The early non-increase of serum BDNF predicts failure of antidepressant treatment in patients with major depression: A pilot study Canadian Network for Mood and Anxiety Treatments (CANMAT) clinical guidelines for the management of major depressive disorder in adults. II. Psychotherapy alone or in combination with antidepressant medication. Short-term SSRI treatment normalises amygdala hyperactivity in depressed patients Does prior antidepressant treatment of major depression impact brain function during current treatment? Pre-treatment letter fluency performance predicts antidepressant response to transcranial direct current stimulation. Association Between Placebo-Activated Neural Systems and Antidepressant Responses: Neurochemistry of Placebo Effects in Major Depression. Concurrent Cognitive Control Training Augments the Antidepressant Efficacy of tDCS: A Pilot Study Depression and Chronic Obstructive Pulmonary Disease: Treatment Trials. Prediction of outcome and early vs. late improvement in OCD patients treated with cognitive behaviour therapy and pharmacotherapy Differential prediction of first clinical response to serotonergic and noradrenergic antidepressants using the loudness dependence of auditory evoked potentials in patients with major depressive disorder. Early improvement under mirtazapine and paroxetine predicts later stable response and remission with high sensitivity in patients with major depression. Amygdala Reactivity to Emotional Faces in the Prediction of General and Medication-Specific Responses to Antidepressant Treatment in the Randomized iSPOT-D Trial Onset and Early Behavioral Effects of Pharmacologically Different Antidepressants and Placebo in Depression A double blind, placebo-controlled pilot study of galantamine augmentation of antidepressant treatment in older adults with major depression. Are there predictors of outcome in depressed elderly nursing home residents during treatment with mirtazapine orally disintegrating tablets? Effect of antidepressant treatment on cognitive impairments associated with depression: a randomised longitudinal study. Comparative effectiveness of biomarkers and clinical indicators for predicting outcomes of SSRI treatment in Major Depressive Disorder: Results of the BRITE-MD study Clinical Significance and Predictors of Treatment Response to Cognitive-Behavior Therapy for Insomnia Secondary to Chronic Pain Establishing moderators and biosignatures of antidepressant response in clinical care (EMBARC): Rationale and design. Reviewing long-term antidepressants can reduce drug burden: a prospective observational cohort study. Does Antidepressant Treatment Improve Cognition in Older People with Schizophrenia or Schizoaffective Disorder and Comorbid Subsyndromal Depression? Differential change in specific depressive symptoms during antidepressant medication or cognitive therapy. Challenging the amphetamine challenge test: report of an antidepressant treatment study.
In the treatment of patients with major depressive disorder ( MDD ) , early non-improvement of symptoms after initiation of antidepressant treatment is a highly sensitive and specific marker for final treatment failure . On the other h and , meta-analyses of clinical studies investigating serum BDNF ( sBDNF ) concentration before and after antidepressant treatment showed an increase of sBDNF during treatment , which was correlated with amelioration of depressive symptoms . No study has yet investigated the predictive value of early changes of sBDNF for final treatment outcome of the individual patient . The aim of this study was to investigate in patients with MDD , whether i ) the non-increase of sBDNF in the early course of treatment is a specific and sensitive marker for final treatment failure , ii ) whether the sensitivity and specificity of early non-improvement for treatment failure can be increased by combining it with the marker " early non-increase of sBDNF " . For this purpose , we performed a pilot study with 41 in patients with MDD according to DSM-IV , who were treated in a naturalistic setting .  Depression severity and sBDNF were measured in weekly intervals from baseline to week six with the 21-item Hamilton Depression Rating Scale ( HAMD-21 ) and ELISA , respectively . The individual markers sBDNF non-increase and HAMD-21 non-improvement from baseline to day 7 or 14 predicted later non-response and non-remission with moderate to high specificity . The combined marker sBDNF non-increase plus HAMD-21 non-improvement at day 14 increased the specificity for non-response and non-remission to 100 % . Our data provide the first evidence that the absence of an early increase of sBDNF in conjunction with early non-improvement might be a highly specific peripheral marker predictive for treatment failure in patients with MDD . If replicated , this combined marker could be considered useful for prospect i ve confirmatory trials in patients with MDD BACKGROUND In 2001 , the Canadian Psychiatric Association and the Canadian Network for Mood and Anxiety Treatments ( CANMAT ) partnered to produce evidence -based clinical guidelines for the treatment of depressive disorders .  A revision of these guidelines was undertaken by CANMAT in 2008 - 2009 to reflect advances in the field . This article , one of five in the series , review s new studies of psychotherapy in the acute and maintenance phase of MDD , including computer-based and telephone-delivered psychotherapy . METHODS The CANMAT guidelines are based on a question -answer format to enhance accessibility to clinicians . Evidence -based responses are based on up date d systematic review s of the literature and recommendations are grade d according to the Level of Evidence , using pre-defined criteria . Lines of Treatment are identified based on criteria that included evidence and expert clinical support . RESULTS Cognitive-Behavioural Therapy ( CBT ) and Interpersonal Therapy ( IPT ) continue to have the most evidence for efficacy , both in acute and maintenance phases of MDD , and have been studied in combination with antidepressants . CBT is well studied in conjunction with computer-delivered methods and bibliotherapy . Behavioural Activation and Cognitive-Behavioural Analysis System of Psychotherapy have significant evidence , but need replication . Newer psychotherapies including Acceptance and Commitment Therapy , Motivational Interviewing , and Mindfulness-Based Cognitive Therapy do not yet have significant evidence as acute treatments ; nor does psychodynamic therapy . LIMITATIONS Although many forms of psychotherapy have been studied , relatively few types have been evaluated for MDD in r and omized controlled trials . Evidence about the combination of different types of psychotherapy and antidepressant medication is also limited despite widespread use of these therapies concomitantly . CONCLUSIONS CBT and IPT are the only first-line treatment recommendations for acute MDD and remain highly recommended for maintenance . Both computer-based and telephone-delivered psychotherapy -- primarily studied with CBT and IPT -- are useful second-line recommendations . Where feasible , combined antidepressant and CBT or IPT are recommended as first-line treatments for acute MDD Background Antidepressant drugs such as selective serotonin re-uptake inhibitors ( SSRIs ) remediate negative biases in emotional processing in depressed patients in both behavioural and neural outcome measures . However , it is not clear if these effects occur before , or as a consequence of , changes in clinical state . Method In the present study , we investigated the effects of short-term SSRI treatment in depressed patients on the neural response to fearful faces prior to clinical improvement in mood . Altogether , 42 unmedicated depressed patients received SSRI treatment ( 10 mg escitalopram daily ) or placebo in a r and omised , parallel-group design . The neural response to fearful and happy faces was measured on day 7 of treatment using functional magnetic resonance imaging .  A group of healthy controls was imaged in the same way . Results Amygdala responses to fearful facial expressions were significantly greater in depressed patients compared to healthy controls . However , this response was normalised in patients receiving 7 days treatment with escitalopram . There was no significant difference in clinical depression ratings at 7 days between the escitalopram and placebo-treated patients . Conclusions Our results suggest that short-term SSRI treatment in depressed patients remediates amygdala hyperactivity in response to negative emotional stimuli prior to clinical improvement in depressed mood . This supports the hypothesis that the clinical effects of antidepressant treatment may be mediated in part through early changes in emotional processing . Further studies will be needed to show if these early effects of antidepressant medication predict eventual clinical outcome The relationship between prior antidepressant treatment and prefrontal brain functional response to subsequent treatment with antidepressant medication or placebo is unknown . Eighty-nine adults with Major Depressive Disorder ( MDD ) , characterized as antidepressant-experienced or antidepressant-naive , received one week of single-blind placebo treatment prior to eight weeks of r and omized treatment with medication ( fluoxetine or venlafaxine ; n = 47 ) or placebo ( n = 42 ) in one of three similar placebo-controlled trials . Brain function was assessed at baseline , end of placebo lead-in , and during r and omized treatment using quantitative electroencephalography ( qEEG ) . The authors assessed change in prefrontal theta-b and cordance ( PFC ) in antidepressant-experienced vs. antidepressant-naive subjects . Treatment history groups differed significantly on PFC change during the placebo lead-in even when controlling for clinical and demographic variables ( F(1,62 ) = 4.27 , p = .04 ) . As assessed in linear mixed models that examined treatment history ( antidepressant-experienced or antidepressant-naive ) , treatment assignment ( medication or placebo ) , and their interaction as predictors , treatment history also predicted PFC change during the r and omized phase of treatment even when controlling for pretreatment clinical and demographic and symptom improvement during treatment ( F(1,5o ) = 5.20 , p = .03 ) . The interaction was not significant . Post hoc analyses showed that antidepressant-experienced subjects treated with placebo showed PFC changes that did not differ from PFC changes seen in the medication group . Results suggest that prefrontal brain functional changes during treatment for MDD may differ depending upon prior treatment with antidepressant medication BACKGROUND Transcranial direct current stimulation ( tDCS ) is a promising new treatment for depression , however , clinical trials to- date indicate variable efficacy , thereby raising the need to identify inter-individual predictors of response . In the current study we aim ed to investigate pre-treatment neurocognitive performance as a predictor of antidepressant response to tDCS . METHODS Data was pooled from five clinical trials , including two r and omised controlled trials ( RCTs ) , which investigated the antidepressant effects of anodal tDCS administered to the prefrontal cortex . Data from 57 patients were included in the analysis . Mood was assessed before and after an acute course of treatment using the Montgomery-Åsberg Depression Rating Scale . The following neurocognitive tests were administered prior to treatment : Simple and choice reaction time , the Symbol Digit Modalities Test ( SDMT ) , Rey Auditory Verbal Memory Task ( RAVLT ) , Digit Span , and the Controlled Oral Word Association Test ( COWAT ) . RESULTS Better pre-treatment letter fluency performance measured using the COWAT predicted antidepressant response to tDCS after controlling for confounds . LIMITATIONS Small sample size and analysis included data from both RCTs and open label studies . CONCLUSION Pre-treatment letter fluency performance , an ability subserved by the left prefrontal cortex , the primary site of stimulation , is a predictor of response for tDCS treatment for depression . This study highlights the importance of inter-individual neurobiological differences in mediating tDCS antidepressant effects IMPORTANCE High placebo responses have been observed across a wide range of pathologies , severely impacting drug development . OBJECTIVE To examine neurochemical mechanisms underlying the formation of placebo effects in patients with major depressive disorder ( MDD ) . DESIGN , SETTING , AND PARTICIPANTS In this study involving 2 placebo lead-in phases followed by an open antidepressant administration , we performed a single-blinded 2-week crossover r and omized clinical trial of 2 identical oral placebos ( described as having either active or inactive fast-acting antidepressant-like effects ) followed by a 10-week open-label treatment with a selective serotonin reuptake inhibitor or , in some cases , another agent as clinical ly indicated . The volunteers ( 35 medication-free patients with MDD at a university health system ) were studied with positron emission tomography and the µ-opioid receptor-selective radiotracer [11C]carfentanil after each 1-week inactive and active oral placebo treatment . In addition , 1 mL of isotonic saline was administered intravenously within sight of the volunteer during positron emission tomographic scanning every 4 minutes over 20 minutes only after the 1-week active placebo treatment , with instructions that the compound may be associated with the activation of brain systems involved in mood improvement . This challenge stimulus was used to test the individual capacity to acutely activate endogenous opioid neurotransmision under expectations of antidepressant effect . MAIN OUTCOMES AND MEASURES Changes in depressive symptoms in response to active placebo  and antidepressant . Baseline and activation measures of µ-opioid receptor binding . RESULTS Higher baseline µ-opioid receptor binding in the nucleus accumbens was associated with better response to antidepressant treatment ( r = 0.48 ; P = .02 ) . Reductions in depressive symptoms after 1 week of active placebo treatment , compared with the inactive , were associated with increased placebo-induced µ-opioid neurotransmission in a network of regions implicated in emotion , stress regulation , and the pathophysiology of MDD , namely , the subgenual anterior cingulate cortex , nucleus accumbens , midline thalamus , and amygdala ( nucleus accumbens : r = 0.6 ; P < .001 ) . Placebo-induced endogenous opioid release in these regions was associated with better antidepressant treatment response , predicting 43 % of the variance in symptom improvement at the end of the antidepressant trial . CONCLUSIONS AND RELEVANCE These data demonstrate that placebo-induced activation of the µ-opioid system is implicated in the formation of placebo antidepressant effects in patients with MDD and also participate in antidepressant responses , conferring illness resiliency , during open administration . TRIAL REGISTRATION clinical trials.gov Identifier : NCT02178696 BACKGROUND Major depressive disorder ( MDD ) is frequently associated with underactivity of the dorsolateral prefrontal cortex ( DLPFC ) which has led to this brain region being identified as an important target for the development of neurobiological treatments . Transcranial direct current stimulation ( tDCS ) administered to the DLPFC has antidepressant efficacy , however the magnitude of antidepressant outcomes are limited . Concurrent cognitive activity has been shown to enhance tDCS induced stimulation effects . Cognitive control training ( CCT ) is a new cognitive therapy for MDD that aims to enhance DLPFC activity via behavioral methods . HYPOTHESIS We tested the hypothesis that co-administration of DLPFC tDCS and CCT would result in a greater reduction in depressive symptomology than administration of tDCS or CCT alone . METHODS 27 adult participants with MDD were r and omized into a three-arm sham-controlled between-groups pilot study comparing the efficacy of 2 mA tDCS + CCT , sham tDCS + CCT and sham CCT + 2 mA tDCS ( 5 sessions administered on consecutive working days ) . Blinded assessment s of depression severity and cognitive control were conducted at baseline , end of treatment and a three week follow up review . RESULTS All three treatment conditions were associated with a reduction in depression severity at the end of five treatment sessions . However , only administration of tDCS + CCT result ed in sustained antidepressant response at follow up , the magnitude of which was greater than that observed immediately following conclusion of the treatment course . CONCLUSIONS The results provide preliminary evidence that concurrent CCT enhances antidepressant outcomes from tDCS . In the current sample , participants receiving concurrent tDCS and CCT continued to improve following cessation of treatment . The clinical superiority of a combined therapeutic approach was apparent even in a small sample and following a relatively short treatment course Chronic obstructive pulmonary disease ( COPD ) affects over 16 million people in the United States and is a major cause of disability and death worldwide . Its prevalence and mortality are increasing disproportionately among the elderly , women , African-Americans , persons of lower socioeconomic status , and the population s of developing countries in which tobacco is aggressively marketed . In contrast to other major chronic diseases such as heart disease and cancer , medical treatments for COPD have not made decisive inroads into its morbidity or death rates over the last 20 years , result ing in continuing efforts to reduce disability in patients with established disease . Depression is a source of increased disability in COPD , and , as in other chronically ill patient population s , is often unrecognized and untreated in the primary and specialty care sectors . Nearly half of all patients experience some depressive symptoms and at least one-fifth have had one or more major depressive episodes , frequently of long duration . Evidence