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Adolescent major depressive disorder (MDD) is associated with disrupted processing of emotional stimuli and difficulties in cognitive reappraisal. Little is known however about how current pharmacotherapies act to modulate the neural mechanisms underlying these key processes. The current study therefore investigated the neural effects of fluoxetine on emotional reactivity and cognitive reappraisal in adolescent depression.
Methods
Thirty-one adolescents with MDD were randomised to acute fluoxetine (10 mg) or placebo. Seventeen healthy adolescents were also recruited but did not receive any treatment for ethical reasons. During functional magnetic resonance imaging (fMRI), participants viewed aversive images and were asked to either experience naturally the emotional state elicited (‘Maintain’) or to reinterpret the content of the pictures to reduce negative affect (‘Reappraise’). Significant activations were identified using whole-brain analysis.
Results
No significant group differences were seen when comparing Reappraise and Maintain conditions. However, when compared to healthy controls, depressed adolescents on placebo showed reduced visual activation to aversive pictures irrespective of the condition. The depressed adolescent group on fluoxetine showed the opposite pattern, i.e. increased visuo-cerebellar activity in response to aversive pictures, when compared to depressed adolescents on placebo.
Conclusions
These data suggest that depression in adolescence may be associated with reduced visual processing of aversive imagery and that fluoxetine may act to reduce avoidance of such cues. This could reflect a key mechanism whereby depressed adolescents engage with negative cues previously avoided. Future research combining fMRI with eye-tracking is nonetheless needed to further clarify these effects.
Studies suggest that d-cycloserine (DCS) may have antidepressant potential through its interaction with the glycine site of the N-methyl-D-aspartate receptor; however, clinical evidence of DCS's efficacy as a treatment for depression is limited. Other evidence suggests that DCS affects emotional learning which may also be relevant for the treatment of depression and anxiety. The aim of the present investigation was to assess the effect of DCS on emotional processing in healthy volunteers and to further characterise its effects on emotional and autobiographical memory.
Methods
Forty healthy volunteers were randomly allocated to a single dose of 250 mg DCS or placebo in a double-blind design. Three hours later, participants performed an Emotional Test Battery [including Facial Expression Recognition Task (FERT), Emotional Categorisation Task (ECAT), Emotional Recall Task (EREC), Facial Dot-Probe Task (FDOT) and Emotional Recognition Memory Task (EMEM)] and an Autobiographical Memory Test (AMT). Also, participants performed the FERT, EREC and AMT tasks again after 24 h in order to assess longer lasting effects of a single dose of DCS.
Results
DCS did not significantly affect the FERT, EMEM and FDOT performance but significantly increased emotional memory and classification for positive words v. negative words. Also, DCS enhanced the retrieval of more specific autobiographical memories, and this effect persisted at 24 h.
Conclusions
These findings support the suggestion that low-dose DCS increases specific autobiographical memory retrieval and positive emotional memory. Such effects make it an intriguing agent for further investigation in clinical depression, which is characterised by decreased autobiographical memory specificity and increased negative bias in memory recall. It also underscores the potential role of DCS as an adjunct to cognitive behavioural therapy in depression.
Treatment of medical patients with the inflammatory cytokine, interferon-α (IFN-α), is frequently associated with the development of clinical depressive symptomatology. Several important biological correlates of the effect of IFN-α on mood have been described, but the neuropsychological changes associated with IFN-α treatment are largely unexplored. The aim of the present preliminary study was to assess the effect of IFN-α on measures of emotional processing.
Method
We measured changes in emotional processing over 6–8 weeks in 17 patients receiving IFN-α as part of their treatment for hepatitis C virus infection. Emotional processing tasks included those which have previously been shown to be sensitive to the effects of depression and antidepressant treatment, namely facial expression recognition, emotional categorisation and the dot probe attentional task.
Results
Following IFN-α, patients were more accurate at detecting facial expressions of disgust; they also showed diminished attentional vigilance to happy faces. IFN-α produced the expected increases in scores on depression rating scales, but there was no correlation between these scores and the changes in emotional processing.
Conclusions
Our preliminary findings suggest that IFN-α treatment produces negative biases in emotional processing, and this effect is not simply a consequence of depression. It is possible that increased recognition of disgust may represent a neuropsychological marker of depressive disorders related to inflammation.
