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BACKGROUND: The serotonin 4 receptor (5-HT4R) is a promising target for the treatment of depression. Highly selective 5-HT4R agonists, such as prucalopride, have antidepressant-like and procognitive effects in preclinical models, but their clinical effects are not yet established. AIMS: To determine whether prucalopride (a 5-HT4R agonist and licensed treatment for constipation) is associated with reduced incidence of depression in individuals with no past history of mental illness, compared with anti-constipation agents with no effect on the central nervous system. METHOD: Using anonymised routinely collected data from a large-scale USA electronic health records network, we conducted an emulated target trial comparing depression incidence over 1 year in individuals without prior diagnoses of major mental illness, who initiated treatment with prucalopride versus two alternative anti-constipation agents that act by different mechanisms (linaclotide and lubiprostone). Cohorts were matched for 121 covariates capturing sociodemographic factors, and historical and/or concurrent comorbidities and medications. The primary outcome was a first diagnosis of major depressive disorder (ICD-10 code F32) within 1 year of the index date. Robustness of the results to changes in model and population specification was tested. Secondary outcomes included a first diagnosis of six other neuropsychiatric disorders. RESULTS: Treatment with prucalopride was associated with significantly lower incidence of depression in the following year compared with linaclotide (hazard ratio 0.87, 95% CI 0.76-0.99; P = 0.038; n = 8572 in each matched cohort) and lubiprostone (hazard ratio 0.79, 95% CI 0.69-0.91; P < 0.001; n = 8281). Significantly lower risks of all mood disorders and psychosis were also observed. Results were similar across robustness analyses. CONCLUSIONS: These findings support preclinical data and suggest a role for 5-HT4R agonists as novel agents in the prevention of major depression. These findings should stimulate randomised controlled trials to confirm if these agents can serve as a novel class of antidepressant within a clinical setting.
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BACKGROUND: 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.
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Transtorno Depressivo Maior , Regulação Emocional , Humanos , Adolescente , Fluoxetina/farmacologia , Fluoxetina/uso terapêutico , Transtorno Depressivo Maior/diagnóstico por imagem , Transtorno Depressivo Maior/tratamento farmacológico , Emoções/fisiologia , Encéfalo/diagnóstico por imagem , Mapeamento Encefálico , Imageamento por Ressonância Magnética/métodosRESUMO
BACKGROUND: The COVID-19 pandemic highlighted the need for mental health interventions that can be easily disseminated during a crisis. Behavioural activation (BA) is a cost-effective treatment that can be administered by non-specialists; however, it is unclear whether it is still effective during a time of lockdown and social distancing, when opportunities for positive activity are significantly constrained. METHODS: Between May and October 2020, we randomised 68 UK participants with mild to moderate low mood to either a 4-week online programme of non-specialist administered BA or to a passive control group. Before and after the intervention, we collected self-report data on mood and COVID-related disruption, as well as measuring emotional cognition as an objective marker of risk for depression. RESULTS: In comparison to the control group, the BA group showed a significant decrease in depression, anxiety and anhedonia after the intervention, as well as an increase in self-reported activation and social support. Benefits persisted at 1-month follow-up. BA also decreased negative affective bias on several measures of the Facial Emotion Recognition Task and early change in bias was associated with later therapeutic gain. Participants rated the intervention as highly acceptable. CONCLUSION: This study highlights the benefits of online BA that can be administered by non-specialists after brief training. These findings can help inform the policy response towards the rising incidence of mental health problems during a crisis situation such as a pandemic. They also highlight the use of objective cognitive markers of risk across different treatment modalities.
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COVID-19 , Humanos , COVID-19/prevenção & controle , Pandemias/prevenção & controle , Depressão/terapia , Depressão/psicologia , Controle de Doenças Transmissíveis , Terapia ComportamentalRESUMO
Anhedonia, a pronounced reduction in interest or pleasure in any of life's daily activities, is a cardinal symptom of major depression. In this Perspective article, we synthesise the recent evidence from rodent, monkey and human neuroimaging literature to highlight how the habenula, a small evolutionarily conserved subcortical structure located in the midbrain, may orchestrate the behavioural expression of anhedonia across fronto-mesolimbic networks. We then review how this circuitry can be modulated by ketamine, an NMDA receptor antagonist with rapid antidepressant properties. We propose that experimental paradigms founded in reinforcement learning and value-based decision-making can usefully probe this network and thereby help elucidate the mechanisms underlying ketamine's rapid antidepressant action.