from r and omized controlled trials supports the thesis that patients with mild depression improve with multidisciplinary rehabilitation , whereas patients with major depression may require specific pharmacotherapy to achieve significant improvement in mood disorder and day-to-day function . In addition to its impact on disability , depression may contribute indirectly to the etiology and progression of COPD through its relationship to addictive smoking . Mood disorder in adolescence and early adulthood contributes to early smoking and failure to quit , even after the onset of respiratory disease in later life . Patients with a history of major depression are more likely to fail in smoking cessation programs and to develop a major depressive episode when they do stop . This relationship calls for psychiatrically informed intervention models to improve long-term abstinence rates . The functional impairments associated with COPD are themselves potential promoters of depressive morbidity and chronicity , acting through complex causal pathways . Progressive hypoxia due to respiratory insufficiency leads to structural brain changes and neurocognitive deficits that impair day-to-day function and reduce adaptive potential ;  and oxygen therapy , as now practice d , offers minimal neurocognitive and mood benefits to most patients . Limited data from studies of experimental hypoxia in animals suggest that relatively mild lack of oxygen impairs the function and plasticity of critical neurotransmitter systems implicated in both cognition and mood , although current practice st and ards withhold oxygen therapy until late in the course of disease when the damaging effects of hypoxia on the brain have become well established . Neuropsychiatric approaches to the prevention , delay , and treatment of brain dysfunction should be a primary objective of research to improve patient outcomes . A comprehensive relational model that links pulmonary disease , hypoxia , neurocognitive impairment , and structural brain disease with depression provides a useful framework for the design of such studies . The near-term research agenda should include three components : ( 1 ) practical methods for improving physician and patient recognition of depression and neurocognitive impairment as targets for intervention ; ( 2 ) additional trials of st and ard antidepressant treatment approaches for both major and minor depression ; and ( 3 ) tests of the hypothesis that late-onset depression in patients with COPD is a marker for the presence of neurocognitive deficits and structural brain changes . The long-range research agenda must aim at preventive interventions design ed to forestall brain deterioration . Controlled clinical trials of supplemental oxygen in patients with mild hypoxia and minimal cognitive deficits are needed to determine whether early treatment can reverse or moderate decline , reduce the incidence and chronicity of depression , and improve response to antidepressant treatment . Novel neuroprotective therapies such as antioxidant supplementation and modulation of monoaminergic neurotransmission , coupled with overall improvements in long-term respiratory disease management that minimize episodes of increased systemic oxidative stress , should be considered for multisite trials design ed to define optimal treatment and prevention In this study , follow‐up results of cognitive‐behaviour therapy and of a combination of cognitive‐behaviour therapy with a serotonergic antidepressant were determined . The study also examined factors that can predict this treatment effect , both in the long term and in the short term . In addition , it investigated whether differential prediction is possible for cognitive‐behaviour therapy vs. a combination of cognitive‐behaviour therapy with a serotenergic antidepressant .  A total of 99 patients were included in the study . Treatment lasted 16 weeks , and a naturalistic follow‐up measurement was made 6 months later . Of the 70 patients who completed the treatment , follow‐up information was available for 61 subjects . Significant time effects were found on all outcome measures at both post‐treatment measurement and follow‐up . No differences in efficacy were found between the treatment conditions . Effectiveness at post‐treatment measurement appears to predict success at follow‐up . However , 17 of the 45 non‐responders at the post‐treatment measurement had become responders by the follow‐up . The severity of symptoms , motivation for treatment and the dimensional score on the PDQ‐R for cluster A personality disorder appear to predict treatment outcome . No predictors were found that related specifically to cognitive‐behaviour therapy or combined treatment . These results indicate that the effectiveness  of cognitive‐behaviour therapy or a combination of cognitive‐behaviour therapy and fluvoxamine at the post‐treatment measurement is maintained at follow‐up . However , non‐response at post‐treatment does not always imply non‐response at follow‐up . Patients with more severe symptoms need a longer period of therapy to become responders . Although predictors for treatment success were found , no evidence was found to determine the choice of one of the treatment modalities 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 Current clinical knowledge holds that antidepressants have a delayed onset of efficacy . However , the delayed onset hypothesis has been question ed recently by survival analytical approaches . We aim ed to test whether early improvement under antidepressant treatment is a clinical ly useful predictor of later stable response and remission . METHOD We analyzed data from a r and omized double-blind controlled trial with  mirtazapine and paroxetine  in patients with major depression ( DSM-IV ) .  