Cognitive impairment in depression and its (non-)response to antidepressant treatment

ABSTRACT FROM: Shilyansky C, Williams LM, Gyurak A, et al. Effect of antidepressant treatment on cognitive impairments associated with depression: a randomised longitudinal study. Lancet Psychiatry 2016;3:425–35

The neural basis of hot and cold cognition in depressed patients, unaffected relatives, and low -risk healthy controls: An fMRI investigation

BACKGROUND: Modern cognitive neuropsychological models of depression posit that negatively biased emotional (“hot”) processing confers risk for depression, while preserved executive function (“cold”) cognition promotes resilience. METHODS: We compared neural responses during hot and cold cognitive tasks in 99 individuals: those at familial risk for depression (N = 30 unaffected first-degree relatives of depressed individuals) and those currently experiencing a major depressive episode (N = 39 unmedicated depressed patients) with low-risk healthy controls (N = 30). Primary analyses assessed neural activation on two functional magnetic resonance imaging tasks previously associated with depression: dorsolateral prefrontal cortex (DLPFC) responsivity during the n-back working memory task; and amygdala and subgenual anterior cingulate cortex (sgACC) responsivity during incidental emotional face processing. RESULTS: Depressed patients exhibited significantly attenuated working memory-related DLPFC activation, compared to low-risk controls and unaffected relatives; unaffected relatives did not differ from low-risk controls. We did not observe a complementary pattern during emotion processing. However, we found preliminary support that greater DLPFC activation was associated with lower amygdala response during emotion processing. LIMITATIONS: These findings require confirmation in a longitudinal study to observe each individual's risk of developing depression; without this, we cannot identify the true risk level of the first-degree relative or low-risk control group. CONCLUSIONS: These findings have implications for understanding the neural mechanisms of risk and resilience in depression: they are consistent with the suggestion that preserved executive function might confer resilience to developing depression in first-degree relatives of depressed patients

Reward-Processing Behavior in Depressed Participants Relative to Healthy Volunteers: A Systematic Review and Meta-analysis

IMPORTANCE: Dysfunctional reward processing is a leading candidate mechanism for the development of certain depressive symptoms, such as anhedonia. However, to our knowledge, there has not yet been a systematic assessment of whether and to what extent depression is associated with impairments on behavioral reward-processing tasks. OBJECTIVE: To determine whether depression is associated with impairments in reward-processing behavior. DATA SOURCES: The MEDLINE/PubMed, Embase, and PsycInfo databases were searched for studies that investigated reward processing using performance on behavioral tasks by individuals with depression and nondepressed control groups, published between January 1, 1946, and August 16, 2019. STUDY SELECTION: Studies that contained data regarding performance by depressed and healthy control groups on reward-processing tasks were included in the systematic review and meta-analysis. DATA EXTRACTION AND SYNTHESIS: Summary statistics comparing performance between depressed and healthy groups on reward-processing tasks were converted to standardized mean difference (SMD) scores, from which summary effect sizes for overall impairment in reward processing and 4 subcomponent categories were calculated. Study quality, heterogeneity, replicability-index, and publication bias were also assessed. MAIN OUTCOME AND MEASURES: Performance on reward-processing tasks. RESULTS: The final data set comprised 48 case-control studies (1387 healthy control individuals and 1767 individuals with major depressive disorder). The mean age was 37.85 years and 58% of the participants were women. These studies used tasks assessing option valuation (n = 9), reward bias (n = 6), reward response vigor (n = 12), reinforcement learning (n = 20), and grip force (n = 1). Across all tasks, depression was associated with small to medium impairments in reward-processing behavior (SMD = 0.345; 95% CI, 0.209-0.480). When examining reward-processing subcomponent categories, impairment was associated with tasks assessing option valuation (SMD = 0.309; 95% CI, 0.147-0.471), reward bias (SMD = 0.644; 95% CI, 0.270-1.017), and reinforcement learning (SMD = 0.352; 95% CI, 0.115-0.588) but not reward response vigor (SMD = 0.083; 95% CI, −0.144 to 0.309). The medication status of the major depressive disorder sample did not explain any of the variance in the overall effect size. There was significant between-study heterogeneity overall and in all subcomponent categories other than option valuation. Significant publication bias was identified overall and in the reinforcement learning category. CONCLUSIONS AND RELEVANCE: Relative to healthy control individuals, individuals with depression exhibit reward-processing impairments, particularly for tests of reward bias, option valuation, and reinforcement learning. Understanding the neural mechanisms driving these associations may assist in designing novel interventions