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Transtorno Depressivo Maior , Ketamina , Anedonia , Antidepressivos/farmacologia , Antidepressivos/uso terapêutico , Transtorno Depressivo Maior/tratamento farmacológico , Humanos , Ketamina/farmacologia , Ketamina/uso terapêutico , Receptores de N-Metil-D-Aspartato/metabolismoRESUMO
Animal experimental studies suggest that 5-HT4 receptor activation holds promise as a novel target for the treatment of depression and cognitive impairment. 5-HT4 receptors are post-synaptic receptors that are located in striatal and limbic areas known to be involved in cognition and mood. Consistent with this, 5-HT4 receptor agonists produce rapid antidepressant effects in a number of animal models of depression, and pro-cognitive effects in tasks of learning and memory. These effects are accompanied by molecular changes, such as the increased expression of neuroplasticity-related proteins that are typical of clinically useful antidepressant drugs. Intriguingly, these antidepressant-like effects have a fast onset of their action, raising the possibility that 5-HT4 receptor agonists may be a particularly useful augmentation strategy in the early stages of SSRI treatment. Until recently, the translation of these effects to humans has been challenging. Here, we review the evidence from animal studies that the 5-HT4 receptor is a promising target for the treatment of depression and cognitive disorders, and outline a potential pathway for the efficient and cost-effective translation of these effects into humans and, ultimately, to the clinic.
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Antidepressivos/uso terapêutico , Depressão/tratamento farmacológico , Receptores 5-HT4 de Serotonina/metabolismo , Agonistas do Receptor 5-HT4 de Serotonina/uso terapêutico , Animais , Camundongos , Inibidores Seletivos de Recaptação de Serotonina/uso terapêuticoRESUMO
OBJECTIVES: While cognitive bias in younger adults with depression has been extensively researched, there have been relatively few investigations of the presence of cognitive bias in late life depression (LLD). This exploratory study aimed to ascertain whether negative cognitive bias exists across a range of cognitive domains in participants with LLD. METHODS/DESIGN: Participants were 19 patients with LLD and 19 matched non-depressed older adults. Participants completed standardised tests to assess bias in facial expression recognition, attention, recall of adjectives and interpretation. RESULTS: LLD participants were slower to identify surprised faces, and more likely to create negative statements in the interpretation task. There was no evidence of negative bias in memory or attention, but participants with LLD performed more poorly on the recall task. CONCLUSIONS: This study provides new evidence of negative bias in interpretation in LLD, but the findings are not consistent with a global cognitive bias Further work is needed to investigate cognitive bias in LLD. It may be that interventions which target negative interpretation biases, such as cognitive bias modification, could be helpful in treating LLD.
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Disfunção Cognitiva , Reconhecimento Facial , Idoso , Viés , Estudos de Casos e Controles , Depressão , Expressão Facial , HumanosRESUMO
BACKGROUND: 5-HT4 receptor stimulation has pro-cognitive and antidepressant-like effects in animal experimental studies; however, this pharmacological approach has not yet been tested in humans. Here we used the 5-HT4 receptor partial agonist prucalopride to assess the translatability of these effects and characterise, for the first time, the consequences of 5-HT4 receptor activation on human cognition and emotion. METHODS: Forty one healthy volunteers were randomised, double-blind, to a single dose of prucalopride (1 mg) or placebo in a parallel group design. They completed a battery of cognitive tests measuring learning and memory, emotional processing and reward sensitivity. RESULTS: Prucalopride increased recall of words in a verbal learning task, increased the accuracy of recall and recognition of words in an incidental emotional memory task and increased the probability of choosing a symbol associated with a high likelihood of reward or absence of loss in a probabilistic instrumental learning task. Thus acute prucalopride produced pro-cognitive effects in healthy volunteers across three separate tasks. CONCLUSIONS: These findings are a translation of the memory enhancing effects of 5-HT4 receptor agonism seen in animal studies, and lend weight to the idea that the 5-HT4 receptor could be an innovative target for the treatment of cognitive deficits associated with depression and other neuropsychiatric disorders. Contrary to the effects reported in animal models, prucalopride did not reveal an antidepressant profile in human measures of emotional processing.
