title: Increased positive versus negative affective perception and memory in healthy volunteers following selective serotonin and norepinephrine reuptake inhibition. Short-term SSRI treatment normalises amygdala hyperactivity in depressed patients Effect of acute antidepressant administration on negative affective bias in depressed patients. The effects of reboxetine on emotional processing in healthy volunteers: an fMRI study Acute SSRI Administration Affects the Processing of Social Cues in Healthy Volunteers Agomelatine facilitates positive versus negative affective processing in healthy volunteer models A randomized, controlled trial of sequential bilateral repetitive transcranial magnetic stimulation for treatment-resistant depression. Bupropion-SR, sertraline, or venlafaxine-XR after failure of SSRIs for depression. Antidepressant Drug Treatment Modifies the Neural Processing of Nonconscious Threat Cues A Randomized Trial of rTMS Targeted with MRI Based Neuro-Navigation in Treatment-Resistant Depression Dissociable effects of acute antidepressant drug administration on subjective and emotional processing measures in healthy volunteers A randomized trial of the anti-depressant effects of low- and high-frequency transcranial magnetic stimulation in treatment-resistant depression. The effect of serotonergic and noradrenergic antidepressants on face emotion processing in depressed patients.
abstract: OBJECTIVE Antidepressants that inhibit the reuptake of serotonin ( SSRIs ) or norepinephrine ( SNRIs ) are effective in the treatment of disorders such as depression and anxiety . Cognitive psychological theories emphasize the importance of correcting negative biases of information processing in the nonpharmacological treatment of these disorders , but it is not known whether antidepressant drugs can directly modulate the neural processing of affective information . The present study therefore assessed the actions of repeated antidepressant administration on perception and memory for positive and negative emotional information in healthy volunteers . METHOD Forty-two male and female volunteers were r and omly assigned to 7 days of double-blind intervention with the SSRI citalopram ( 20 mg/day ) , the SNRI reboxetine ( 8 mg/day ) , or placebo . On the final day , facial expression recognition , emotion-potentiated startle response , and memory for affect-laden words were assessed . Question naires monitoring mood , hostility , and anxiety were given before and after treatment . RESULTS In the facial expression recognition task , citalopram and reboxetine reduced the identification of the negative facial expressions of anger and fear . Citalopram also abolished the increased startle response found in the context of negative affective images . Both antidepressants increased the relative recall of positive ( versus negative ) emotional material . These changes in emotional processing occurred in the absence of significant differences in ratings of mood and anxiety . However , reboxetine decreased subjective ratings of hostility and elevated energy . CONCLUSIONS Short-term administration of two different antidepressant types had similar effects on emotion-related tasks in healthy volunteers , reducing the processing of negative relative to positive emotional material . Such effects of antidepressants may ameliorate the negative biases in information processing that characterize mood and anxiety disorders . They also suggest a mechanism of action potentially compatible with cognitive theories of anxiety and depression 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 OBJECTIVE Acute administration of an antidepressant increases positive affective processing in healthy volunteers , an effect that may be relevant to the therapeutic actions of these medications . The authors investigated whether this effect is apparent in depressed patients early in treatment , prior to changes in mood and symptoms . METHOD In a double-blind , placebo-controlled , between-groups r and omized design , the authors examined the effect of a single 4-mg dose of the norepinephrine reuptake inhibitor reboxetine on emotional processing . Thirty-three depressed patients were recruited through primary care clinics and the community and matched to 31 healthy comparison subjects . Three hours after dosing , participants were given a battery of emotional processing tasks comprising facial expression recognition , emotional categorization , and memory . Ratings of mood , anxiety , and side effects were also obtained before and after treatment . RESULTS Depressed patients who received placebo showed reduced recognition of positive facial expressions , decreased speed in responding to positive self-relevant personality adjectives , and reduced memory for this positive information compared to healthy volunteers receiving placebo . However , this effect was reversed in patients who received a single dose of reboxetine , despite the absence of changes in subjective ratings of mood or anxiety . CONCLUSIONS Antidepressant drug administration modulates emotional processing in depressed patients very early in treatment , before changes occur in mood and symptoms . This effect may ameliorate the negative biases in information processing that characterize mood and anxiety disorders . It also suggests a mechanism of action compatible with cognitive theories of depression Recent neuropsychological studies in healthy volunteers suggest that antidepressants enhance the processing of positive emotional information . However , the neural substrates underpinning these changes have not been fully eluci date d. The current study , therefore , used functional magnetic resonance imaging ( fMRI ) to map brain systems activated during successful categorization and subsequent recognition of self-referent positive and negative personality characteristics in healthy volunteers following short-term ( 7 days ) repeated administration of the selective noradrenergic reuptake inhibitor reboxetine .  