical Global Impression scale ( CGI ) and mean change from baseline in the patient-rated Liebowitz Social Anxiety Scale ( LSAS ) total score .  Ninety-three patients participated at 9 South African sites ; their data are reported here . RESULTS There was a significant drug effect on both the CGI Global Improvement score and the LSAS at 12 weeks . In addition , there was no significant difference in overall rate of adverse experiences between those on paroxetine and those on placebo . CONCLUSIONS Paroxetine is both effective and safe in the acute treatment of social phobia . The findings here are consistent with those of previous controlled studies of the SSRIs as well as with previous work done in the USA on the use of paroxetine in the treatment of this disorder . Early diagnosis and treatment of social phobia should be encouraged . However , further research on long-term pharmacotherapy of social phobia is needed BACKGROUND AND OBJECTIVE Selective serotonin reuptake inhibitors ( SSRIs ) are currently the first-line treatment for panic disorder , although up to 30 % of patients either do not respond to SSRIs or withdraw due to adverse events . Reboxetine , a selective norepinephrine reuptake inhibitor ( selective NRI ) , is effective in treating depression and may alleviate depression-related anxiety . This study aim ed to investigate the efficacy of reboxetine in the treatment of patients with panic disorder who did not respond to SSRIs . METHOD In this 6-week , open-label study , 29 adult out patients with panic disorder who had previously failed to respond to SSRI treatment received reboxetine 2 mg/day , titrated to a maximum of 8 mg/day over the first 10 days .  Efficacy was assessed using the Panic Self- Question naire ( PSQ ) , the Hamilton Rating Scale for Anxiety ( HAM-A ) , the 17-item Hamilton Rating Scale for Depression ( HRSD ) and the Global Assessment of Functioning ( GAF ) Scale . RESULTS The 24 patients who completed the study responded well to reboxetine treatment . Significant improvement ( p < 0.001 ) was observed in the number of daily panic attacks , and on the scales measuring anxiety , depression and functioning . Reboxetine was generally well tolerated . Five patients withdrew due to  adverse events . CONCLUSIONS Reboxetine appears to be effective in the treatment of SSRI-refractory panic disorder patients and warrants further clinical investigation OBJECTIVE Selective serotonin reuptake inhibitors ( SSRIs ) appear to be an effective class of medications for the treatment of  generalized anxiety disorder .  Within the SSRI class , however , there have been no comparative treatment studies for this disorder . Therefore , in the present study , we compared the efficacy and tolerability of 2 SSRIs , paroxetine and sertraline , in the treatment of generalized anxiety disorder . METHOD In this parallel-group , double-blind , flexible-dose study , 55 patients with primary generalized anxiety disorder ( DSM-IV criteria ) were r and omly assigned to receive either paroxetine or sertraline treatment for 8 weeks . Primary efficacy measures were the mean changes in Hamilton Rating Scale for Anxiety ( HAM-A ) scores as well as responder and remission rates based on the Clinical Global Impressions scale . Secondary efficacy measures consisted of the Indiana University Generalized Anxiety Measurement Scale and self-report ratings of anxiety , and quality -of-life outcome . Tolerability was assessed using the Systematic Assessment for Treatment Emergent Events question naire for treatment-emergent symptoms . RESULTS The intent-to-treat sample consisted of 53 patients who received medication for at least 1 week . Of the 53 patients , 43 completed the entire 8 weeks of treatment . Both paroxetine and sertraline result ed in significant decreases in mean HAM-A scores ( paroxetine = 57 % + /- 28 % ; sertraline = 56 % + /- 28 % ) . There were no differences between medication groups on response or remission rates , and tolerability was comparable . CONCLUSIONS Both paroxetine and sertraline appear similarly effective and well tolerated for the treatment of generalized anxiety disorder BACKGROUND Many patients with depression take benzodiazepine drugs long term despite the absence of continuing therapeutic value . AIMS To evaluate a treatment programme involving gradual discontinuation with or without simultaneous selective serotonin reuptake inhibitor ( SSRI ) prescribing and to determine the long-term outcome after benzodiazepine withdrawal . METHOD Patients went through three phases - change to an equivalent dose of diazepam ; subsequent r and omisation to either 20 mg of paroxetine or placebo ; and gradual reduction of diazepam in depression-free patients - with a follow-up after 2 or 3 years . RESULTS A total of 230 patients were recruited and 75 % in the paroxetine group and 61 % in the placebo group were successfully treated after 6 weeks ( P:=0.067 ) . After 2 or 3 years 13 % of patients were still benzodiazepine free : 26 % of those who had successfully tapered off benzodiazepine and 6 % of the total group . CONCLUSIONS Transfer to diazepam followed by gradual withdrawal is an effective way of discontinuing chronic benzodiazepine use . The addition of SSRI treatment is of limited value This double-blind , placebo-controlled study compared venlafaxine ( immediate release ) , the first modern serotonin-norepinephrine reuptake inhibitor , with the selective serotonin reuptake inhibitor fluoxetine .  Out patients were r and omly assigned to 6 weeks of treatment with venlafaxine  ( 75 - 225mg/day ; n=102 ) , fluoxetine ( 20 - 60mg/day ; n=104 ) , or placebo ( n=102 ) . Efficacy was assessed using the 21-item Hamilton Depression Rating Scale ( HAM-D(21 ) ) , the Montgomery-Asberg Depression Rating Scale ( MADRS ) , the Clinical Global Impression-Severity of Illness ( CGI-S ) scale , response and remission rates , and several other measures . Intent-to-treat analyses utilized both the last observation carried forward and ETRANK methods to account for missing data . At week 6 or study endpoint , venlafaxine ( mean dose : 142mg/day ) was superior to placebo on most outcomes measures , whereas the differences between fluoxetine ( mean dose : 41mg/day ) and placebo were less consistent . Final remission ( defined as HAM-D < or = 7 ) rates were 32 % , 28 % , and 22 % for venlafaxine , fluoxetine , and placebo , respectively . Few differences between the active treatments attained statistical significance . Both active therapies were generally well tolerated ; however , attrition due to adverse events , incidence of selected side effects , and increases in pulse and blood pressure favored fluoxetine over venlafaxine . This study provides further evidence that venlafaxine is effective after 6 weeks of treatment compared with placebo . The efficacy profile of fluoxetine was somewhat less consistent . It is strongly recommended that future studies of comparative antidepressant efficacy be adequately powered to detect modest between-drug differences in efficacy Despite the widespread application of combined selective serotonin reuptake inhibitors ( SSRI ) and benzodiazepine treatment for panic disorder , there has been relatively little systematic assessment of the safety and efficacy of this therapeutic strategy . Although the limited number of studies to date suggest a more rapid onset of benefit with combined treatment , this study is the first to address the critical question of whether continued combined treatment confers superior efficacy . This study is a r and omized , double-blind , three-arm study in patients with panic disorder ( n = 60 ) , comparing the efficacy and safety of paroxetine and placebo ( PP ) , paroxetine coadministered with clonazepam followed by a tapered benzodiazepine discontinuation phase ( PC-D ) , and ongoing combination treatment ( PC-M ) . All treatment groups demonstrated significant improvement by endpoint . There was a significant advantage for the combined treatment groups early in treatment but , subsequently , outcome in all three groups was similar . A trend towards greater achievement of endpoint remission status for the PC-D group was attenuated when variability in baseline severity was considered . The results of this study should be interpreted in the context of a relatively moderate sample size and higher rates of early dropout . Combined treatment with paroxetine and clonazepam result ed in more rapid response than with the SSRI alone , but there was no differential benefit beyond the initial few weeks of therapy . Initiating combined treatment followed by benzodiazepine taper after a few weeks may provide early benefit while avoiding the potential adverse consequences of long-term