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Benzofuranos/farmacologia , Rememoração Mental/efeitos dos fármacos , Agonistas do Receptor 5-HT4 de Serotonina/farmacologia , Aprendizagem Verbal/efeitos dos fármacos , Adulto , Método Duplo-Cego , Feminino , Voluntários Saudáveis , Humanos , Masculino , Análise e Desempenho de Tarefas , Adulto JovemRESUMO
The article Salivary cortisol response to infant distress in pregnant women with depressive symptoms, written by Susannah E. Murphy, Elizabeth C. Braithwaite, Isabelle Hubbard, Kate V. Williams, Elizabeth Tindall, Emily A. Holmes, and Paul G. Ramchandani, was originally published electronically.
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Prenatal depression is associated with adverse offspring outcomes, and the prevailing mechanistic theory to account for mood-associated effects implicates alterations of the maternal and foetal hypothalamic-pituitary adrenal (HPA) axes. Recent research suggests that depression may be associated with a failure to attenuate cortisol reactivity during early pregnancy. The aim of the current study is to investigate whether this effect continues into mid and late gestation. A further aim is to test whether maternal prenatal cortisol reactivity directly predicts infant cortisol reactivity. One hundred three pregnant women were recruited during either the second or third trimester. Depressive symptoms were assessed by self-report, and maternal salivary cortisol responses to a stressor (infant distress film) were measured. Approximately 2 months after birth, mothers (n = 88) reported postnatal depression and infant salivary cortisol responses to inoculation were measured. Prenatal depression was not associated with cortisol reactivity to acute stress in mid and late pregnancy. Similarly, neither prenatal depression nor maternal prenatal cortisol reactivity predicted infant cortisol reactivity to inoculation at 2 months. If the effects of prenatal depression on foetal and infant development are mediated by alterations of the maternal and foetal HPA axes, then early pregnancy may be a particularly vulnerable period. Alternatively, changes to HPA reactivity may not be as central to this association as previously thought.
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Depressão/metabolismo , Depressão/fisiopatologia , Hidrocortisona/análise , Adulto , Feminino , Idade Gestacional , Humanos , Lactente , Modelos Logísticos , Mães/psicologia , Gravidez , Gestantes , Saliva/química , Estresse Psicológico/metabolismo , Inquéritos e QuestionáriosRESUMO
Higher levels of well-being are associated with longer life expectancies and better physical health. Previous studies suggest that processes involving the self and autobiographical memory are related to well-being, yet these relationships are poorly understood. The present study tested 32 older and 32 younger adults using scales measuring well-being and the affective valence of two types of autobiographical memory: episodic autobiographical memories and semantic self-images. Results showed that valence of semantic self-images, but not episodic autobiographical memories, was highly correlated with well-being, particularly in older adults. In contrast, well-being in older adults was unrelated to performance across a range of standardised memory tasks. These results highlight the role of semantic self-images in well-being, and have implications for the development of therapeutic interventions for well-being in aging.
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Envelhecimento/psicologia , Memória Episódica , Satisfação Pessoal , Autoimagem , Adolescente , Adulto , Idoso , Feminino , Humanos , Masculino , Semântica , Adulto JovemRESUMO
The Hypothalamic-Pituitary-Adrenal (HPA) axis has been proposed as a potential underlying biological mechanism linking prenatal depression with adverse offspring outcomes. However, it is unknown whether the reactivity of this system to stress is altered in pregnant women experiencing depression. The objective of this study was to investigate whether salivary cortisol response to a distressed infant film is enhanced in pregnant women with symptoms of depression compared with non-depressed controls. Salivary cortisol and subjective mood responses to the film were measured in 53 primiparous women, between 11 and 18 weeks gestation. Both groups showed similar increases in state anxiety in response to the film, but there was a significantly increased cortisol response in women experiencing symptoms of depression. Depression during pregnancy is associated with increased reactivity of the HPA axis. This is consistent with altered HPA axis functioning being a key mechanism by which prenatal mood disturbance can impact upon fetal development.