Twenty-four healthy volunteers were r and omly assigned to 7-day double-blind intervention with reboxetine or placebo . On day 7 , neural responses during the categorization and subsequent recognition of positive and negative characteristics were assessed using fMRI . Question naires monitoring mood , hostility and anxiety were given before and during this intervention . During categorization , reboxetine was associated with greater activation to positive words , relative to negative words , in left precuneus and right inferior frontal gyrus . By contrast , at subsequent recognition reboxetine was associated with reduced response to positive words , relative to negative words , in left precuneus , anterior cingulate and medial frontal gyrus . These changes in the neural processing of positive and negative words occurred in the absence of significant differences in ratings of mood and anxiety . Such adaptations in the neural processing of emotional information support the hypothesis that antidepressants have early effects on emotional processing in a manner which would be expected to reverse negative biases in depression Enhancement of serotonin neurotransmission plays an important role in the antidepressant response to agents presently available to treat depression . This response forms the major evidence for the role of serotonin in affective and social behaviour in humans . The present study investigated the effects of acute administration of the selective serotonin reuptake inhibitor ( SSR1 ) , citalopram ( 10 mg , i.v . ) upon a measure of emotional processing in healthy female volunteers . Subjects completed a facial expression recognition task following infusion of citalopram or saline ( between-subjects design , double-blind ) . Facial expressions associated with five basic emotions — happiness , sadness , fearfulness , anger and disgust — were displayed . Each face had been ‘ morphed ’ between neutral ( 0 % ) and each emotional st and ard ( 100 % ) in 10 % steps , leading to a range of emotional intensities . Mood and subjective experience were also monitored throughout the testing session . Volunteers receiving citalopram detected a higher number of facial expressions of fear and happiness , with reduced response times , relative to those given the placebo . By contrast , changes in the recognition of other basic emotions were not observed following citalopram . Notable differences in mood were also not apparent in these volunteers . These results suggest that acute administration of antidepressant drugs may affect neural processes involved in the processing of social information . This effect may represent an early acute effect of SSRIs on social and emotional processing that is relevant to their therapeutic actions Agomelatine is a new antidepressant with a novel profile of pharmacological action . The clinical efficacy of agomelatine has been established in major depression , but its actions on emotional bias are unknown . Consequently , the current experimental study assessed the effect of agomelatine on emotional processing in healthy volunteers using an Emotional Test Battery shown to be sensitive to serotonin and noradrenaline reuptake inhibitors . Volunteers were r and omized to receive placebo , 25 mg or 50 mg of agomelatine over a 7-day period in a double-blind parallel groups design . Emotional processing ( n = 48 ) was assessed on the morning of day 8 using the Emotional Test Battery which included facial expression recognition , emotional memory , attentional visual probe and emotion-potentiated startle . Mood and subjective state were monitored before and during treatment . Agomelatine ( 25 mg ) decreased subjective ratings of sadness , reduced recognition of sad facial expressions , improved positive affective memory and reduced the emotion-potentiated startle response . The results show that agomelatine has more selective effects on the processing of social facial cues than conventional antidepressants , which could contribute to less blunting of emotional experience . The study highlights the potential value of volunteer models in drug development for screening and profiling of novel antidepressants OBJECTIVE High-frequency left-side repetitive transcranial magnetic stimulation ( rTMS ) and low-frequency stimulation to the right prefrontal cortex have both been shown to have antidepressant effects , but doubts remain about the magnitude of previously demonstrated treatment effects . The authors evaluated sequentially combined high-frequency left-side rTMS and low-frequency rTMS to the right prefrontal cortex for treatment-resistant depression . METHOD The authors conducted a 6-week double-blind , r and omized , sham-controlled trial in 50 patients with treatment-resistant depression .  