combination therapy BACKGROUND  Generalized social phobia is common , persistent , and disabling and is often treated with selective serotonin reuptake inhibitor drugs or cognitive behavioral therapy . OBJECTIVE We compared fluoxetine ( FLU ) , comprehensive cognitive behavioral group therapy ( CCBT ) , placebo ( PBO ) , and the combinations of CCBT/FLU and CCBT/PBO . DESIGN R and omized , double-blind , placebo-controlled trial . SETTING Two academic outpatient psychiatric centers . PATIENTS Subjects meeting a primary diagnosis of generalized social phobia were recruited via advertisement . Seven hundred twenty-two were screened , and 295 were r and omized and available for inclusion in an intention-to-treat efficacy analysis ; 156 ( 52.9 % ) were male , 226 ( 76.3 % ) were white , and mean age was 37.1 years . INTERVENTIONS Treatment lasted for 14 weeks . Fluoxetine and PBO were administered at doses from 10 mg/d to 60 mg/d ( or equivalent ) . Group comprehensive cognitive behavioral therapy was administered weekly for 14 sessions . MAIN OUTCOME MEASURES An independent blinded evaluator assessed response with the Brief Social Phobia Scale and Clinical Global Impressions scales as primary outcomes . A videotaped behavioral assessment served as a secondary outcome , using the Subjective Units of Distress Scale . Adverse effects were measured by self-rating . Each treatment was compared by means of chi2 tests and piecewise linear mixed-effects models . RESULTS Clinical Global Impressions scales response rates in the intention-to-treat sample were 29 ( 50.9 % ) ( FLU ) , 31 ( 51.7 % ) ( CCBT ) , 32 ( 54.2 % ) ( CCBT/FLU ) , 30 ( 50.8 % ) ( CCBT/PBO ) , and 19 ( 31.7 % ) ( PBO ) , with all treatments being significantly better than PBO . On the Brief Social Phobia Scale , all active treatments were superior to PBO . In the linear mixed-effects models analysis , FLU was more effective than CCBT/FLU , CCBT/PBO , and PBO at week 4 ; CCBT was also more effective than CCBT/FLU and CCBT/PBO . By the final visit , all active treatments were superior to PBO but did not differ from each other . Site effects were found for the Subjective Units of Distress Scale assessment , with FLU and CCBT/FLU superior to PBO at Duke University Medical Center , Durham , NC . Treatments were well tolerated . CONCLUSIONS All active treatments were superior to PBO on primary outcomes . Combined treatment did not yield any further advantage . Notwithst and ing the benefits of treatment , many patients remained symptomatic after 14 weeks 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 Neuropathic pain ( NeP ) , generated by disorders of the peripheral and central nervous system , can be particularly severe and disabling . Prevalence estimates indicate that 2 % to 3 % of the population in the developed world suffer from NeP , which suggests that up to one million Canadians have this disabling condition . Evidence -based guidelines for the pharmacological management of NeP are therefore urgently needed . R and omized , controlled trials , systematic review s and existing guidelines focusing on the pharmacological management of NeP were evaluated at a consensus meeting . Medications are recommended in the guidelines if their analgesic efficacy was supported by at least one method ologically sound , r and omized , controlled trial showing significant benefit relative to placebo or another relevant control group . Recommendations for treatment are based on degree of evidence of analgesic efficacy , safety , ease of use and cost-effectiveness .  Analgesic agents recommended for first-line treatments are certain antidepressants ( tricyclics ) and anticonvulsants ( gabapentin and pregabalin ) . Second-line treatments recommended are serotonin noradrenaline reuptake inhibitors and topical lidocaine . Tramadol and controlled-release opioid analgesics are recommended as third-line treatments for moderate to severe pain . Recommended fourth-line treatments include cannabinoids , methadone and anticonvulsants with lesser evidence of efficacy , such as lamotrigine , topiramate and valproic acid . Treatment must be individualized for each patient based on efficacy , side-effect profile and drug accessibility , including cost . Further studies are required to examine head-to-head comparisons among analgesics , combinations of analgesics , long-term outcomes , and treatment of pediatric and central The aim of this study was to evaluate the efficacy , tolerability , and effects on quality of life of sertraline , a selective serotonin reuptake inhibitor , in the prevention of relapse of generalized social phobia .  Fifty adult out patients with generalized social phobia who were rated much or very much improved on the Clinical Global Impression Scale of Improvement ( CGI-I ) after 20 weeks of sertraline treatment ( 50 - 200 mg/day ) were r and omly assigned in a one-to-one ratio to either continue double-blind treatment with sertraline or immediately switch to placebo for another 24 weeks . The initial 20-week study was placebo-controlled , and 15 responders to placebo also continued to receive double-blind placebo treatment in the continuation study . Eighty-eight percent of patients in the sertraline-continuation group and only 40 % of patients in the placebo-switch and placebo-responder groups completed the study . In intent-to-treat endpoint analyses , 1 ( 4 % ) of 25 patients in the sertraline-continuation group and 9 ( 36 % ) of 25 patients in the placebo-switch group had relapsed at study endpoint ( chi2 = 8.0 , Fisher exact test , p = 0.01 ) . The relative risk ( hazards ratio ) for relapse associated with placebo-switch relative to sertraline-continuation treatment was 10.2 ( 95 % confidence interval , 1.3 - 80.7 ) . Mean CGI-Severity , Marks Fear Question naire ( MFQ ) Social Phobia subscale , and Duke Brief Social Phobia Scale ( BSPS ) total scores were reduced by 0.07 , 0.34 , and 1.86 in the Sertraline-Continuation group and increased by 0.88 , 4.09 , and 5.99 in the Placebo-Switch group ( all F > 5.3 , p < 0.03 ) , respectively . CGI-Severity , MFQ Social Phobia subscale , and BSPS scores also increased in the Placebo-Responder group . Discontinuations because of lack of efficacy were 4 % in the sertraline-continuation group , 28 % in the placebo-switch group ( chi2 = 5.36 , Fisher exact test , p = 0.049 ) , relative to sertraline , and 27 % in the placebo-responder group . Sertraline was effective in preventing relapse of generalized social phobia . Future research should assess whether improvements may be maintained or further increased by longer periods of treatment or through the addition of cognitive-behavioral techniques BACKGROUND Generalized social anxiety disorder ( GSAD ) is a pervasive form of social anxiety that affects approximately 5 % of persons in the community . Among evidence -based pharmacologic treatments for the disorder , selective serotonin reuptake inhibitors ( SSRIs ) have become widely used and are known to be efficacious . Monotherapy with the benzodiazepine clonazepam is also efficacious for GSAD , but the adjunctive use of clonazepam with an SSRI to potentially improve outcomes has not been studied to date . METHOD Twenty-eight patients ( 22 men and 6 women ) with DSM-IV-defined GSAD were r and omly assigned to receive double-blind clonazepam ( or placebo ) , 1.0 to 2.0 mg/day ( divided b.i.d . ) along with open-label paroxetine , 20 to 40 mg/day , for 10 weeks . A 2-week taper of double-blind medication was followed by an additional 8 weeks of open-label paroxetine treatment ( during which the dose of paroxetine could be increased to a maximum of 50 mg/day ) . Twenty-three patients ( 82 % ) met DSM-IV criteria for avoidant personality disorder . The patients ' mean + /- SD age was 31.2 + /- 7.7 years , and their mean duration of illness was 12.1 + /- 5.8 years . Data were gathered from August 2001 to April 2002 . RESULTS Nineteen ( 68 % ) of 28 patients completed treatment . At the end of the 10-week double-blind treatment , there was a trend ( p < .06 ) favoring the paroxetine/clonazepam group , who had a 79 % response rate ( Clinical Global Impressions-Global Improvement scale [ CGI-I ] score of 1 or 2 ) compared with a 43 % response rate for the paroxetine/placebo group . However , no significant differences on other outcome measures were noted between the 2 groups in an intent-to-treat analysis , in terms of either very early ( 2 - 4 weeks ) or not as early ( 5 - 10 weeks ) responses during treatment . Dropout rates due to adverse events were rare ( 1 patient in each group ) , indicating that the paroxetine/clonazepam combination was well tolerated . CONCLUSION Coadministration of clonazepam with an SSRI , in contrast to