Improvement was defined as a 17-item Hamilton Rating Scale for Depression ( HAM-D-17 ) score reduction of > or = 20 % . Stable response was defined as > or = 50 % HAM-D-17 score reduction at week 4 and week 6 , and stable remission as a HAM-D-17 score of < or = 7 at week 4 and week 6 . Sensitivity , specificity , positive predictive value ( PPV ) , and negative predictive value ( NPV ) were calculated . RESULTS Improvement occurred in a majority of the analyzed patients within 2 weeks ( mirtazapine : 72.7 % of 109 patients ; paroxetine : 64.9 % of 103 patients ) . Early improvement was a highly sensitive predictor of later stable response or stable remission for both drugs . NPV approached maximum values as early as week 2 for mirtazapine and week 3 for paroxetine . After 2 weeks of treatment with mirtazapine and 3 weeks with paroxetine , almost none of the patients who had not yet improved became a stable responder or stable remitter in the later course . CONCLUSION Our results strongly suggest that early improvement predicts later stable response with high sensitivity . These empirically derived data question the delayed onset hypothesis for both antidepressants tested and provide important clinical clues for an individually tailored antidepressant treatment Although the cost of poor treatment outcomes of depression is staggering , we do not yet have clinical ly useful methods for selecting the most effective antidepressant for each depressed person . Emotional brain activation is altered in major depressive disorder ( MDD ) and implicated in treatment response . Identifying which aspects of emotional brain activation are predictive of general and specific responses to antidepressants may help clinicians and patients when making treatment decisions . We examined whether amygdala activation probed by emotion stimuli is a general or differential predictor of response to three commonly prescribed antidepressants , using functional magnetic resonance imaging ( fMRI ) . A test – retest design was used to assess patients with MDD in an academic setting as part of the International Study to Predict Optimized Treatment in Depression . A total of 80 MDD out patients were scanned prior to treatment and 8 weeks after r and omization to the selective serotonin reuptake inhibitors escitalopram and sertraline and the serotonin – norepinephrine reuptake inhibitor , venlafaxine-extended release ( XR ) . A total of 34 matched controls were scanned at the same timepoints . We quantified the blood oxygen level-dependent signal of the amygdala during subliminal and supraliminal viewing of facial expressions of emotion . Response to treatment was defined by ⩾50 % symptom improvement on the 17-item Hamilton Depression Rating Scale . Pre-treatment amygdala hypo-reactivity to subliminal happy and threat was a general predictor of treatment response , regardless of medication type ( Cohen ’s d effect size 0.63 to 0.77 ; classification accuracy , 75 % ) . Responders showed hypo-reactivity compared to controls at baseline , and an increase toward ‘ normalization ’ post-treatment . Pre-treatment amygdala reactivity to subliminal sadness was a differential moderator of non-response to venlafaxine-XR ( Cohen ’s d effect size 1.5 ; classification accuracy , 81 % ) . Non-responders to venlafaxine-XR  showed pre-treatment hyper-reactivity , which progressed to hypo-reactivity rather than normalization post-treatment , and hypo-reactivity post-treatment was abnormal compared to controls . Impaired amygdala activation has not previously been highlighted in the general vs differential prediction of antidepressant outcomes . Amygdala hypo-reactivity to emotions signaling reward and threat predicts the general capacity to respond to antidepressants . Amygdala hyper-reactivity to sad emotion is involved in a specific non-response to a serotonin – norepinephrine reuptake inhibitor . The findings suggest amygdala probes may help inform the personal selection of antidepressant treatments This study was aim ed at resolving the time course of clinical action of antidepressants ( ADs ) and the type of early behavioral changes that precede recovery in treatment-responsive depressed patients . The first goal was to identify , during the first 2 weeks of treatment , the onset of clinical actions of the selective serotonin reuptake inhibitor ( SSRI ) , paroxetine , and the selective noradrenergic reuptake inhibitor , desipramine ( DMI ) . The second aim was to test the hypothesis that the two pharmacologic subtypes would induce different early behavioral changes in treatment-responsive patients . The design was a r and omized , parallel group , placebo-controlled , double-blind study for 6 weeks of treatment following a 1-week washout period . The study utilized measures of the major behavioral components of the depressive disorder as well as overall severity . The results indicated that the onset of clinical actions of DMI ranged from 3 to 13 days , averaged 13 days for paroxetine , and was 16–42 days for placebo . Furthermore , as hypothesized , the different types of ADs initially impacted different behavioral aspects of the disorder . After 1 week of treatment , DMI produced greater reductions in motor retardation and depressed mood than did paroxetine and placebo , and this difference persisted at the second week of treatment . Early improvement in depressed mood – motor retardation differentiated patients who responded to DMI after 6 weeks of treatment from those that did not . Paroxetine initially reduced anxiety more in responders than in nonresponders , and by the second week , significantly improved depressed mood and distressed expression in responders to a greater extent . Depressed patients who responded to placebo showed no consistent early pattern of behavior improvement . Early drug-specific behavioral changes were highly predictive of ultimate clinical response to the different ADs , results that could eventually be applied directly to clinical practice OBJECTIVE Depression in older adults is often associated with cognitive abnormalities and may predict later development of a primary cognitive disorder . This double-blind , r and omized , placebo-controlled pilot study was design ed to assess the safety and efficacy of galantamine augmentation of antidepressant treatment for depressive and cognitive symptoms in older adults with major depression . METHODS Thirty-eight , non-demented older adults ( age > 50 ) with major depression were r and omized to receive galantamine or placebo augmentation of st and ard antidepressant pharmacotherapy ( venlafaxine XR or citalopram ) .  