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The use of SSRIs for the treatment of depression and anxiety in young people is increasing. However, the effects of SSRIs in adolescence, a time when there are substantial changes in neural, cognitive, and social functioning, are not well understood. Here, we review evidence from clinical trials about the benefits and risks of SSRIs in young people and consider their mechanisms of action, as shown through human experimental work and animal models. We emphasise key outstanding questions about the effects of SSRIs in youth, identified through gaps in the literature and in consultation with young people with lived experience. It is crucial to characterise the mechanisms underpinning risks and benefits of SSRIs in this age group to progress the field, and to narrow the chasm between the widespread use of SSRIs in youth and the science on which this use is based., Competing Interests: Declaration of interests SLCG and LPC declare no competing interests. PJC reports grants from Wellcome Trust, during the conduct of the study. SEM reports grants from Wellcome Trust, during the conduct of the study; and grants from Janssen Pharmaceuticals, UCB Pharma, and Zogenix and personal fees from Janssen Pharmaceuticals, Zogenix, and Sumitomo Dainippon Pharma, outside the submitted work. CJH reports grants from Wellcome Trust, during the conduct of the study; and grants from Janssen Pharmaceuticals, UCB Pharma, and Zogenix and personal fees from Janssen Pharmaceuticals, Zogenix, Sage Pharmaceuticals, P1vital, Lundbeck, and Pfizer, outside the submitted work. AS reports fees from Cambridge and Oxford University Press, outside the submitted work., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: The difficulty in treating mood disorders has brought about clinical interest in alternative treatments, such as transcranial direct current stimulation (tDCS) of the dorsolateral prefrontal cortex (DLPFC). However, the optimal parameters for stimulation and underlying mechanisms of action are unclear. Psychiatric treatments have acute effects on emotional processing that predict later therapeutic action. Such effects have been proposed as cognitive biomarkers for screening novel treatments for depression and anxiety., Methods: This study assessed the effect of tDCS on a battery of emotional processing measures sensitive to antidepressant action. To refine optimal stimulation parameters, DLPFC stimulation using two common electrode montages was compared with sham. Sixty healthy volunteers received 20 minutes of active or sham DLPFC stimulation before completing computerized emotional processing tasks, including a dot-probe measure of vigilance to threat., Results: Relative to sham stimulation, participants receiving simultaneous anodal stimulation of left DLPFC and cathodal stimulation of right DLPFC (bipolar-balanced montage) showed reduced vigilance to threatening stimuli. There was no such significant effect when the cathode was placed on the supraorbital ridge (bipolar-unbalanced montage). There were no effects of tDCS on other measures of emotional processing., Conclusions: Our findings provide the first experimental evidence that modulating activity in the DLPFC reduces vigilance to threatening stimuli. This significant reduction in fear vigilance is similar to that seen with anxiolytic treatments in the same cognitive paradigm. The finding that DLPFC tDCS acutely alters the processing of threatening information suggests a potential cognitive mechanism that could underwrite treatment effects in clinical populations., (Copyright © 2016 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Background: C-reactive protein (CRP) is a candidate biomarker for major depressive disorder (MDD), but it is unclear how peripheral CRP levels relate to the heterogeneous clinical phenotypes of the disorder.AimTo explore CRP in MDD and its phenotypic associations.Method: We recruited 102 treatment-resistant patients with MDD currently experiencing depression, 48 treatment-responsive patients with MDD not currently experiencing depression, 48 patients with depression who were not receiving medication and 54 healthy volunteers. High-sensitivity CRP in peripheral venous blood, body mass index (BMI) and questionnaire assessments of depression, anxiety and childhood trauma were measured. Group differences in CRP were estimated, and partial least squares (PLS) analysis explored the relationships between CRP and specific clinical phenotypes.Results: Compared with healthy volunteers, BMI-corrected CRP was significantly elevated in the treatment-resistant group (P = 0.007; Cohen's d = 0.47); but not significantly so in the treatment-responsive (d = 0.29) and untreated (d = 0.18) groups. PLS yielded an optimal two-factor solution that accounted for 34.7% of variation in clinical measures and for 36.0% of variation in CRP. Clinical phenotypes most strongly associated with CRP and heavily weighted on the first PLS component were vegetative depressive symptoms, BMI, state anxiety and feeling unloved as a child or wishing for a different childhood.Conclusions: CRP was elevated in patients with MDD, and more so in treatment-resistant patients. Other phenotypes associated with elevated CRP included childhood adversity and specific depressive and anxious symptoms. We suggest that patients with MDD stratified for proinflammatory biomarkers, like CRP, have a distinctive clinical profile that might be responsive to second-line treatment with anti-inflammatory drugs.Declaration of interestS.R.C. consults for Cambridge Cognition and Shire; and his input in this project was funded by a Wellcome Trust Clinical Fellowship (110049/Z/15/Z). E.T.B. is employed half time by the University of Cambridge and half time by GlaxoSmithKline; he holds stock in GlaxoSmithKline. In the past 3 years, P.J.C. has served on an advisory board for Lundbeck. N.A.H. consults for GlaxoSmithKline. P.d.B., D.N.C.J. and W.C.D. are employees of Janssen Research & Development, LLC., of Johnson & Johnson, and hold stock in Johnson & Johnson. The other authors report no financial disclosures or potential conflicts of interest. [ABSTRACT FROM AUTHOR]