findings in panic disorder , did not lead to more rapid resolution of symptoms in GSAD . On the other h and , there is some evidence that the clonazepam-added group had superior global outcomes ( e.g. , as measured on the CGI-I ) , although power to detect such differences in this study was small . These observations suggest that a role for adjunctive benzodiazepines in patients with GSAD ( e.g. , for augmenting SSRI partial response or nonresponse ) is deserving of further controlled investigation Abstract : Selective serotonin reuptake inhibitors ( SSRIs ) are the gold st and ard for the pharmacological treatment of generalized social phobia ( GSP ) . However , little is known about the predictors of response to treatment . Two hundred and four out patients with GSP were r and omized to sertraline ( Zoloft ) or placebo , for a 20-week double-blind study , with a flexible dose range of sertraline 50 to 200 mg/d . Response was defined as the percentage of patients with a Clinical Global Impression-Improvement scale ( CGI-I ) of 1 ( very much improved ) or 2 ( much improved ) . Outcome analyses were conducted using regression models including treatment group as a categorical predictor and study visit as a repeated measure . Dependent measures included Marks Fear Question naire ( MFQ ) , Brief Social Phobia Scale ( BSPS ) , CGI-I , and Sheehan Disability Scale ( SDS ) . We investigated several possible predictors of response to treatment including DSM-IV comorbidity , age , sex , age of onset of GSP , and duration of illness . Patients with later-onset ( especially adult-onset ) GSP tend to have a better response to treatment than those with earlier-onset GSP . This result generally appears in our analyses as a 2-way interaction , where the association with response is greatest for patients with adult-onset GSP ( in contrast to those with child or adolescent onset ) . This finding is most robust for symptom measures , but is still apparent for the Sheehan measure of disability at work . This advantage for later-onset GSP can be accounted for neither by severity of illness nor by duration of illness . Superior treatment outcome for later-onset GSP may be mediated by the degree of social and family disability Clinical trials of social anxiety disorder ( SAD ) have largely focused on the effect of treatment on symptoms of fear and avoidance , while neglecting the third clinical ly relevant dimension , physiological arousal . Data were combined from two previously reported placebo‐controlled trials of sertraline in the treatment of moderate‐to‐severe generalized SAD . Efficacy was evaluated using the Brief Social Phobia Scale ( BSPS ) . Three hundred forty‐six subjects were r and omized to 12–13 weeks of treatment with sertraline and 273 subjects to placebo .  Following treatment , significant improvement was noted in favor of sertraline on the full BSPS ( P<.001 ) , as well as on each of the individual BSPS subscales : fear ( P=.001 ) ; avoidance ( P<.0001 ) ; and physiological arousal ( P<.0001 ) . Of the physiological symptoms assessed , the treatment advantage with sertraline was maintained for blushing ( P<.003 ) and palpitations ( P<.03 ) , but not for trembling and sweating . These results confirm the efficacy of treatment with a selective serotonin reuptake inhibitor ( SSRI ) , sertraline , across the spectrum of fear , avoidance , and physiological arousal in generalized SAD ( GSAD ) . Among common physiological symptoms in this population , blushing and palpitations appear more treatment responsive than trembling and sweating to acute treatment with sertraline . Depression and Anxiety 23:6–10 , 2006 . © 2005 Wiley‐Liss , More than half of anxiety and depression patients treated with an adequate course of antidepressants fail to fully improve . We retrospectively examined whether treatment-resistant depression and anxiety disorder patients responded to and tolerated augmentation with the atypical antipsychotic , aripiprazole . We report on patients with depression and anxiety disorders , including panic disorder , generalized anxiety disorder , social anxiety and post-traumatic stress disorder , who had an incomplete response to a variety of selective serotonin reuptake inhibitors ( SSRIs ) and who received augmentation with aripiprazole .  The primary outcome measure was the Clinical Global Impression of Improvement ( CGI-I ) . In the intent-to-treat analysis , the mean±SD CGI-S was 3.8±1.3 at endpoint . Fifty-nine percent of subjects received CGI-I ratings of 1 or 2 , ‘ much improved ’ or ‘ very much improved , ’ in terms of their depression and anxiety symptoms at the end of 12 weeks . Several patients showed an early ( weeks 1–5 ) , as well as sustained , response to augmentation with doses of aripiprazole between 15 and 30 mg/day . The results suggest that aripiprazole may be effective as an augmentation for patients with persistent depressive and anxiety disorders despite initial SSRI treatment . Because this is a retrospective case review , further prospect i ve studies are required to confirm these findings BACKGROUND Depression after myocardial infa rct ion ( MI ) is associated with higher morbidity and mortality . Although antidepressants are effective in reducing depression , their use in patients with cardiovascular disease remains controversial . OBJECTIVE To undertake a secondary analysis to determine the effects of using antidepressants on morbidity and mortality in post-MI patients who participated in the Enhancing Recovery in Coronary Heart Disease study . DESIGN Observational secondary analysis . SETTING Eight academic sites . PATIENTS The Enhancing Recovery in Coronary Heart Disease clinical trial r and omized 2481 depressed and /or socially isolated patients from October 1 , 1996 , to October 31 , 1999 . Depression was diagnosed using a structured clinical interview . This analysis was conducted on the 1834 patients enrolled with depression ( 849 women and 985 men ) . INTERVENTION Use of antidepressant medication . MAIN OUTCOME MEASURES Event-free survival was defined as the absence of death or recurrent MI . All-cause mortality was also examined . To relate exposure to antidepressants to subsequent morbidity and mortality , the data were analyzed using a time-dependent covariate model . RESULTS During a mean follow-up of 29 months , 457 fatal and nonfatal cardiovascular events occurred . The risk of death or recurrent MI was significantly lower in patients taking selective serotonin reuptake inhibitors ( adjusted hazard ratio [ HR ] , 0.57 ; 95 % confidence interval [ CI ] , 0.38 - 0.84 ) , as were the risk of all-cause mortality ( adjusted HR , 0.59 ; 95 % CI , 0.37 - 0.96 ) and recurrent MI ( adjusted HR , 0.53 ; 95 % CI , 0.32 - 0.90 ) , compared with patients who did not use selective serotonin reuptake inhibitors . For patients taking non-selective serotonin reuptake inhibitor antidepressants , the comparable HRs ( 95 % CIs ) were 0.72 ( 0.44 - 1.18 ) , 0.64 ( 0.34 - 1.22 ) , and 0.73 ( 0.38 - 1.38 ) for risk of death or recurrent MI , all-cause mortality , or recurrent MI , respectively , compared with nonusers . CONCLUSIONS Use of selective serotonin reuptake inhibitors in depressed patients who experience an acute MI might reduce subsequent cardiovascular morbidity and mortality . A controlled trial is needed to examine this important issue Attempts have been made to find appropriate drug regimens to treat binge eating disorder ( BED ) . Several reports have examined the use of selective serotonin reuptake inhibitors ( SSRIs ) or mood stabilizers ; both serotonin and noradrenalin reuptake inhibitors ( SNRIs ) have been reported to be useful for binge eating , but the available data are limited . We evaluated the efficacy of duloxetine , an SNRI , in 45 obese patients who reported binge eating & NA ; R and omized , double‐blind , placebo‐controlled trials on neuropathic pain treatment are accumulating , so an up date d review of the available evidence is needed . Studies were identified using MEDLINE and EMBASE search es . Numbers needed to treat ( NNT ) and numbers needed to harm ( NNH ) values were used to compare the efficacy and safety of different treatments for a number of neuropathic pain conditions . One hundred and seventy‐four studies were included , representing a 66 % increase in published r and omized , placebo‐controlled trials in the last 5 years . Painful poly‐neuropathy ( most often due to diabetes ) was examined in 69 studies , postherpetic neuralgia in 23 , while peripheral nerve injury , central pain , HIV neuropathy , and trigeminal neuralgia were less often studied . Tricyclic antidepressants , serotonin noradrenaline reuptake inhibitors , the anticonvulsants gabapentin