Pragmatic studies indicate that a substantial number of depressed patients do not remit with current first-line antidepressant treatments and after two failed treatment steps the chance of remission with subsequent therapies is around 15%. This paper focuses on current evidence for pharmacological treatments in resistant depression as well as possible future developments. For patients who have failed to respond to two antidepressant trials, augmentation with atypical antipsychotic drugs, specifically quetiapine and aripiprazole, has the best evidence for efficacy, though older treatments such as lithium and triiodothyronine still have utility. The striking antidepressant effect of ketamine in resistant depression has stimulated research into glutamatergic compounds; however, capturing the efficacy of ketamine with drugs suitable for continuous use has proved challenging. Growing knowledge of the pathophysiological role of inflammation in depression offers great opportunities for future treatment in terms of repurposing anti-inflammatory agents from general medicine and pre-treatment stratification of those depressed patients in whom such interventions are likely to be beneficial. Finally an older drug, the dopamine receptor agonist pramipexole, if used carefully may well improve the prospects of depressed patients who are refractory to current approaches.
Fluoxetine is generally regarded as the first-line pharmacological treatment for young people, as it is believed to show a more favourable benefit:risk ratio than other antidepressants. However, the mechanisms through which fluoxetine influences symptoms in youth have been little investigated. This study examined whether acute administration of fluoxetine in a sample of young healthy adults altered the processing of affective information, including positive, sad and anger cues.
Method
A total of 35 male and female volunteers aged between 18 and 21 years old were randomized to receive a single 20 mg dose of fluoxetine or placebo. At 6 h after administration, participants completed a facial expression recognition task, an emotion-potentiated startle task, an attentional dot-probe task and the Rapid Serial Visual Presentation. Subjective ratings of mood, anxiety and side effects were also taken pre- and post-fluoxetine/placebo administration.
Results
Relative to placebo-treated participants, participants receiving fluoxetine were less accurate at identifying anger and sadness and did not show the emotion-potentiated startle effect. There were no overall significant effects of fluoxetine on subjective ratings of mood.
Conclusions
Fluoxetine can modulate emotional processing after a single dose in young adults. This pattern of effects suggests a potential cognitive mechanism for the greater benefit:risk ratio of fluoxetine in adolescent patients.
Major depression is associated with abnormalities in reward processing at neural and behavioural levels. Neural abnormalities in reward have been described in young people at familial risk of depression but behavioural changes in reward-based decision making have been less studied in this group.
Method
We studied 63 young people (mean age 18.9 years) with a parent with a diagnosis of major depression but who had never been depressed themselves, that is with a positive family history of depression (the FH+ group). Participants performed the Cambridge Gambling Task (CGT), which provides several measures of decision making including deliberation time, quality of decision making, risk taking, risk adjustment and delay aversion. A control group of 49 age- and gender-matched young people with no history of mood disorder in a first-degree relative undertook the same task.
Results
Both FH+ participants and controls had low and equivalent scores on anxiety and depression self-rating scales. Compared to controls, the FH+ participants showed overall lower risk taking, although like controls they made more risky choices as the odds of a favourable outcome increased. No other measures of decision making differed between the two groups.
Conclusions
Young people at increased familial risk of depression have altered risk taking that is not accounted for by current affective symptomatology. Lowered risk taking might represent an impairment in reward seeking, which is one of several changes in reward-based behaviours seen in acutely depressed patients; however, our findings suggest that decreased reward seeking could be part of a risk endophenotype for depression.
Major depression is associated with abnormalities in the function and structure of the hippocampus. However, it is unclear whether these abnormalities might also be present in people ‘at risk’ of illness.
Method
We studied 62 young people (mean age 18.8 years) at familial risk of depression (FH+) but who had never been depressed themselves. Participants underwent magnetic resonance imaging to assess hippocampal structure and neural responses to a task designed to activate hippocampal memory networks. Magnetic resonance spectroscopy was used to measure levels of a combination of glutamine and glutamate (Glx) in the right hippocampus. A total of 59 matched controls with no history of mood disorder in a first-degree relative underwent the same investigations.
Results
Hippocampal volume did not differ between FH+ participants and controls; however, relative to controls, during the memory task, FH+ participants showed increased activation in brain regions encompassing the insular cortices, putamen and pallidum as well as the dorsal anterior cingulate cortex (ACC). FH+ participants also had increased hippocampal levels of Glx.
Conclusions
Euthymic individuals with a parental history of depression demonstrate increased activation of hippocampal-related neural networks during a memory task, particularly in brain regions involved in processing the salience of stimuli. Changes in the activity of the ACC replicate previous findings in FH+ participants using different psychological tasks; this suggests that task-related abnormalities in the ACC may be a marker of vulnerability to depression. Increased levels of Glx in the hippocampus might also represent a risk biomarker but follow-up studies will be required to test these various possibilities.