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Ansiedade/psicologia , Depressão/psicologia , Gravidez/psicologia , Estresse Psicológico/complicações , Adulto , Afeto , Ansiedade/sangue , Estudos de Casos e Controles , Depressão/sangue , Feminino , Humanos , Hidrocortisona/sangue , Sistema Hipotálamo-Hipofisário/fisiopatologia , Lactente , Sistema Hipófise-Suprarrenal/fisiopatologia , Saliva/química , Saliva/metabolismo , Estresse Psicológico/sangueRESUMO
Affective biases can change how past events are recalled from memory. To capture mechanisms underlying affective memory formation, recall, and bias, we studied value-based decision-making (VBDM) between reward memories encoded in different mood states. Our findings suggest that following discrete affective events, created by large magnitude wins and losses on a Wheel of Fortune (WoF), healthy volunteers display an overall positive memory bias [favoring higher probability shapes learned after a WoF win compared with those learnt after a WoF loss outcome]. During this VBDM process, participants' pupils constrict before decision-onset for higher-value choices, and remained dilated for a sustained period after choice. Sustained pupil dilation was particularly sensitive to the reward values of abstract memories encoded in a positive mood. Taken together, we demonstrate that experimentally induced affective memories are recalled with a positive bias, and pupil-linked central arousal systems are actively engaged during VBDM between affective and non-affective memories.
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The role of serotonin in human behaviour is informed by approaches which allow in vivo modification of synaptic serotonin. However, characterising the effects of increased serotonin signalling in human models of behaviour is challenging given the limitations of available experimental probes, notably selective serotonin reuptake inhibitors. Here we use a now-accessible approach to directly increase synaptic serotonin in humans (a selective serotonin releasing agent) and examine its influence on domains of behaviour historically considered core functions of serotonin. Computational techniques, including reinforcement learning and drift diffusion modelling, explain participant behaviour at baseline and after week-long intervention. Reinforcement learning models reveal that increasing synaptic serotonin reduces sensitivity for outcomes in aversive contexts. Furthermore, increasing synaptic serotonin enhances behavioural inhibition, and shifts bias towards impulse control during exposure to aversive emotional probes. These effects are seen in the context of overall improvements in memory for neutral verbal information. Our findings highlight the direct effects of increasing synaptic serotonin on human behaviour, underlining its role in guiding decision-making within aversive and more neutral contexts, and offering implications for longstanding theories of central serotonin function.
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Serotonina , Humanos , Serotonina/metabolismo , Masculino , Feminino , Adulto , Adulto Jovem , Reforço Psicológico , Aprendizagem da Esquiva/efeitos dos fármacos , Aprendizagem da Esquiva/fisiologia , Emoções/fisiologia , Inibição Psicológica , Inibidores Seletivos de Recaptação de Serotonina/farmacologia , Aprendizagem/fisiologia , Tomada de Decisões/fisiologia , Memória/fisiologia , Memória/efeitos dos fármacosRESUMO
Parental depression is a risk factor for psychiatric problems in children and adolescents. Exciting scientific developments have elucidated potential early mechanisms of intergenerational risk transmission and new models of intervention may help to prevent some childhood problems. However, caution is needed in interpreting such associations as causal and in targeting interventions appropriately.