Rimonabant is a cannabinoid type 1 receptor (CB1) antagonist formerly used to treat obesity, but which was withdrawn from the market in late 2008 because of its association with psychiatric adverse effects such as depression and anxiety. Previously, we showed that a single dose of rimonabant produced a negative bias on an emotional word memory task, in the absence of subjective mood effects. The present study investigated whether a similar effect on emotional processing could be seen after 7 days’ daily treatment with rimonabant 20 mg, using a randomized, placebo-controlled, between-subjects design in healthy volunteers (final n = 21). In comparison with placebo, rimonabant induced a negative bias on a memory recognition task without producing a change in subjective mood. This raises the possibility that the depressogenic effects of rimonabant may be linked to emotional memory biases, and that such biases may be detectable in the absence of subjective mood changes. Investigating such effects could be useful in detecting adverse psychiatric effects of novel treatments. [ABSTRACT FROM PUBLISHER]

Emotional processing measures are sensitive to acute administration of clinically useful antidepressant drugs. We wished to test the hypothesis that these models would also be able to detect agents likely to cause depression as an adverse effect. The anti-obesity drug and cannabinoid type 1 receptor antagonist, rimonabant, is associated with significant rates of depression and anxiety in clinical use. Thirty healthy adult volunteers were randomly assigned to receive a single dose of rimonabant (20 mg) or lactose placebo in a double-blind, between-groups design. Three hours after medication administration, subjects undertook an emotional processing test battery including facial emotion recognition, emotional word attentional dot probe, self-relevant word classification, emotional and declarative memory and the emotion-potentiated acoustic startle response. Subjective state was assessed via self-report measures. A single dose of rimonabant did not alter subjective mood. However, rimonabant selectively reduced incidental recall of positive self-relevant adjectives, an effect contrary to that seen following the administration of antidepressants. There were no effects of rimonabant on the other measures of emotional processing. These results suggest that a single dose of rimonabant decreases positive emotional memory in the absence of changes in subjective state. Further studies are required to examine whether rimonabant might produce a wider range of negative emotional biases with repeated treatment. [ABSTRACT FROM AUTHOR]

Rationale: The serotonin precursor L-tryptophan (TRP) is available as a nutritional supplement and is licensed as an antidepressant in a number of countries. However, evidence of its efficacy as the primary treatment for depression is limited, and the direct action of TRP on the symptoms of depression and anxiety has not been well-characterised. Objectives: The present study assessed whether TRP induces cognitive changes opposite to the negative biases found in depression and characteristic of those induced by serotonergic antidepressants in healthy volunteers. Materials and methods: Thirty eight healthy volunteers were randomised to receive 14 days doubleblind intervention with TRP (1 g 3x a day) or placebo. On the final day, emotional processing was assessed using four tasks: facial expression recognition, emotion-potentiated startle, attentional probe and emotional categorisation and memory. Results: TRP increased the recognition of happy facial expressions and decreased the recognition of disgusted facial expressions in female, but not male, volunteers. TRP also reduced attentional vigilance towards negative words and decreased baseline startle responsivity in the females. Conclusions: These findings provide evidence that TRP supplementation in women induces a positive bias in the processing of emotional material that is reminiscent of the actions of serotonergic antidepressants. This highlights a key role for serotonin in emotional processing and lends support to the use of TRP as a nutritional supplement in people with mild depression or for prevention in those at risk. Future studies are needed to clarify the effect of tryptophan on these measures in men. [ABSTRACT FROM AUTHOR]

Objective: Antidepressants that inhibit the reuptake of serotonin (SSRI5) or nor- epinephrine (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 randomly 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. Questionnaires 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 antidepresants 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. [ABSTRACT FROM AUTHOR]

We used functional magnetic resonance imaging to investigate the effects of short-term treatment with reboxetine, a selective noradrenaline reuptake inhibitor, on emotional facial processing in healthy volunteers. Reboxetine was associated with a reduced amygdala response to fearful faces and increased activation to happy v. neutral facial expressions in the right fusiform gyrus, relative to placebo treatment and in the absence of changes in mood. Our results show that reboxetine modulates the neural substrates of emotional processing, highlighting a mechanism by which drug treatment could normalise negative bias in depression and anxiety. [ABSTRACT FROM AUTHOR]

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 randomized 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. [Copyright &y& Elsevier]