and pregabalin , and opioids are the drug classes for which there is the best evidence for a clinical relevant effect . Despite a 66 % increase in published trials only a limited improvement of neuropathic pain treatment has been obtained . A large proportion of neuropathic pain patients are left with insufficient pain relief . This fact calls for other treatment options to target chronic neuropathic pain . Large‐scale drug trials that aim to identify possible subgroups of patients who are likely to respond to specific drugs are needed to test the hypothesis that a mechanism‐based classification may help improve treatment of the individual patients 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 Objective : This study assessed the efficacy , safety , and tolerability of the serotonin-norepinephrine reuptake inhibitor desvenlafaxine and the selective serotonin reuptake inhibitor escitalopram for major depressive disorder ( MDD ) in postmenopausal women . Methods : In this r and omized , double-blind study , postmenopausal out patients ( aged 40 - 70 y ) with Diagnostic and Statistical Manual of Mental Disorders , Fourth Edition MDD received flexible-dose desvenlafaxine ( 100 - 200 mg/d ) or escitalopram ( 10 - 20 mg/d ) for 8 weeks . Acute-phase responders , that is , women with a 50 % or greater reduction from baseline in the 17-item Hamilton Rating Scale for Depression ( HAM-D17 ) total score , were eligible to continue the same double-blind treatment in the 6-month continuation phase . The primary efficacy outcomes were mean change from baseline in HAM-D17 total score ( acute phase ) , analyzed using a mixed-effects model for repeated measures , and the proportion of women who maintained response ( continuation phase ) , analyzed using logistic regression . Results : Reductions in HAM-D17 total score at acute-phase endpoint were similar for desvenlafaxine- and escitalopram-treated women ( −13.6 vs −14.3 , respectively ; P = 0.24 ) . No significant difference was observed between groups at continuation-phase endpoint in the proportion of women who maintained response ( desvenlafaxine , 82 % ; escitalopram , 80 % ; P = 0.70 ) . In both phases , desvenlafaxine and escitalopram  were generally safe and well tolerated . Conclusions : Among postmenopausal out patients with MDD , there were no significant differences in the efficacy of desvenlafaxine and escitalopram based on primary efficacy analyses . The results do not support the overall hypothesis that the serotonin-norepinephrine reuptake inhibitor desvenlafaxine has an efficacy advantage for the treatment of MDD in postmenopausal women because , in this particular subgroup , desvenlafaxine failed to prove superiority over escitalopram  . Safety and tolerability were comparable Fluvoxamine belongs to the class of selective serotonin reuptake inhibitors ( SSRIs ) which have recently gained large popularity as antidepressant agents essentially because they lack the most troublesome adverse effects of older antidepressants ( i.e. tricyclic antidepressants ) such as anticholinergic effects and cardiotoxicity . Recent studies in the literature suggest that HIV-1 infected subjects are affected by depressive episodes with a relatively high frequency , often requiring an antidepressant treatment . Due to its favorable adverse effects profile , we used fluvoxamine as first line treatment for sixteen depressed HIV-1 infected subjects . They were administered the drug at a daily dosage of 100 mg in the evening . Fluvoxamine provided a good clinical efficacy for six of these patients , whereas the other ten had to discontinue the drug because of the presence of severe adverse effects such as acute total insomnia , gastro-intestinal disturbances together with anorexia , aggressive and impulsive behavior and excessive sedation . The observed fluvoxamine side-effects are not typical or specific for this particular patient group since they are also described in seronegative subjects taking fluvoxamine ; however , our findings seem to indicate that they become more frequent and more severe when the drug is administered to HIV-1 infected patients The antidepressant efficacy and tolerability of milnacipran , a dual action serotonin-noradrenaline reuptake inhibitor , were compared with those of the selective serotonin reuptake inhibitor , fluvoxamine , in 113 patients with moderate to severe major depression . Treatment with milnacipran , 50 mg b.d . for 6 weeks , produced a significantly greater reduction in Montgomery-Asberg Depression Rating Scale ( MADRS ) scores than fluvoxamine , 100 mg b.d . ( P = 0.007 ; 65.4 % versus 49.9 % , respectively ) ; significantly greater decreases were also seen on days 7 ( P = 0.04 ) and 28 ( P = 0.03 ) . The response rate ( the proportion of patients showing a decrease in MADRS scores of at least 50 % ) was 78.9 % in patients receiving milnacipran , compared with 60.7 % in fluvoxamine-treated patients ( P = 0.04 ) . Milnacipran also produced greater improvements in 24-item Hamilton Depression Rating Scale scores ( P = 0.05 ) . On the Clinical Global Impression Improvement scale , 77.2 % of milnacipran-treated patients were rated as considerably or markedly improved , compared with 60.7 % of patients receiving fluvoxamine ( P = 0.06 chi-squared ) . Both treatments were well tolerated ; the only significant difference between the two groups was a higher incidence of tremor and drowsiness in patients treated with fluvoxamine . It is concluded that milnacipran may offer some advantages over selective serotonin reuptake inhibitors , such as fluvoxamine , in the treatment of moderate to severe major depression Background : Parkinson disease ( PD ) is a common neurodegenerative disease affecting up to 1 million individuals in the United States . Depression affects up to 50 % of these patients and is associated with a variety of poor outcomes for patients and their families . Despite this , there are few evidence -based data to guide clinical care . Methods : An NIH-funded , r and omized , controlled trial of paroxetine CR , nortriptyline , and placebo in 52 patients with PD and depression . The primary outcomes were the change in the Hamilton Depression Rating Scale ( HAM-D ) and the percentage of depression responders at 8 weeks . Results : Nortriptyline was superior to placebo for the change in HAM-D ( p < 0.002 ) ; paroxetine CR was not . There was a trend for superiority of nortriptyline over paroxetine CR at 8 weeks ( p < 0.079 ) . Response rates favored nortriptyline ( p = 0.024 ) : nortriptyline 53 % , paroxetine CR 11 % , placebo 24 % . In planned contrasts of response rates , nortriptyline was superior to paroxetine CR ( p = 0.034 ) . Nortriptyline was also superior to placebo in many of the secondary outcomes , including sleep , anxiety , and social functioning , while paroxetine CR was not . Both active drug treatments were well tolerated . Conclusions : Though relatively modest in size , this is the largest placebo-controlled trial done to date in patients with Parkinson disease ( PD ) and depression .  Nortriptyline was efficacious in the treatment of depression and paroxetine CR was not . When compared directly , nortriptyline produced significantly more responders than did paroxetine CR . The trial suggests that depression in patients with PD is responsive to treatment and raises questions about the relative efficacy of dual reuptake inhibitors and selective serotonin reuptake inhibitors . ARR = absolute risk reduction ; DSM-IV = Diagnostic and Statistical Manual of Mental Disorders , 4th edition ; HAM-A = Hamilton Anxiety Scale ; HAM-D = Hamilton Depression Rating Scale ; MMSE = Mini-Mental State Examination ; NNT = number needed to treat ; PD = Parkinson disease ; PDQ = Parkinson ’s Disease Question naire ; PSQI = Pittsburgh Sleep Quality Index ; SCID = Structured Clinical Interview ; SSRI = selective serotonin reuptake inhibitor ; TCA = tricyclic antidepressant ; UPDRS = Unified Parkinson ’s Disease Rating Scale OBJECTIVES To determine whether current use of central nervous system (CNS)-active medications , including benzodiazepines , antidepressants , anticonvulsants , and narcotics , increases the risk for subsequent falls . DESIGN Prospect i ve cohort study . SETTING Four clinical centers in Baltimore , Maryl and ; Portl and , Oregon ; Minneapolis , Minnesota ; and the Monongahela Valley , Pennsylvania . PARTICIPANTS Eight thous and one hundred twenty-seven women aged 65 and older participating in the fourth examination of the Study of Osteoporotic Fractures between 1992 and 1994 . MEASUREMENTS Current use of CNS-active medications  was assessed with an interviewer-administered question naire with verification of use from medication