Three trains of low-frequency rTMS to the right prefrontal cortex of 140 seconds ' duration at 1 Hz were applied daily , followed immediately by 15 trains of 5 seconds ' duration of high-frequency left-side rTMS at 10 Hz . Sham stimulation was applied with the coil angled at 45 degrees from the scalp , resting on the side of one wing of the coil . The primary outcome variable was the score on the Montgomery-Asberg Depression Rating Scale . RESULTS There was a significantly greater response to active than sham stimulation at 2 weeks and across the full duration of the study . A significant proportion of the study group receiving active treatment met response ( 11 of 25 [ 44 % ] ) or remission ( nine of 25 [ 36 % ] ) criteria by study end compared to the sham stimulation group ( two of 25 [ 8 % ] and none of 25 respectively ) . CONCLUSIONS Sequentially applying both high-frequency left-side rTMS and low-frequency rTMS to the right prefrontal cortex , has substantial treatment efficacy in patients with treatment-resistant major depression . The treatment response accumulates to a clinical ly meaningful level over 4 to 6 weeks of active treatment BACKGROUND After unsuccessful treatment for depression with a selective serotonin-reuptake inhibitor ( SSRI ) , it is not known whether switching to one antidepressant is more effective than switching to another . METHODS We r and omly assigned 727 adult out patients with a nonpsychotic major depressive disorder who had no remission of symptoms or could not tolerate the SSRI citalopram  to receive one of the following drugs for up to 14 weeks : sustained-release bupropion ( 239 patients ) at a maximal daily dose of 400 mg , sertraline ( 238 patients ) at a maximal daily dose of 200 mg , or extended-release venlafaxine ( 250 patients ) at a maximal daily dose of 375 mg . The study was conducted in 18 primary and 23 psychiatric care setting s. The primary outcome was symptom remission , defined by a total score of 7 or less on the 17-item Hamilton Rating Scale for Depression ( HRSD-17 ) at the end of the study . Scores on the Quick Inventory of Depressive Symptomatology - Self Report ( QIDS-SR-16 ) , obtained at treatment visits , determined secondary outcomes , including remission ( a score of 5 or less at exit ) and response ( a reduction of 50 percent or more on baseline scores ) . RESULTS Remission rates as assessed by the HRSD-17 and the QIDS-SR-16 , respectively , were 21.3 percent and 25.5 percent for sustained-release bupropion , 17.6 percent and 26.6 percent for sertraline , and 24.8 percent and 25.0 percent for extended-release venlafaxine . QIDS-SR-16 response rates were 26.1 percent for sustained-release bupropion , 26.7 percent for sertraline , and 28.2 percent for extended-release venlafaxine . These treatments did not differ significantly with respect to outcomes , tolerability , or adverse events . CONCLUSIONS After unsuccessful treatment with an SSRI , approximately one in four patients had a remission of symptoms after switching to another antidepressant . Any one of the medications in the study provided a reasonable second-step choice for patients with depression . ( Clinical Trials.gov number , NCT00021528 . ) BACKGROUND The amygdala is believed to play a key role in processing emotionally salient , threat-relevant , events that require further online processing by cortical regions . Emotional disorders such as depression and anxiety have been associated with hyperactivity of the amygdala , but it is unknown whether antidepressant treatment directly affects amygdala responses to emotionally significant information . METHODS The current study assessed the effects of 7 days administration of the selective serotonin reuptake inhibitor ( SSRI ) , citalopram , on amygdala responses to masked presentations of fearful and happy facial expressions in never-depressed volunteers using blood oxygenation level-dependent ( BOLD ) functional magnetic resonance imaging . A double-blind , between-groups design was used with volunteers r and omized to 20 mg/day citalopram versus placebo . RESULTS Volunteers receiving citalopram showed decreased amygdala responses to masked presentations of threat compared with those receiving placebo . Citalopram also reduced responses within the hippocampus and medial prefrontal cortex ( mPFC ) specifically during the fear-relevant stimuli . These neural differences were accompanied by decreased recognition of fearful facial expressions assessed after the scan . By contrast , there was no effect of citalopram on the neural or behavioral response to the happy facial expressions . CONCLUSIONS These results suggest a direct effect of serotonin potentiation on amygdala response to threat-relevant stimuli in humans . Such effects may be important in the therapeutic actions of antidepressants in depression and anxiety The aim of this study is to investigate whether repetitive transcranial magnetic stimulation ( rTMS ) targeted to a specific site in the dorsolateral prefrontal cortex ( DLPFC ) , with a neuro-navigational method based on structural MRI , would be more effective than rTMS applied using the st and ard localization technique . Fifty-one patients with treatment-resistant depression were r and omized to receive a 3-week course ( with a potential 1-week extension ) of high-frequency ( 10 Hz ) left-sided rTMS . Thirty trains ( 5 s duration ) were applied daily 5 days per week at 100 % of the resting motor threshold . Treatment was targeted with either the st and ard 5 cm technique ( n=27 ) or using a neuro-navigational approach ( n=24 ) . This involved localizing the scalp location that corresponds to a specific site at the junction of Brodmann areas 46 and 9 in the DLPFC based on each individual subject 's MRI scan . There was an overall significant reduction in the Montgomery – Asberg Depression Rating Scale scores over the course of the trial , and a better outcome in the targeted group compared with the st and ard localization group at 4 weeks ( p=0.02 ) . Significant differences were also