Meta-analyses suggest that reboxetine may be less effective than other antidepressants. Such comparisons may be biased by lower adherence to reboxetine and subsequent handling of missing outcome data. This study illustrates how to adjust for differential non-adherence and hence derive an unbiased estimate of the efficacy of reboxetine compared with citalopram in primary care patients with depression.
Method
A structural mean modelling (SMM) approach was used to generate adherence-adjusted estimates of the efficacy of reboxetine compared with citalopram using GENetic and clinical Predictors Of treatment response in Depression (GENPOD) trial data. Intention-to-treat (ITT) analyses were performed to compare estimates of effectiveness with results from previous meta-analyses.
Results
At 6 weeks, 92% of those randomized to citalopram were still taking their medication, compared with 72% of those randomized to reboxetine. In ITT analysis, there was only weak evidence that those on reboxetine had a slightly worse outcome than those on citalopram [adjusted difference in mean Beck Depression Inventory (BDI) scores: 1.19, 95% confidence interval (CI) –0.52 to 2.90, p = 0.17]. There was no evidence of a difference in efficacy when differential non-adherence was accounted for using the SMM approach for mean BDI (–0.29, 95% CI –3.04 to 2.46, p = 0.84) or the other mental health outcomes.
Conclusions
There was no evidence of a difference in the efficacy of reboxetine and citalopram when these drugs are taken and tolerated by depressed patients. The SMM approach can be implemented in standard statistical software to adjust for differential non-adherence and generate unbiased estimates of treatment efficacy for comparisons of two (or more) active interventions.
Patients with depression show abnormalities in the neural circuitry supporting working memory. However, it is unclear if these abnormalities are present in unmedicated remitted depressed patients. To address this question, the current study employed functional magnetic resonance imaging (fMRI), in combination with a simple verbal n-back task, in a cohort of unmedicated remitted depressed patients.
Method
We studied 15 healthy control subjects (HC) and 15 unmedicated remitted depressed patients (rMDD). Participants performed a verbal working memory task of varying cognitive load (n-back) while undergoing fMRI. We used multiple regression analyses to assess overall capacity (1-, 2-, 3-back versus 0-back) as well as quadratic modulation of cognitive demand.
Results
Performance accuracy and response latency did not differ between groups, and overall capacity was similar. However, rMDD showed a positive quadratic load response in the bilateral hippocampus; the converse was true for HC.
Conclusions
Our data suggest that remitted depression was associated with a perturbed pattern of activation in the bilateral hippocampus during a verbal working memory task. We propose that a reduced ability to dampen task-irrelevant activity may reflect a neurobiological risk factor for recurrent depression.
The development of depressive symptomatology is a recognized complication of treatment with the cytokine interferon-α (IFN-α) and has been seen as supporting inflammatory theories of the pathophysiology of major depression. Major depression has been associated with changes in glutamatergic activity and recent formulations of IFN-induced depression have implicated neurotoxic influences that could also lead to changes in glutamate function. The present study used magnetic resonance spectroscopy (MRS) to measure glutamate and its major metabolite glutamine in patients with hepatitis C who received treatment with pegylated IFN-α and ribavirin.
Method
MRS measurements of glutamate and glutamine were taken from a 25 × 20 × 20 mm voxel including the pregenual anterior cingulate cortex in 12 patients before and after 4–6 weeks of treatment with IFN.
Results
IFN treatment led to an increase in cortical levels of glutamine (p = 0.02) and a significant elevation in the ratio of glutamine to glutamate (p < 0.01). Furthermore, changes in glutamine level correlated significantly with ratings of depression and anxiety at the time of the second scan.
Conclusions
We conclude that treatment with IFN-α is associated with MRS-visible changes in glutamatergic metabolism. However, the changes seen differ from those reported in major depression, which suggests that the pathophysiology of IFN-induced depression may be distinct from that of major depression more generally.
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 randomised, 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.
Antidepressant drug treatments increase the processing of positive compared to negative affective information early in treatment. Such effects have been hypothesized to play a key role in the development of later therapeutic responses to treatment. However, it is unknown whether these effects are a common mechanism of action for different treatment modalities. High-density negative ion (HDNI) treatment is an environmental manipulation that has efficacy in randomized clinical trials in seasonal affective disorder (SAD).
Method
The current study investigated whether a single session of HDNI treatment could reverse negative affective biases seen in seasonal depression using a battery of emotional processing tasks in a double-blind, placebo-controlled randomized study.