containers . A computerized dictionary was used to categorize type of medication from product br and and generic names . Incident falls were reported every 4 months for 1 year after the fourth examination . RESULTS During an average follow-up of 12 months , 2,241 women ( 28 % ) reported falling at least once , including 917 women ( 11 % ) who experienced two or more ( frequent ) falls . Compared with nonusers , women using benzodiazepines ( multivariate odds ratio ( MOR ) = 1.51 , 95 % confidence interval ( CI ) = 1.14 - 2.01 ) , those taking antidepressants ( MOR = 1.54 , 95 % CI = 1.14 - 2.07 ) , and those using anticonvulsants ( MOR = 2.56 , 95 % CI = 1.49 - 4.41 ) were at increased risk of experiencing frequent falls during the subsequent year . We found no evidence of an independent association between narcotic use and falls ( MOR = 0.99 for frequent falling , 95 % CI = 0.68 - 1.43 ) . Among benzodiazepine users , both women using short-acting benzodiazepines ( MOR = 1.42 , 95 % CI = 0.98 - 2.04 ) and those using long-acting benzodiazepines ( MOR = 1.56 , 95 % CI = 1.00 - 2.43 ) appeared to be at greater risk of frequent falls than nonusers , although the CIs overlapped 1.0 . We found no evidence to suggest that women using selective serotonin-reuptake inhibitors ( MOR = 3.45 , 95 % CI = 1.89 - 6.30 ) had a lower risk of frequent falls than those using tricyclic antidepressants ( MOR 1.28 , 95 % CI = 0.90 - 1.84 ) . CONCLUSIONS Community-dwelling older women taking CNS-active  medications , including those taking benzodiazepines , antidepressants , and anticonvulsants , are at increased risk of frequent falls . Minimizing use of these CNS-active medications may decrease risk of future falls . Our results suggest that fall risk in women taking benzodiazepines  is at best marginally decreased by use of short-acting preparations . Similarly , our findings indicate that preferential use of selective serotonin-reuptake inhibitors is unlikely to reduce fall risk in older women taking antidepressants 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 Industry funding and author financial conflicts of interest may influence the production and synthesis of scientific evidence ( 1 ) . Associations with the pharmaceutical company developing and marketing a drug have been found to influence the design of trials ( 2 ) , the conduct of trials ( 3 ) , and the reporting of trial results ( 47 ) . Furthermore , financial ties and industry funding seem to result in greater rates of favorable conclusions in clinical trials examining new drugs ( 812 ) . Fewer studies have considered the potential influence of financial conflicts of interest on the synthesis of clinical evidence in systematic review s ( 13 , 14 ) . Neuraminidase inhibitors , which are used in the prophylaxis and treatment of seasonal and p and emic influenza , have been the subject of ongoing uncertainty about their specific clinical benefits ( 15 , 16 ) . This is the result of not only the continuing emergence of strains with unknown drug responses but also the increasing awareness in the medical community that , until recently , its knowledge of the safety and efficacy of these drugs has been incomplete ( 17 ) . Despite the abundance of clinical trials and publications on neuraminidase inhibitors , the details of many key trials had not been disclosed ( 18 , 19 ) . As a result , systematic review ers analyzing and synthesizing evidence on the effectiveness of these agents have faced incomplete information , unresolved discrepancies in the data , and a high risk of publication and reporting biases among the primary clinical trials ( 20 , 21 ) . This prompted extensive efforts to access complete records of all published and unpublished clinical trials from manufacturers , culminating in the publication of several review s on the basis of comprehensive clinical study reports and potentially changing the way systematic review s will be undertaken in the future ( 2227 ) . Review s of neuraminidase inhibitors exhibit wide variation in their conclusions , ranging from strong endorsements of the use of these agents in the prophylaxis and treatment of influenza ( 28 , 29 ) to more conservative assessment s question ing the evidence on the drugs ' safety and efficacy ( 15 , 30 ) . The reasons for this discordance in review conclusions are likely multifactorial and may be related in part to the manner in which evidence is accessed , synthesized , and presented ( 23 , 27 ) , both in terms of the numerical results and the authors ' emphasis and interpretation ( 31 , 32 ) . Our aim was to determine whether there is an association between financial conflicts of interest and the favorable presentation of evidence in systematic review s on the use of neuraminidase inhibitors for the prophylaxis and treatment of influenza . Methods Data Sources Systematic review s were identified in PubMed , PubMed In Process , EMBASE , and the Cochrane Data base of Systematic Review s. Search es were done using the keywords influenza , neuraminidase inhibitors , oseltamivir , zanamivir , peramivir , and laninamivir . Articles were retrieved if the search terms appeared in the title or abstract or were included as data base-specific keywords . In PubMed and EMBASE , search es were also constrained to review publication types . We limited our search to English- language articles published since 1 January 2005 . These articles were manually review ed to identify those that focused on the use of neuraminidase inhibitors for influenza prophylaxis or treatment ( such as excluded articles primarily about drug development or other manufacturing processes ) . We selected all review s that used a systematic search protocol , which we defined as the inclusion and reporting of an explicit search strategy , including reasons for subsequent exclusion of articles . The final search es were done on 26 May 2014 . Cochrane review s are periodically up date d to incorporate new evidence , and the results and conclusions are resynthesized as indicated . The authors of these review s are typically different , and there may be differences in the methods as well as the results and language of the review . These up date d review s were included separately . Other Cochrane review s are occasionally rewritten by a subset of the authors for publication in medical journals as abridged versions to increase dissemination . These reports have separate peer review s and are prepared on the basis of a selection of the complete results . We considered these review s separately as well but also did a sensitivity analysis in which they were combined with the original Cochrane review s. Data Extraction Financial conflicts of interest were identified for all authors of the review s and included affiliations with or funding from the pharmaceutical company manufacturing any of the neuraminidase inhibitors under review . We defined financial conflicts of interest as employment , the funding of grants paid to an author or an author 's research group , and the funding of medical writers for the systematic review . These financial conflicts of interest were identified using information about affiliations or funding listed in the systematic review s , as well as in any other articles published by one of the authors during the 3 years before the publication of the index systematic review . In addition , we search ed authors ' personal and institutional Web sites ; lists of disclosures from GlaxoSmithKline ( Research Triangle Park , North Carolina ) and Roche Pharmaceuticals ( Basel , Switzerl and ) ; and performed Web search es combining the names of the authors , drugs , and pharmaceutical companies to identify any additional information about financial relationships . Details of the specific financial conflicts of interest identified for each author are listed in Appendix Table 1 . Appendix Table 1 . Financial Conflicts of Interest Among Authors of the Systematic Review s For each systematic review , we recorded whether prophylaxis or treatment was assessed , the forms of evidence to be included ( such as r and omized , controlled trials and observational studies ) , the specific clinical outcomes assessed , the population s examined , and whether meta-analyses were done . We also examined whether the review s included information about the validity or quality of the primary literature . In particular , we recorded whether there were statements addressing nonpublication of primary studies or publication bias , including tests done by the review ers to assess for bias in meta-analyses ( such as the Egger or Begg test [ 33 , 34 ] ) , difficulty in accessing comprehensive study data , and the prevalence or role of industry in conducting and funding