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Filho de Pais com Deficiência/estatística & dados numéricos , Transtornos Mentais/epidemiologia , Mães/psicologia , Feminino , Humanos , MasculinoRESUMO
Experimental tasks comparing participants' performance for categorising, remembering, and recognising positive and negative words are widely used in the emotional cognitive domain. Such tasks are commonly used in experimental psychology and psychiatry research, and have been shown to be sensitive biomarkers of depression and antidepressant drug action [1,2]. In addition, several of these tasks investigate self-referential processing i.e., the processing of information relevant to oneself; this has been shown to modify the way emotional words are encoded and remembered and may be a target that is amenable to treatment [3,4]. In practice, the development of such tasks for implementation in research studies often depends on the selection and matching of words according to characteristics such as valence or arousal, imageability, word frequency and word length to investigate differences in a chosen domain of interest whilst keeping important confounds constant. This introduces a need for ratings covering a range of word attributes that have been shown to affect processing. In particular, ratings of self-referential valence (how positively or negatively subjects feel about a word when this is used to describe themselves/their circumstances) have been seldom included in databases, despite the frequent investigation of the concept in research [1,5]. Other important attributes often considered in the process of matching and selection are word imageability and subjective frequency [6,7]. To facilitate the word selection and matching process required in cognitive-emotional task development, the present dataset provides subjective ratings for 150 positive and 150 negative adjectives describing personality characteristics. Across four online surveys, the 300 words were rated on self-referential valence, imageability and subjective frequency by representative samples of 200 UK-based, English-speaking adults. Basic demographics and data on depressive symptoms and state anxiety were collected from all participants. Comprehensive descriptive statistics and word length were calculated for each of the 300 words. All data cleaning and statistical analysis was performed in R. Our work is based on years of experience using the Oxford Emotional Task Battery [1,5] and may be particularly relevant for researchers using self-referential cognitive tasks with UK-based samples.
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Clinical depression is a common, debilitating and heterogenous disorder. Existing treatments for depression are inadequate for a significant minority of patients and new approaches are urgently needed. A wealth of evidence implicates the serotonin 1A (5-HT1A) receptor in the pathophysiology of depression. Stimulation of the 5-HT1A receptor is an existing therapeutic target for treating depression and anxiety, using drugs such as buspirone and tandospirone. However, activation of 5-HT1A raphe autoreceptors has also been suggested to be responsible for the delay in the therapeutic action of conventional antidepressants such as selective serotonin reuptake inhibitors (SSRIs). This narrative review provides a brief overview of the 5-HT1A receptor, the evidence implicating it in depression and in the effects of conventional antidepressant treatment. We highlight that pre- and post-synaptic 5-HT1A receptors may have divergent roles in the pathophysiology and treatment of depression. To date, developing this understanding to progress therapeutic discovery has been limited, partly due to a paucity of specific pharmacological probes suitable for use in humans. The development of 5-HT1A 'biased agonism', using compounds such as NLX-101, offers the opportunity to further elucidate the roles of pre- and post-synaptic 5-HT1A receptors. We describe how experimental medicine approaches can be helpful in profiling the effects of 5-HT1A receptor modulation on the different clinical domains of depression, and outline some potential neurocognitive models that could be used to test the effects of 5-HT1A biased agonists.
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Receptor 5-HT1A de Serotonina , Serotonina , Humanos , Depressão/tratamento farmacológico , Antidepressivos/farmacologia , Antidepressivos/uso terapêutico , Inibidores Seletivos de Recaptação de Serotonina , Agonistas do Receptor 5-HT1 de Serotonina/farmacologia , Agonistas do Receptor 5-HT1 de Serotonina/uso terapêuticoRESUMO
BACKGROUND: Evidence suggests inflammation may be a key mechanism by which psychosocial stress, including loneliness, predisposes to depression. Observational and clinical studies have suggested simvastatin, with its anti-inflammatory properties, may have a potential use in the treatment of depression. Previous experimental medicine trials investigating 7-day use of statins showed conflicting results, with simvastatin displaying a more positive effect on emotional processing compared with atorvastatin. It is possible that statins require longer administration in predisposed individuals before showing the expected positive effects on emotional processing. AIMS: Here, we aim to test the neuropsychological effects of 28-day simvastatin administration versus placebo, in healthy volunteers at risk for depression owing to loneliness. METHOD: This is a remote experimental medicine study. One hundred participants across the UK will be recruited and randomised to either 28-day 20 mg simvastatin or placebo in a double-blind fashion. Before and after administration, participants will complete an online testing session involving tasks of emotional processing and reward learning, processes related to vulnerability to depression. Working memory will also be assessed and waking salivary cortisol samples will be collected. The primary outcome will be accuracy in identifying emotions in a facial expression recognition task, comparing the two groups across time.