Pramipexole augmentation for the acute phase of treatment-resistant, unipolar depression: a placebo-controlled, double-blind, randomised trial in the UK

\ua9 2025 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 licenseBackground: About 30% of patients with depression treated with antidepressant medication do not respond sufficiently to the first agents used. Pramipexole might usefully augment antidepressant medication in such cases of treatment-resistant depression, but data on its effects and tolerability are scarce. We aimed to assess the efficacy and tolerability of pramipexole augmentation of ongoing antidepressant treatment, over 48 weeks, in patients with treatment-resistant depression. Methods: We did a multicentre, double-blind, placebo-controlled randomised trial in which adults with resistant major depressive disorder were randomly assigned (1:1; using an online randomisation system) to 48 weeks of pramipexole (titrated to 2\ub75 mg) or placebo added to their ongoing antidepressant medication. The study was conducted in nine National Health Service Trusts in England. Participants, investigators, and researchers involved in recruitment and assessment were masked to group allocation, and the central pharmacy team dispensing the medication was not masked. The primary outcome was change from baseline to week 12 in the total score of the 16-item Quick Inventory of Depressive Symptomology self-report version (QIDS-SR16). The primary analysis was performed on the intention-to-treat population that included all eligible, randomly assigned participants. People with lived experience were involved in the design, oversight, and interpretation of the study. The trial was registered with ISCTRN (ISRCTN84666271) and EudraCT (2019-001023-13) and is complete. Findings: Between Feb 16 and May 29, 2024, 217 participants attended a screening visit, of whom 66 were excluded due to ineligibility. 151 participants were randomly assigned (75 to the pramipexole group and 75 to the placebo group, after one participant was found to be ineligible after randomisation). 84 (56%) participants were female and 66 (44%) were male and the mean age of participants was 44\ub79 years (SD 14\ub70). Ethnicity data were not available. The mean QIDS-SR16 total score at baseline was 16\ub74 (SD 3\ub74) in the pramipexole group and 16\ub72 (3\ub75) in the placebo group. The mean dose of pramipexole received at week 12 was 2\ub73 mg (SD 0\ub745). Adjusted mean decrease from baseline to week 12 of the QIDS-SR16 total score was 6\ub74 (SD 4\ub79) for the pramipexole group and 2\ub74 (4\ub70) for the placebo group; the mean difference between groups was −3\ub791 (95% CI −5\ub737 to −2\ub745; p<0\ub70001). Termination of trial treatment due to adverse events was more frequent in the pramipexole group (15 participants [20%]) than in the placebo group (four participants [5%]), with reported adverse events consistent with known side-effects of pramipexole, in particular nausea, headache, and sleep disturbance or somnolence. Interpretation: In this trial involving participants with treatment-resistant depression, pramipexole augmentation of antidepressant treatment, at a target dose of 2\ub75 mg, demonstrated a reduction in symptoms relative to placebo at 12 weeks but was associated with some adverse effects. These results suggest that pramipexole is a clinically effective option for reducing symptoms in patients with treatment-resistant depression. Future trials directly comparing pramipexole with existing treatments for this disorder are needed. Funding: National Institute of Health and Care Research, Efficacy and Mechanism Evaluation Programme

Enhanced taste recognition following subacute treatment with the dopamine D2/D3 receptor agonist pramipexole in healthy volunteers