the primary studies . Data Analysis Two investigators were provided with redacted copies of each review that did not include the review s ' authors , their affiliations , or information on financial conflicts of interest . These versions also did not contain the journal name , journal formatting , or the article 's acknowledgments or references . The investigators independently evaluated the review s and classified the prophylaxis and treatment assessment s as favorable or not favorable toward the use of neuraminidase inhibitors . They were instructed to do this grading on the basis of the entirety of the review text without restriction to conclusions or recommendations made in any specific section of the review , thus allowing them to take into account the emphasis and interpretation of the authors throughout the review . The agreement between the investigators was strong at 86 % ( Cohen , 0.72 ; P < 0.001 ) . Disagreements were resolved by a third investigator using the same redacted copies . Descriptive analyses were done to examine the associations between financial conflicts of interest and the grading of the systematic review s. A sensitivity analysis excluding the summary review s was done to further examine this association . We also assessed the association between financial conflicts of interest and the inclusion of statements addressing the validity or quality of the primary evidence . Role of the Funding Source This study was funded by the Australian National Health and Medical Research Council . The funding source had no role in the design and conduct of the study , analysis of the results , or the decision to su bmi t the manuscript for publication . Results We identified 827 published articles across the 4 data bases using the specified search criteria , with 26 systematic review s included in the final cohort ( Figure ) . Thirteen review s examined prophylaxis and 24 examined treatment of influenza , accounting for 37 distinct assessment s ( Appendix Table 2 ) . In terms of review methods , 7 were Cochrane systematic review s and 19 conducted and reported a meta- analysis ( 73 % ) . The evidence inclusion criteria were limited to r and omized , controlled trials for 14 of the systematic review s ( 54 % ) , and 5 included evidence from clinical study reports or patient-level data . The main population s examined were healthy adults ( 18 of 26 systematic review s ) , children ( 13 of 26 ) , and hospitalized patients ( 6 of 24 ) . The outcome measures for prophylaxis assessment s included influenza-like illness and laboratory-confirmed influenza . For the treatment assessment s , the outcomes were illness duration , influenza-related complications , hospitalization , and mortality , mostly in combination . Five review s were up date s of previous Cochrane review s , and 3 were summary review s based on Cochrane review s. Figure . Summary of evidence search and selection . Eligible systematic review s included those with outcomes related to the prophylaxis or treatment of influenza . Appendix Table 2 . Characteristics of Systematic Review s Examining Prophylaxis and Treatment Outcomes for Neuraminidase Inhibitors Association Between Financial Conflicts of Interest and Favorable Assessment s Seven of the 26 systematic review s ( 27 % ) , corresponding to 8 of the 37 assessment s ( 22 % ) , were associated with a financial conflict of interest ( Appendix Table 1 ) . We identified financial conflicts of interest in publications other than the index systematic review in 2 cases , and no additional 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 BACKGROUND The " long/short"polymorphism ( 5HTTLPR ) in the promoter of the serotonin transporter gene ( SLC6A4 ) has been proposed as a pharmacogenetic marker for antidepressant efficacy . Some but not all studies have found that the short form of 5HTTLPR ( S allele ) results in decreased efficacy of selective serotonin reuptake inhibitors . OBJECTIVE To determine if the 5HTTLPR polymorphism influences the efficacy and tolerability of mirtazapine and paroxetine hydrochloride , 2 frequently prescribed antidepressants with differing pharmacologic profiles , in geriatric depression . DESIGN Double-blind , r and omized 8-week study . SETTING Eighteen academic and private outpatient clinics . PATIENTS We evaluated 246 cognitively intact patients 65 years or older with major depression . INTERVENTIONS Antidepressant therapy with 15 to 45 mg/d of mirtazapine ( n = 124 ) or 20 to 40 mg/d of paroxetine ( n = 122 ) . MAIN OUTCOME MEASURES The Hamilton Depression Rating Scale-17 and Geriatric Depression Scale , severity of adverse events and dosing compliance indexes , and discontinuations due to adverse events . Outcome measures were stratified according to 5HTTLPR genotypes . RESULTS Geriatric Depression Scale scores indicated that S allele carriers treated with paroxetine showed a small impairment in antidepressant response . Among mirtazapine-treated patients , there was little indication that the 5HTTLPR genotype affected antidepressant efficacy . However , the 5HTTLPR polymorphism had a dramatic effect on adverse events . Among paroxetine-treated subjects , S allele carriers experienced more severe adverse events during the course of the study , achieved significantly lower final daily doses , and had more discontinuations at days 14 , 21 , 28 , 42 , and 49 . Surprisingly , among mirtazapine-treated subjects , S allele carriers had fewer discontinuations due to adverse events , experienced less severe adverse events , and achieved higher final daily doses . CONCLUSIONS These results support the hypothesis that the S allele of 5HTTLPR at the SLC6A4 locus is associated with a poor outcome after treatment with selective serotonin reuptake inhibitors . However , the major effect was on the tolerability of these drugs rather than efficacy . Results from mirtazapine-treated patients indicate that the effect of this polymorphism on outcome may depend on the mechanism of antidepressant action 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 The objective of this study was to assess the efficacy of sertraline in migraine prophylaxis . Other selective serotonin reuptake inhibitors have been studied for migraine prophylaxis , but this is the first report with sertraline .  Twenty-seven subjects were enrolled and baseline assessment of migraine frequency and severity were measured over a 4-week period . Subjects were then r and omized to receive placebo or sertraline in a double-blind fashion with headache frequency and severity measured over an 8-week period . Subjects completed a daily diary reporting the occurrence , severity , and degree of impairment associated with migraine . The headache index , a composite measure of migraine frequency and severity , scores did not significantly improve between assessment s at baseline ( 20.8 + /- 14.88 ) , 8 weeks ( 17.6 + /- 12.27 ) , and 12 weeks ( 16.7 + /- 6.38 ) in the treatment group ( n=6 ) ( P=0.956 ) . This finding is compared to other studies with the serotonin selective reuptake inhibitors , fluoxetine , fluvoxamine , and paroxetine . The authors believe that the selective serotonin reuptake inhibitors are not as effective as conventional migraine prophylaxis medications such as beta-blockers , tricyclic antidepressants , or divalproex sodium , but that in patients with comorbid depression who have failed conventional therapy selective serotonin reuptake inhibitors may be effective The aim of this double‐blind cross‐over study was to investigate whether treatment with the selective serotonin reuptake inhibitor , citalopram reduces aggressiveness in chronically violent schizophrenic in patients . Initially 19 patients were enrolled into this double‐blind cross‐over study in which the patients were treated for 24 weeks with placebo and 24 weeks with citalopram ( 20–60 mg/day ) as a supplement to their previous neuroleptic medication .  