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BACKGROUND: Cognitive deficits are often comorbid with mood disorders and can cause significant functional impairment even after resolution of the primary mood symptoms. We do not currently have pharmacological treatments that adequately address these deficits. 5-HT4 receptor agonists show promise as potential procognitive agents in animal and early human translational studies. Optimal cognitive performance in humans is directly associated with appropriate functional connectivity between specific resting-state neural networks. However, so far the effect of 5-HT4 receptor agonism on resting-state functional connectivity (rsFC) in the brain in humans is unknown. METHODS: We collected resting-state functional magnetic resonance imaging scans from 50 healthy volunteers, of whom 25 received 6 days × 1 mg prucalopride (a highly selective 5-HT4 receptor agonist) and 25 received placebo in a randomized double-blind design. RESULTS: Network analyses identified that participants in the prucalopride group had enhanced rsFC between the central executive network and the posterior/anterior cingulate cortex. Seed analyses also showed greater rsFC between the left and right rostral anterior cingulate cortex and the left lateral occipital cortex, and reduced rsFC between the hippocampus and other default mode network regions. CONCLUSIONS: Similar to other potentially procognitive medications, low-dose prucalopride in healthy volunteers appeared to enhance rsFC between regions involved in cognitive networks and reduce rsFC within the default mode network. This suggests a mechanism for the behavioral cognitive enhancement previously seen with 5-HT4 receptor agonists in humans and supports the potential for 5-HT4 receptor agonists to be used in clinical psychiatric populations.
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Mapeamento Encefálico , Serotonina , Animais , Humanos , Serotonina/farmacologia , Mapeamento Encefálico/métodos , Encéfalo , Giro do Cíngulo , ComorbidadeRESUMO
BACKGROUND: There is growing interest in the antidepressant potential of statins. We tested whether statin use is associated with cognitive markers previously found to indicate psychological vulnerability to depression within the context of the COVID-19 pandemic. METHODS: Between April 2020 and February 2021, we conducted an observational online study of 2043 adults in the United Kingdom. Participants completed cognitive tasks assessing processes related to depression vulnerability, including affective bias and reward processing. We also measured working memory, medication use, and current psychiatric symptoms. Using mixed analysis of covariance and regression models, we compared participants on statins alone (n = 81), antihypertensive medication alone (n = 126), both medications (n = 111), and on neither medication (n = 1725). RESULTS: Statin use was associated with reduced recognition of angry and fearful faces (F1 = 9.19, p = .002; F1 = 6.9, p = .009) and with increased misclassification of these expressions as positive. Increased recognition of angry faces at baseline predicted increased levels of depression and anxiety 10 months later (ß = 3.61, p = .027; ß = 2.37, p = .002). Statin use was also associated with reduced learning about stimuli associated with loss (F1,1418 = 9.90, p = .002). These indicators of reduced negative bias were not seen in participants taking antihypertensive medication alone, suggesting that they were related to statin use in particular rather than nonspecific demographic factors. In addition, we found no evidence of an association between statin use and impairment in working memory. CONCLUSIONS: Statin use was associated with cognitive markers indicative of reduced psychological vulnerability to depression, supporting their potential use as a prophylactic treatment for depression.
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COVID-19 , Inibidores de Hidroximetilglutaril-CoA Redutases , Adulto , Anti-Hipertensivos , Depressão/psicologia , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/efeitos adversos , PandemiasRESUMO
Impaired cognition is often overlooked in the clinical management of depression, despite its association with poor psychosocial functioning and reduced clinical engagement. There is an outstanding need for new treatments to address this unmet clinical need, highlighted by our consultations with individuals with lived experience of depression. Here we consider the evidence to support different pharmacological approaches for the treatment of impaired cognition in individuals with depression, including treatments that influence primary neurotransmission directly as well as novel targets such as neurosteroid modulation. We also consider potential methodological challenges in establishing a strong evidence base in this area, including the need to disentangle direct effects of treatment on cognition from more generalised symptomatic improvement and the identification of sensitive, reliable and objective measures of cognition.