Results
Under placebo conditions, participants with seasonal mood disturbance showed reduced recognition of happy facial expressions, increased recognition memory for negative personality characteristics and increased vigilance to masked presentation of negative words in a dot-probe task compared to matched healthy controls. Negative ion treatment increased the recognition of positive compared to negative facial expression and improved vigilance to unmasked stimuli across participants with seasonal depression and healthy controls. Negative ion treatment also improved recognition memory for positive information in the SAD group alone. These effects were seen in the absence of changes in subjective state or mood.
Conclusions
These results are consistent with the hypothesis that early change in emotional processing may be an important mechanism for treatment action in depression and suggest that these effects are also apparent with negative ion treatment in seasonal depression.
Processing emotional facial expressions is of interest in eating disorders (EDs) as impairments in recognizing and understanding social cues might underlie the interpersonal difficulties experienced by these patients. Disgust and anger are of particular theoretical and clinical interest. The current study investigated the neural response to facial expressions of anger and disgust in bulimia nervosa (BN).
Method
Participants were 12 medication-free women with BN in an acute episode (mean age 24 years), and 16 age-, gender- and IQ-matched healthy volunteers (HVs). Functional magnetic resonance imaging (fMRI) was used to examine neural responses to angry and disgusted facial expressions.
Results
Compared with HVs, patients with BN had a decreased neural response in the precuneus to facial expressions of both anger and disgust and a decreased neural response to angry facial expressions in the right amygdala.
Conclusions
The neural response to emotional facial expressions in BN differs from that found in HVs. The precuneus response may be consistent with the application of mentalization theory to EDs, and the amygdala response with relevant ED theory. The findings are preliminary, but novel, and require replication in a larger sample.
Previous imaging studies have revealed that acute major depression is characterized by altered neural responses to negative emotional stimuli. Typically, responses in limbic regions such as the amygdala are increased while activity in cortical regulatory regions such as the dorsolateral prefrontal cortex (DLPFC) is diminished. Whether these changes persist in unmedicated recovered patients is unclear.
Method
We used functional magnetic resonance imaging to examine neural responses to emotional faces in a facial expression-matching task in 16 unmedicated recovered depressed patients and 21 healthy controls.
Results
Compared with controls, recovered depressed patients had increased responses bilaterally to fearful faces in the DLPFC and right caudate. Responses in the amygdala did not distinguish the groups.
Conclusions
Our findings indicate that clinical recovery from depression is associated with increased activity in the DLPFC to negative emotional stimuli. We suggest that this increase may reflect a compensatory cortical control mechanism with the effect of limiting emotional dysregulation in limbic regions such as the amygdala.
In normal women sedation following intravenous administration of the α2-adrenoceptor agonist clonidine (1·3 μg/kg) was significantly greater following 3 weeks' continuous treatment with the combined contraceptive pill than at the end of the 7-day withdrawal period. In contrast, sedative responses to the dopamine agonist apomorphine (5 μg/kg subcutaneously) were decreased when subjects were taking the contraceptive pill. These findings are in agreement with animal experimental studies, indicating that oestrogen can alter α-adrenoceptor and dopamine autoreceptor sensitivity. Such interactions may be involved in the effects of female sex steroids on mood.
We studied the prolactin and cortisol responses to the 5-HT releasing agent, D-fenfluramine in 31 drug-free depressed patients and 29 healthy controls, using a double-blind, placebo-controlled design. There was no difference in either endocrine response between depressives and controls. Examining the sexes separately, or restricting comparisons to patients with melancholic depression, did not lead to any differences between the groups. Our findings suggest that in contrast to other 5-HT neuroendocrine probes such as L-tryptophan and clomipramine, the prolactin response to fenfluramine are not consistently blunted in depressed patients.
Dieting is a widespread behaviour in developed countries, which in predisposed individuals can lead to the development of clinical eating disorders such as bulimia nervosa and anorexia nervosa. We studied the effect of moderate dieting in healthy women on the prolactin response to the serotonin (5-HT) receptor agonist, m-chlorophenylpiperazine (mCPP), a measure of the sensitivity of post-synaptic 5-HT2C receptors. Dieting significantly increased the prolactin response to mCPP and lowered plasma concentrations of the 5-HT precursor, tryptophan. We propose that dieting in women is associated with the development of functional supersensitivity of 5-HT2C receptors, probably in response to lowered levels of brain 5-HT. Alterations in brain 5-HT neurotransmission could play a part in dieting-induced dysregulation of eating and the development of clinical eating disorders in predisposed individuals.