Background: Patients with Parkinson’s disease (PD) show impaired performance in taste recognition tests, which suggests a possible dopaminergic influence on gustatory functioning. To experimentally test this hypothesis, we assessed whether pharmacological manipulation of dopaminergic signalling in healthy volunteers can affect performance in a standardised taste recognition test. Methods: Physically and mentally healthy volunteers (n = 40, age 18 to 43 years) were randomly allocated to treatment with either pramipexole or placebo using a double-blind, parallel-group design. After 12 to 15 days of treatment (dose titrated up from 0.25 mg/day of pramipexole salt to 1.0 mg/day), taste recognition performance was assessed using a standardised and validated assay (taste strip test). Additionally, visual analogue scale ratings of subjective pleasantness and disgustingness of taste samples were obtained. Results: Compared to the placebo group, participants receiving pramipexole showed significantly higher total recognition accuracy (Median Pramipexole = 14.0, Median Placebo = 13.0, U = 264.5, p = 0.04). This was driven by a higher sensitivity for taste in the pramipexole group. Exploratory analysis of pleasantness and disgustingness ratings of appetitive (sweet) versus aversive (bitter) stimuli suggested that pramipexole treatment was associated with overall blunted hedonic responses, but this effect did not survive the inclusion of nausea (a side effect of treatment) as a covariate in the analysis. Conclusions: Healthy volunteers who received subacute pramipexole treatment exhibited higher taste recognition performance in comparison to a placebo group. This finding is consistent with a proposed role of the dopaminergic system in gustatory functioning and could have important theoretical and clinical implications

The neural basis of hot and cold cognition in depressed patients, unaffected relatives, and low-risk healthy controls: An fMRI investigation.

BACKGROUND: Modern cognitive neuropsychological models of depression posit that negatively biased emotional ("hot") processing confers risk for depression, while preserved executive function ("cold") cognition promotes resilience. METHODS: We compared neural responses during hot and cold cognitive tasks in 99 individuals: those at familial risk for depression (N = 30 unaffected first-degree relatives of depressed individuals) and those currently experiencing a major depressive episode (N = 39 unmedicated depressed patients) with low-risk healthy controls (N = 30). Primary analyses assessed neural activation on two functional magnetic resonance imaging tasks previously associated with depression: dorsolateral prefrontal cortex (DLPFC) responsivity during the n-back working memory task; and amygdala and subgenual anterior cingulate cortex (sgACC) responsivity during incidental emotional face processing. RESULTS: Depressed patients exhibited significantly attenuated working memory-related DLPFC activation, compared to low-risk controls and unaffected relatives; unaffected relatives did not differ from low-risk controls. We did not observe a complementary pattern during emotion processing. However, we found preliminary support that greater DLPFC activation was associated with lower amygdala response during emotion processing. LIMITATIONS: These findings require confirmation in a longitudinal study to observe each individual's risk of developing depression; without this, we cannot identify the true risk level of the first-degree relative or low-risk control group. CONCLUSIONS: These findings have implications for understanding the neural mechanisms of risk and resilience in depression: they are consistent with the suggestion that preserved executive function might confer resilience to developing depression in first-degree relatives of depressed patients

An experimental medicine investigation of the effects of subacute pramipexole treatment on emotional information processing in healthy volunteers

Treatment with the dopamine D2/D3 receptor agonist pramipexole has demonstrated promising clinical effects in patients with depression. However, the mechanisms through which pramipexole might alleviate depressive symptoms are currently not well understood. Conventional antidepressant drugs are thought to work by biasing the processing of emotional information in favour of positive relative to negative appraisal. In this study, we used an established experimental medicine assay to explore whether pramipexole treatment might have a similar effect. Employing a double-blind, parallel-group design, 40 healthy volunteers (aged 18 to 43 years, 50% female) were randomly allocated to 12 to 15 days of treatment with either pramipexole (at a peak daily dose of 1.0 mg pramipexole salt) or placebo. After treatment was established, emotional information processing was assessed on the neural level by measuring amygdala activity in response to positive and negative facial emotional expressions, using functional magnetic resonance imaging (MRI). In addition, behavioural measures of emotional information processing were collected at baseline and on drug, using an established computerized task battery, tapping into different cognitive domains. As predicted, pramipexole-treated participants, compared to those receiving placebo, showed decreased neural activity in response to negative (fearful) vs. positive (happy) facial expressions in bilateral amygdala. Contrary to our predictions, however, pramipexole treatment had no significant antidepressant-like effect on behavioural measures of emotional processing. This study provides the first experimental evidence that subacute pramipexole treatment in healthy volunteers modifies neural responses to emotional information in a manner that resembles the effects of conventional antidepressant drugs