Fourteen patients completed the entire study , but sufficient data on 15 patients could be used in the end – point analysis of efficacy . Psychiatric assessment s ( Brief Psychiatric Rating Scale , Clinical Global Impression Scale for Severity of Illness , Social Dysfunction and Aggression Scale and the Global Aggression Scale ) and side effects ( UKU Side Effect Scale ) were recorded at baseline and 4 times during both periods . Aggressive incidents ( Staff Observation Aggression Scale ) were recorded throughout the study . During citalopram treatment , the frequency of aggressive incidents was significantly lower and the mental state did not deteriorate . Patients either experienced no side effects or else side effects were equally mild during both periods 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 Background : Treatment-resistant depression is a persistent clinical problem . Exogenous testosterone therapy has psychotropic effects and has been proposed as an antidepressant supplement , although this strategy has received limited systematic study . Objective : The aim of the study was to examine the mood effects of testosterone supplementation to a serotonergic antidepressant in men with treatment-resistant depression . Method : Twenty-six healthy adult men with major depressive disorder , partial or nonresponse to 2 adequate antidepressant trials during the current episode , and currently using a selective serotonin reuptake inhibitor were r and omized under double-blind conditions to receive intramuscular injections of escalating doses of testosterone or placebo , in addition to their existing selective serotonin reuptake inhibitor regimen , for 6 weeks . The main outcome measure was the Hamilton Rating Scale for Depression score . Results : The mean age was 46.4 ± 10.8 years ; mean total testosterone level , 417.5 ± 197 ng/dL ; mean baseline Hamilton Rating Scale for Depression score , 22.2 ± 5.2 ; and median duration of the current depressive episode , 6.3 ± 10.6 years . Hamilton Rating Scale for Depression scores decreased significantly in both testosterone ( 8.4 ) and placebo ( 7.4 ) groups . Antidepressant response , defined as a 50 % decline in Hamilton Rating Scale for Depression score , was achieved by 53.8 % ( 7/13 ) in the testosterone group and 23.1 % ( 3/13 ) in the placebo group ( P = 0.226 ) . Conclusion : Both injectable testosterone and placebo supplementation to selective serotonin reuptake inhibitor were associated with improvement in mood ; group differences were not distinguishable in this small sample of predominantly eugonadal men with treatment-resistant depression Clinical effectiveness of group cognitive-behavioral therapy ( GCBT ) versus fluoxetine in obsessive-compulsive disorder out patients that could present additional psychiatric comorbidities was assessed . Patients ( 18 - 65 years ; baseline Yale-Brown Obsessive-Compulsive-Scale [ Y-BOCS ] scores ≥ 16 ; potentially presenting additional psychiatric comorbidities ) were sequentially allocated for treatment with GCBT ( n=70 ) or fluoxetine ( n=88 ) . Mean Y-BOCS scores decreased by 23.13 % in the GCBT and 21.54 % in the SSRI groups ( p=0.875 ) . Patients presented a mean of 2.7 psychiatric comorbidities , and 81.4 % showed at least one additional disorder . A reduction of at least 35 % in baseline Y-BOCS scores and CGI ratings of 1 ( much better ) or 2 ( better ) was achieved by 33.3 % of GCBT patients and 27.7 % in the SSRI group ( p=0.463 ) . The Y-BOCS reduction was significantly lower in patients with one or more psychiatric comorbidities ( 21.15 % , and 18.73 % , respectively ) than in those with pure OCD ( 34.62 % ; p=0.034 ) . Being male , having comorbidity of Major Depression , Social Phobia , or Dysthymia predicted a worse response to both treatments . Response rates to both treatments were similar and lower than reported in the literature , probably due to the broad inclusion criteria and the result ing sample more similar to the real world population Paroxetine ( 30 mg ) , a selective serotonin ( 5-HT ) reuptake inhibitor , was compared in a double-blind trial to amitriptyline ( 150 mg ) in a sample of 40 in patients aged 18 - 65 years who fulfilled Research Diagnostic Criteria for major depression . Patients were studied after a placebo drug washout period of 10 days and after an active 4-week treatment period . Sleep EEG recordings were performed before and at the end of the study as well as during acute treatment ( first 2 days ) and following withdrawal of active medication . Paroxetine shows an antidepressant effect similar to amitriptyline with a different side-effect profile typical of 5-HT reuptake inhibition . Paroxetine and amitriptyline decreased the amount of REM sleep , a well-known effect of classical antidepressants . Paroxetine also shared with other 5-HT reuptake inhibitors an alerting effect on sleep that was not shown to be detrimental on subjective sleep quality There is circumstantial evidence that antidepressants , particularly monoamine oxidase inhibitors ( MAOIs ) and beta-blockers , may have some beneficial effects in social phobia . In this study 30 patients with social phobia ( DSM-IIIR ) were treated with the selective and reversible MAO-A inhibitor brofaromine , using a 12-week double-blind placebo controlled design . A clinical relevant improvement was seen in 80 % of the patients treated with brofaromine ( 150 mg daily ) . A significant improvement was found on measures of social anxiety , phobic avoidance , general ( or anticipatory ) anxiety and interpersonal sensitivity in patients on brofaromine , but not on placebo . Biochemical measurements revealed a decrease in turnover of noradrenaline , serotonin and dopamine as assessed by the plasma metabolite levels , and an increase in nocturnal release of melatonin . Most prominent side-effect was middle sleep disturbance . No changes in blood pressure were observed . During a follow-up period of 12 weeks a further improvement was found in patients treated with brofaromine Both noradrenergic and serotonergic systems have been implicated in the pathophysiology of panic disorder . The advent of selective serotonin ( 5-HT ) reuptake inhibitors ( SSRIs ) ( e.g. citalopram ) and , more recently , selective noradrenergic ( NA ) reuptake inhibitors ( NRIs ) ( e.g. reboxetine ) has provided potentially important avenues of treatment for the disorder . To date , the comparative efficacy of selective NA and 5-HT reuptake inhibitors for panic disorder remains unresolved . Nineteen patients with panic disorder were r and omized in a single-blind , cross-over design to either citalopram or reboxetine for 8 weeks and after a 2-week washout were switched to the other study drug . At week 18 , seven of 13 patients ( 54 % ) in the intent-to-treat sample responded to reboxetine and nine of 11 patients responded to citalopram ( 82 % ) . Both citalopram and reboxetine led to significant improvements in panic attack severity with no apparent between-drug differences in efficacy . However , citalopram demonstrated superior efficacy in treating depressive symptoms . One non-responder to citalopram responded to reboxetine and three non-responders to reboxetine responded to citalopram . Although SSRIs are viewed as a first-line treatment for panic disorder , these results suggest that a NA agent such as reboxetine may also have a role . These data also suggest an advantage for citalopram in treating comorbid depressive symptoms , although some patients may respond preferentially to an SSRI and other patients to an NRI Practice guidelines are valid if “ they lead to the health gains and costs predicted for them.”1 When implemented , valid guidelines lead to changes in clinical practice and improvements in outcomes for patients .2 - 5 Invalid guidelines , however , may lead to the use of ineffective interventions that waste re sources , or even to harm . Guidelines must offer recommendations for both effective and efficient care , and these have not previously been available in the United Kingdom . We have reported the development and content of guidelines for primary care in the United Kingdom based explicitly on evidence of effectiveness.6 - 9 Here , we present the methods used to develop evidence based guidelines on the use in primary care of four important groups of drugs — angiotensin converting enzyme inhibitors in patients with heart failure , choice of antidepressants , non-steroidal anti-inflammatory drugs in patients with osteoarthritis , and aspirin as an antithrombotic agent.10 - 13 Abridged versions of the guidelines on angiotensin converting enzyme inhibitors , aspirin , and non-steroidal anti-inflammatory drugs will be published in subsequent articles.14 - 16 # # # # Summary points Guideline development groups defined important clinical questions , produced search criteria , and drew up protocol s for systematic review and , where appropriate , meta- analysis Medline and Embase were search ed for systematic review s and meta-analyses , r and omised trials , quality of life studies , and economic studies Meta- analysis was used extensively by the group to answer specific clinical questions Statements on evidence were categorised in relation to study design , reflecting their susceptibility to bias Strength of recommendations was grade d according to the category of evidence and its applicability , economic issues , values of the guideline group and society , and the groups ' awareness of practical issues Recommendations cease to apply in December 