Mood and cognitive status were monitored for 24 weeks using the 24-item Hamilton Rating Scale for Depression and the Repeatable Battery for the Assessment of Neuropsychological Status . RESULTS Both groups showed significant improvements in mood and cognition over 24 weeks , but no significant difference was found in change over time between groups . An exploratory post-hoc analysis suggested that patients r and omized to galantamine had lower depression scores compared to patients in the placebo group after 2 weeks of treatment . Dropout was high with more subjects r and omized to antidepressant plus galantamine  withdrawing early from the study . CONCLUSIONS This pilot study failed to demonstrate a benefit for galantamine augmentation of antidepressant medication in the treatment of depression in older adults . Future studies should explore strategies for reducing dropout in such longitudinal trials and more carefully assess time to response with cholinesterase inhibitor augmentation BACKGROUND Treatment studies of depression in residential care are limited . Reports of predictors of response are rare . In the largest nursing home prospect i ve antidepressant trial reported , we examined predictors of response . METHODS This was a 12-week open-label study of mirtazapine orally disintegrating tablets performed in 30 US nursing homes . Subjects were men and women aged > or=70 , with a Mini Mental State Exam ( MMSE ) score > or=10 , who had a depressive disorder that required antidepressant treatment .  Mirtazapine was started at 15 mg at bedtime , and adjusted to 15 - 45 mg/day . A 16-item Hamilton Depression Rating Scale was used to assess depression at baseline , weeks 2 , 4 , 8 , and 12 or early termination . RESULTS One hundred and twenty-four patients received at least one dose of study drug and of these , 119 had at least one post-drug assessment . Mean age was 82.9 years and 72 % were female .  Response rates at 12 weeks were 47 % on the HAMD and 54 % on the CGI . Age , sex , MMSE score , medical burden , history of prior depression , and baseline HAMD severity were not significantly associated with HAMD response ( > or=50 % improvement ) and in most cases correlations were trivial , < 0.1 . Advanced age , medical burden , and cognitive impairment did not predict adverse events . CONCLUSIONS In this sample of depressed nursing home residents treated with mirtazapine orally disintegrating tablets , advanced age , medical illness , and cognitive impairment did not predict response . The findings suggest that these variables need not be viewed as obstacles to treatment BACKGROUND Antidepressant treatment failure is a common problem worldwide . In this study , we assess whether or not an important aspect of depression , cognitive impairment , is untreated by antidepressants by study ing the effect of acute antidepressant treatment on a range of cognitive domains . METHODS In this r and omised longitudinal study , which is part of the International Study to Predict Optimized Treatment in Depression ( iSPOT-D ) trial , we assessed the effects of acute antidepressant treatment in a large patient population , across clinical remission outcomes , on a range of cognitive domains : attention , response inhibition , executive function during visuospatial navigation , cognitive flexibility , verbal memory , working memory , decision speed , information processing speed , and psychomotor response speed . We enrolled patients from primary or specialty care clinics in a multicentre , international , open-label , r and omised , prospect i ve trial . Eligible patients ( aged 18 - 65 years ) were previously untreated or were willing to undergo a 1-week medication washout before the study start , and could not have had inadequate response to study medications in the past . We enrolled a large population of medication-free ( ie , untreated ) out patients in a depressive episode and assessed them for cognitive function at enrolment ( pre-treatment ) , and again after 8 weeks of treatment with one of three antidepressant drugs ( escitalopram , sertraline , or venlafaxine extended-release ) . Patients were r and omly assigned ( 1:1:1 ) to one of the three antidepressants using a blocked r and omisation procedure ( block size of 12 ) . As a comparison group , we also simultaneously enrolled matched healthy participants . Healthy participants received no medication or intervention , but were assessed for change in cognitive and clinical measures during the same interval and testing protocol . Therefore , this group acts as a test-retest control for the primary outcome measure examined in this study , change in cognitive measures over 8 weeks of treatment in depressed patients . This study is registered with Clinical Trials.gov , number NCT00693849 . FINDINGS Between Dec 8 , 2008 , and Sept 30 , 2011 , we enrolled 1008 eligible people into the study .  Impairment in five domains-attention , response inhibition , verbal memory , decision speed , and information processing-showed no relative improvement with acute treatment ( controlling for time or repeated testing ) , irrespective of antidepressant treatment group , even in patients whose depression remitted acutely according to clinical measures . Broader cognitive impairment was associated with greater illness chronicity ( earlier illness onset ) but not with symptom severity or previous antidepressant failures . INTERPRETATION Depression is associated with impairments in higher-order cognitive functions and information processing , which persist independently of clinical symptom change with treatment . We recorded no difference between the three antidepressants tested , with none showing efficacy for these impairments . Although the 8-week treatment period limits interpretation to acute treatment effects , it