found on secondary outcome variables . The use of neuro-navigational methods to target a specific DLPFC site appears to enhance response to rTMS treatment in depression . Further research is required to confirm this in larger sample s , or to establish whether an alternate method based on surface anatomy , including measurement from motor cortex , can be substituted for the st and ard 5 cm method Background We have previously shown that single doses of serotonin-selective and noradrenaline-selective antidepressant agents produce positive biases in measures of emotional processing in healthy volunteers . The aim of the present study was to confirm and extend this finding by study ing the effects of a single dose of the selective serotonin and noradrenaline re-uptake inhibitor , duloxetine . Material s and methods Healthy volunteers were r and omly allocated to double-blind administration of either duloxetine 60 mg orally or placebo . Participants then completed a battery of emotional-processing tasks measuring facial expression recognition , emotional memory and emotion-potentiated startle . Subjective state was measured using visual analogue scales throughout the test period . Results Duloxetine enhanced the recognition of both disgusted and happy facial expressions and increased memory intrusions for positive personality characteristics in the free recall test . There were no significant effects on startle responses . However , duloxetine was not well tolerated and was associated with a high level of negative subjective effects . Conclusions Despite the induction of negative subjective effects after duloxetine administration , some positive effects on emotional processing were seen in line with acute administration of serotonin-selective and noradrenaline-selective antidepressant agents . These results confirm the induction of fast changes in emotional processing in healthy volunteer groups and suggest a mechanism by which antidepressants may act in depression . Further studies are required to assess whether positive effects on emotional processing are more selective at a lower dose of duloxetine BACKGROUND The majority of studies investigating the effectiveness of repetitive transcranial magnetic stimulation ( rTMS ) as a treatment for major depression have focused on high-frequency rTMS to the left prefrontal cortex ( HFL-rTMS ) . In addition , low-frequency right prefrontal rTMS ( LFR-rTMS ) has also been shown to have antidepressant properties . To date only a small number of studies have directly compared the efficacy of these two approaches . METHODS The aim of this study , therefore , was to investigate further whether LFR-rTMS is as effective as HFL-rTMS in the treatment of major depression . Twenty-seven patients were r and omized to one of two treatment arms ( HFL-rTMS or LFR-rTMS ) for 3 weeks with a possible 1-week extension . Non-responders were offered the opportunity of crossing over to the other treatment type . Stimulation parameters for HFL-rTMS were 30 stimulation trains of 5 s duration at 100 % of the resting motor threshold ( RMT ) ; for LFR-rTMS , stimulation was applied in four trains of 180 s duration ( 30 s inter-train interval ) at 110 % of the RMT . Stimulation was provided 5-week days per week . RESULTS There were significant improvements seen from baseline to end point irrespective of group and on all clinical outcome measures . In addition , there was no deterioration in any of the measures used to assess cognitive change , and significant improvements were seen on measures of immediate verbal memory and verbal fluency . CONCLUSIONS HFL-rTMS and LFR-rTMS appear to be equally efficacious in treating major depression . This study adds to the growing literature supporting LFR-rTMS as an additional viable method of rTMS delivery in the treatment of depression BACKGROUND In healthy volunteers , exposure to antidepressants increases the recognition of positive face emotions and decreases recognition of negative emotions . It has been proposed that this may underlie therapeutic effects of antidepressants , but to date this has not been tested in clinical population s. METHOD Recognition of facial emotions was measured at baseline ( N=108 ) and after 2 ( N=59 ) and 6 weeks ( N=69 ) of treatment in depressed primary care patients who had been r and omised to treatment with either citalopram ( SSRI ) or reboxetine ( NaRI ) in an open-label study . Changes in emotional processing were compared to clinical outcome after 6 weeks of treatment . RESULTS Significant increases in recognition accuracy of disgust , happiness and surprise occurred by two-weeks of treatment with both antidepressants , and did not further change at 6 weeks . There was a significant correlation between the increased accuracy in recognition of happy faces over the first two-weeks of treatment and the clinical improvement after six-weeks of treatment . LIMITATIONS There was no control group and changes over time may be due to practice effects . CONCLUSIONS Antidepressants altered emotional processing in depressed patients with some similarities to the effects seen in healthy volunteers . The largest effect seen was increased recognition of disgust that may be specific to depressed patients . The correlation between increased accurate recognition of happy faces at two-weeks of treatment and clinical outcome at six-weeks of treatment suggests that early changes in emotional processing may underlie clinical response to antidepressants
target: 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: 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 .