1999 , by which time relevant results that may affect recommendations may be known Guideline development groups comprised three broad classes of members — relevant healthcare professionals ( up to five general practitioners ( all with BACKGROUND The efficacy of selective serotonin reuptake inhibitors in the acute treatment of social anxiety disorder ( social phobia ) is well established . OBJECTIVE To evaluate whether the efficacy of paroxetine hydrochloride in this disorder is maintained in the long term . METHODS This was a placebo-controlled multicenter study comprising a single-blind acute treatment phase ( 12 weeks ) and a r and omized , double-blind maintenance treatment phase ( 24 weeks ) for patients who had responded to paroxetine during the acute phase . Four hundred thirty-seven adult patients with social anxiety disorder ( according to Diagnostic and Statistical Manual of Mental Disorders , Fourth Edition , criteria , code 300.23 ) entered the acute phase , and 323 continued into the maintenance phase ( 162 paroxetine and 161 placebo ) . The principal outcome measure was the proportion of patients relapsing during the maintenance phase . RESULTS Two hundred fifty-seven patients completed the study ( 136 paroxetine-treated and 121 placebo-treated patients ) . Significantly fewer patients relapsed in the paroxetine group than in the placebo group ( 14 % vs 39 % ; odds ratio , 0.24 ; 95 % confidence interval , 0.14 - 0.43 ; P<.001 ) . At the end of the study , a significantly greater proportion of patients in the paroxetine group showed improvement as shown on the Clinical Global Impression global improvement rating compared with the placebo group ( 78 % vs 51 % ; odds ratio , 3.66 ; 95 % confidence interval , 2.22 - 6.04 ; P<.001 ) . Compared with placebo , paroxetine treatment significantly ( P<.001 ) improved the symptoms of social anxiety as shown on the Liebowitz Social Anxiety Scale , Social Phobia Inventory , Sheehan Disability Scale , Symptom Checklist-90 score , and EuroQol visual analogue scale , indicating decreased disability and increased well-being .  Paroxetine was well tolerated . CONCLUSION Paroxetine is an effective long-term treatment for social anxiety disorder Objective : To evaluate the efficacy and safety of a selective serotonin reuptake inhibitor ( SSRI ) and a serotonin and norepinephrine reuptake inhibitor ( SNRI ) in the treatment of depression in Parkinson disease ( PD ) . Methods : A total of 115 subjects with PD were enrolled at 20 sites . Subjects were r and omized to receive an SSRI ( paroxetine ; n = 42 ) , an SNRI ( venlafaxine extended release [ XR ] ; n = 34 ) , or placebo ( n = 39 ) . Subjects met DSM-IV criteria for a depressive disorder , or operationally defined subsyndromal depression , and scored > 12 on the first 17 items of the Hamilton Rating Scale for Depression ( HAM-D ) . Subjects were followed for 12 weeks ( 6-week dosage adjustment , 6-week maintenance ) . Maximum daily dosages were 40 mg for paroxetine and 225 mg for venlafaxine XR . The primary outcome measure was change in the HAM-D score from baseline to week 12 . Results : Treatment effects ( relative to placebo ) , expressed as mean 12-week reductions in HAM-D score , were 6.2 points ( 97.5 % confidence interval [ CI ] 2.2 to 10.3 , p = 0.0007 ) in the paroxetine group and 4.2 points ( 97.5 % CI 0.1 to 8.4 , p = 0.02 ) in the venlafaxine XR group . No treatment effects were seen on motor function . Conclusions : Both paroxetine and venlafaxine XR significantly improved  depression in subjects with PD . Both medications were generally safe and well tolerated and did not worsen motor function . Classification of Evidence : This study provides Class I evidence that paroxetine and venlafaxine XR are effective in treating depression in patients with PD Rationale and objective Depression is a significant complication of stroke . The effectiveness of antidepressant drugs in the management of post-stroke depression ( PSD ) has been widely investigated . However , the choice of antidepressant drug is critically influenced by its safety and tolerability and by its effect on concurrent pathologies . Here we investigate the efficacy and safety of a selective serotonin reuptake inhibitor ( SSRI ) , citalopram , and a noradrenaline reuptake inhibitor ( NARI ) , reboxetine , in post-stroke patients affected by anxious depression or retarded depression . Methods This was a r and omized double-blind study . Seventy-four post-stroke depressed patients were diagnosed as affected by anxious or retarded depression by using a synoptic table . R and omisation was planned so that 50 % of the patients in each subgroup were assigned for 16 weeks to treatment with citalopram and the remaining 50 % were assigned to treatment with reboxetine . The Beck Depression Inventory ( BDI ) , the Hamilton Depression Rating Scale ( HDRS ) and a synoptic table were used to score depressive symptoms . Results Both citalopram and reboxetine showed good safety and tolerability . Citalopram exhibited greater efficacy in anxious depressed patients , while reboxetine was more effective in retarded depressed patients . Conclusions Citalopram or other SSRIs and reboxetine may be of first choice treatment in PSD because of their good efficacy and lack of severe side effects . In addition , PSD patients should be classified according to their clinical profile ( similarly to patients affected by primary depression ) for the selection of SSRIs or reboxetine as drugs of choice in particular subgroups of patients BACKGROUND The comparative efficacy of selective serotonin reuptake inhibitors ( SSRIs ) and serotonin-norepinephrine reuptake inhibitors ( SNRIs ) was recently debated . Meta-analyses , based mainly on fluoxetine comparator data , suggest that the SNRI venlafaxine has superior efficacy to SSRIs in treatment of major depression . OBJECTIVE To compare quality of life ( QOL ) , efficacy , safety , and tolerability associated with sertraline and venlafaxine extended release ( XR ) for treatment of DSM-IV major depression . METHOD This was an 8-week , double-blind , r and omized study of sertraline ( 50 - 150 mg/day ) versus venlafaxine XR ( 75 - 225 mg/day ) , followed by a 2-week taper period . Subjects were recruited from 7 sites in Turkey and 6 sites in Australia between October 2002 and July 2003 . The primary outcome measure was the Quality of Life Enjoyment and Satisfaction Question naire . Secondary outcome measures included measures of depression ( including response and remission ) , anxiety , pain , safety ( e.g. , blood pressure ) , and tolerability ( e.g. , discontinuation symptoms ) . RESULTS A total of 163 subjects received study treatment ( women , 69 % ; mean age , 37.0 [ SD = 12.9 ] years ) . No significant differences in QOL or efficacy were noted between treatments on the primary or secondary endpoints for the total study population or the anxious depression and severe depression subgroups . A priori analyses of symptoms associated with treatment discontinuation demonstrated no difference between treatment groups . However , in post hoc analyses , sertraline was associated with less burden of moderate to severe discontinuation symptoms . Venlafaxine XR was associated with a relative increase in mean blood pressure ( supine diastolic blood pressure , -4.4 mm Hg difference at week 8/last observation carried forward ) . CONCLUSION Sertraline and venlafaxine XR demonstrated comparable effects on QOL and efficacy in treatment of major depression , although sertraline may be associated with a lower symptom burden during treatment discontinuation and a reduced risk of blood pressure increase
Cognitive behavior therapy  appears to be more effective than other evidence -based psychological techniques , and its effects appear to be more enduring than those of pharmacotherapy .
There is some evidence , albeit limited to certain drug classes , that the combination of  medication and cognitive behavior therapy may be more effective than either strategy used alone .
This article proposes a number of recommendations for the treatment of  generalized social phobia  , based on a systematic literature review and meta- analysis .
For medications , selective serotonin reuptake inhibitors and dual serotonin-norepinephrine reuptake inhibitors are first-line choices based on their efficacy and tolerability profiles .
There are other medication classes with demonstrated efficacy in social phobia ( benzodiazepines , antipsychotics , alpha-2-delta lig and s ) , but due to limited published clinical trial data and the potential for dependence and withdrawal issues with benzodiazepines , it is unclear how best to incorporate these drugs into treatment regimens .