does highlight cognitive impairment as an untargeted contributor to incomplete treatment success . FUNDING Brain Re source Company Operations Pty Ltd and NIH Patients with Major Depressive Disorder ( MDD ) may not respond to antidepressants for 8 weeks or longer . A biomarker that predicted treatment effectiveness after only 1 week could be clinical ly useful . We examined a frontal quantitative electroencephalographic ( QEEG ) biomarker , the Antidepressant Treatment Response ( ATR ) index , as a predictor of response to escitalopram , and compared ATR with other putative predictors . Three hundred seventy-five subjects meeting DSM-IV criteria for MDD had a baseline QEEG study . After 1 week of treatment with escitalopram , 10 mg , a second QEEG was performed , and the ATR was calculated . Subjects then were r and omly assigned to continue with escitalopram , 10 mg , or change to alternative treatments . Seventy-three evaluable subjects received escitalopram for a total of 49days . Response and remission rates were 52.1 % and 38.4 % , respectively . The ATR predicted both response and remission with 74 % accuracy . Neither serum drug levels nor 5HTTLPR and 5HT2a genetic polymorphisms were significant predictors . Responders had larger decreases in Hamilton Depression Rating Scale ( Ham-D(17 ) ) scores at day 7 ( P=0.005 ) , but remitters did not . Clinician prediction based upon global impression of improvement at day 7 did not predict outcome . Logistic regression showed that the ATR and early Ham-D(17 ) changes were additive predictors of response , but the ATR was the only significant predictor of remission . Future studies should replicate these results prior to clinical use We examined individual responses to cognitive-behavior therapy for  insomnia in 51 persons with chronic pain to determine the rate of clinical ly significant change and to identify predictors of successful treatment response . Outcome measures consisted of the Pittsburgh Sleep Quality Index ( PSQI ) and diary measures of sleep latency and sleep continuity . Using reliable change indices , 57 % of participants were statistically improved on the PSQI after 7 weeks of treatment , but only 18 % were considered fully recovered from their sleep problems . No demographic variables predicted treatment response but persons who reliably improved on the PSQI had a lower sleep self-efficacy at baseline . Improvers showed a significant increase in sleep self-efficacy ratings and a decrease in self-reported levels of distress and pain-related disability . These results suggest that patients with insomnia secondary to chronic medical conditions can be helped with cognitive-behavior therapy , although most individuals continue to have mild or subthreshold sleep problems at posttreatment UNLABELLED Remission rates for Major Depressive Disorder ( MDD ) are low and unpredictable for any given antidepressant . No biological or clinical marker has demonstrated sufficient ability to match individuals to efficacious treatment . Biosignatures developed from the systematic exploration of multiple biological markers , which optimize treatment selection for individuals ( moderators ) and provide early indication of ultimate treatment response ( mediators ) are needed . The rationale and design of a multi-site , placebo-controlled r and omized clinical trial of sertraline examining moderators and mediators of treatment response is described . The target sample is 300 participants with early onset ( ≤30 years ) recurrent MDD . Non-responders to an 8-week trial are switched double blind to either bupropion ( for sertraline non-responders ) or sertraline ( for placebo non-responders ) for an additional 8 weeks . Clinical moderators include anxious depression , early trauma , gender , melancholic and atypical depression , anger attacks , Axis II disorder , hypersomnia/fatigue , and chronicity of depression . Biological moderator and mediators include cerebral cortical thickness , task-based fMRI ( reward and emotion conflict ) , resting connectivity , diffusion tensor imaging ( DTI ) , arterial spin labeling ( ASL ) , electroencephalograpy ( EEG ) , cortical evoked potentials , and behavioral/cognitive tasks evaluated at baseline and week 1 , except DTI , assessed only at baseline . The study is design ed to st and ardize assessment of biomarkers across multiple sites as well as institute replicable quality control methods , and to use advanced data analytic methods to integrate these markers . A Differential Depression Treatment Response Index ( DTRI ) will be developed . The data , including biological sample s ( DNA , RNA , and plasma collected before and during treatment ) , will become available in a public scientific repository . CLINICAL TRIAL REGISTRATION Establishing Moderators and Biosignatures of Antidepressant Response for Clinical Care for Depression ( EMBARC ) . Identifier : NCT01407094 . URL : http:// clinical trials.gov/show/NCT01407094 BACKGROUND Antidepressant prescribing continues to rise . Contributing factors are increased long-term prescribing and possibly the use of higher selective serotonin re-uptake inhibitor ( SSRI ) doses . AIM To review general practice patients prescribed the same antidepressant long-term ( ≥2 years ) and evaluate prescribing and management pre and post- review . DESIGN AND SETTING Prospect i ve observational cohort study using routine data from 78 urban general practice s , Scotl and . METHOD All patients prescribed antidepressants ( excluding amitriptyline ) for ≥2 years were identified from records November 2009 to March 2010 . GPs selected patients for face-to-face review of clinical condition and medication , December 2009 to September 2010 . Pre- and post- review data were collected ; average antidepressant doses and changes in prescribed daily doses were calculated . Onward referral to support services was recorded . RESULTS 8.6 % ( 33 312/388 656 ) of all registered patients were prescribed an antidepressant , 47.1 % ( 15 689 ) were defined as long-term users and 2849 ( 18.2 % ) were review ed . 811 ( 28.5 % ) patients review ed had a change in antidepressant therapy : 7.0 % stopped , 12.8 % reduced dose , 5.3 % increased dose , and 3.4 % changed antidepressant , result ing in 9.5 % ( 95 % CI = 9.1 % to 9.8 % P<0.001 ) reduction in prescribed daily dose and 8.1 % reduction in prescribing costs . 6.3 % were referred onwards , half to NHS Mental Health Services . Pre- review SSRI doses were 10 - 30 % higher than previously reported . CONCLUSION Almost half of all people prescribed antidepressants were long-term users . Appropriate reductions in prescribing can be achieved by review ing patients . Higher SSRI doses may be contributing to current antidepressant growth Background : Subsyndromal symptoms of depression ( SSD ) in patients with schizophrenia are common and clinical ly important . While treatment of depression in major depressive disorder may partially ameliorate cognitive deficits , the cognitive effects of antidepressant medications in patients with schizophrenia or schizoaffective disorder and SSD are unknown . Methods : The goal of this study was to assess the impact of SSD and their treatment on cognition in participants with schizophrenia or schizoaffective disorder aged ≧40 years . Participants were r and omly assigned to a flexible dose treatment with citalopram or placebo augmentation of their current medication for 12 weeks . An ANCOVA compared improvement in the cognitive composite scores , and a linear model determined the moderation of cognition on treatment effects based on the Hamilton Depression Rating Scale and the Calgary Depression Rating Scale scores between treatment groups . Results : There were no differences between the citalopram and placebo groups in changes in cognition . Baseline cognitive status did not moderate antidepressant treatment response . Conclusions : Although there are other cogent reasons why SSD in schizophrenia warrant direct intervention , treatment does not substantially affect the level of cognitive functioning . Given the effects of cognitive deficits associated with schizophrenia on functional disability , there remains an ongoing need to identify effective means of directly ameliorating them Cognitive therapy and antidepressant medications are effective treatments for depression , but little is known about their relative efficacy in reducing individual depressive symptoms . Using data from a recent clinical trial comparing cognitive therapy , antidepressant medication , and placebo in the treatment of moderate-to-severe depression , we examined whether there was a relative advantage of any treatment in reducing the severity of specific depressive symptom clusters . The sample consisted of 231 depressed out patients r and omly assigned to : cognitive therapy for 16 weeks ( n = 58 ) ; paroxetine treatment for 16 weeks ( n = 116 ) ; or pill placebo for 8 weeks ( n = 57 ) . Differential change in five subsets of depressive symptoms was examined : mood , cognitive/suicide , anxiety , typical-vegetative , and atypical-vegetative symptoms . Medication led to a greater reduction in cognitive/suicide symptoms relative to placebo by 4 weeks , and both active treatments reduced these symptoms more than did placebo by 8 weeks . Cognitive therapy reduced the atypical-vegetative symptoms more than placebo by 8 weeks and more than medications throughout the trial . These findings suggest that medications and cognitive therapy led to different patterns of response to specific symptoms of depression and that the general efficacy of these two well-vali date d treatments may be driven in large part by changes in cognitive or atypical-vegetative symptoms The primary goal of this study was to determine whether the amphetamine challenge test ( ACT ) response , as measured by a subjective rating scale , the How I Feel Scale ( HIF ) , could predict antidepressant treatment outcome . Following a 1-day non-blind ACT with dextroamphetamine ( d-AMPH ) , patients were treated double-blind for 6 weeks with either desipramine , alprazolam , or a desipramine-alprazolam combination . Regression ( true score ) analyses were carried out on pre- and post-ACT HIF scores and on baseline and end of study Hamilton Depression Rating Scale ( HDRS ) scores to determine the magnitudes of improvement measured in response to the ACT and antidepressant treatment , respectively . Regression analyses were performed on the residuals ( true scores of improvement ) to determine the best fitting ( linear ) prediction equation . Improvement in the HIF total score predicted HDRS improvement for the whole sample . Possible sources of error contributing to the outcome are identified and the results are discussed in relation to previous clinical investigations of the potential usefulness of the ACT as a predictor of antidepressant response
The available evidence suggests the early changes in cognition may predict treatment response in individuals with MDD .
The results depict an emerging trend towards early changes in facial emotion recognition ( i.e. , a hot cognitive process ) as a predictor of treatment outcome .
Conclusion : The identification of reliable early treatment predictors of antidepressant response would be clinical ly significant , enabling clinicians to more accurately evaluate the efficacy of selected treatment avenues .
HIGHLIGHTSCognitive dysfunction is a principal feature and determinant of health outcome in MDD.Cognitive changes have shown to occur prior to improvements in mood symptoms .
Early changes in emotional processing may predict treatment response in MDD
Background : Despite the widespread use of antidepressants in clinical practice , the current trial‐ and ‐error approach to medication selection contributes to treatment failure and underscores the need to identify reliable predictors of antidepressant response .
Since changes in measures of cognition have been reported to occur early in treatment and prior to improvements in overall mood symptoms , the present review aims to determine whether early changes in measures of cognition can predict response in individuals with MDD .