When deciding on antidepressant maintenance with clinicians, remitted patients must weigh the burdens of continued use against the benefit of less time depressed. This benefit is often inferred qualitatively from relapse-frequency data, even though expected time depressed also depends on episode duration, antidepressant re-initiation, and how evidence from highly recurrent populations applies to patients with fewer prior episodes.

We developed a health-state transition model to combine evidence on recurrence, episode duration, re-initiation, and treatment effects into expected time depressed and time taking antidepressants under maintenance versus active monitoring. Adults in remission were simulated for 5 years across groups based on depression history. We summarized the trade-off as additional antidepressant use required to avert 1 month of depression. The decision framework links this estimate to patient preferences by comparing required with acceptable use, allowing patients who expect greater consequences of relapse or experience fewer treatment burdens to consider more antidepressant use acceptable.

Maintenance efficiency varied substantially with recurrence history. Each month of depression averted required 1.5 additional years of antidepressant use among patients with 4–5 prior episodes; 2.8 years with 2–3 prior episodes, 5.1 years after one moderate-to-severe episode, and 11.8 years after one mild episode. When these trade-offs are acceptable, patients are modeled to prefer maintenance.

The model expresses the maintenance trade-off as a ratio of benefits and burdens. Preferences and clinical judgment determine for whom the ratio is acceptable. Empirical work can determine whether this improves maintenance decisions in practice.

Prior research shows that humans adjust their learning rate based on environmental volatility. This adaptation has been shown to be reduced in individuals with high levels of anxious-depression, but past studies have been cross-sectional, making it unclear whether this adaptation is trait-like or responsive to treatment. There are also questions about the basic replicability of this effect with recent studies failing to find robust associations.

In the Precision in Psychiatry study, we examined changes in learning rate adaptation in a points-loss task, following four weeks of treatment in two patient groups receiving either internet-based cognitive behavioral therapy (n = 677) or antidepressants (n = 95), compared to a group of healthy participants (n = 95).

All groups showed increased learning rates in volatile environments at baseline, but against our prediction, learning rate adaptation was not cross-sectionally associated with individual differences in anxious-depression. There was also no evidence that learning rate adaptation changed post-treatment, despite symptom improvements. However, in the antidepressant group, symptom reductions correlated with learning rate adaptation. This finding should be interpreted cautiously as we found that the key outcome measure had poor test–retest reliability.

Overall, our results suggest that associations between learning rate adaptation and anxious-depression, if present, are likely modest, depend on task characteristics, may not be present in treatment-seeking adults, and do not improve following treatment.

Bipolar disorder is an episodic mental illness, often requiring complex pharmacological management. Lithium is a first-line treatment, while antidepressant monotherapy can precipitate mania symptoms in some patients.

To (a) describe patterns of antidepressant, antipsychotic and mood stabiliser prescribing in the 12-month periods before and after first-recorded bipolar diagnosis; (b) describe treatment trajectories in the year post-diagnosis; and (c) investigate associations between sociodemographic and treatment-related characteristics of (i) antidepressant monotherapy and (ii) lithium prescription post-diagnosis.

A longitudinal cohort study of patients with a first-recorded diagnosis of bipolar disorder between 2000 and 2022 derived from Clinical Practice Research Datalink. Prescriptions for antidepressants, antipsychotics and mood stabilisers were examined in the 12 months before and after diagnosis. Logistic regression models tested associations between sociodemographic and treatment-related characteristics and prescribing outcomes. A web application (https://dop-mhds.shinyapps.io/bpd-prescribing-uk-shiny/) was developed to visualise treatment trajectories over the year following diagnosis.

We included 40 965 patients with a first-recorded diagnosis of bipolar disorder between 2000 and 2022 (median age at diagnosis 43 years, 60.9% female, 11.1% ethnic minority). Of these, 32 460 (79.2%) were prescribed a relevant medication in the year prior to diagnosis compared with 37 208 (90.8%) in the year after. Antidepressant monotherapy was the most common pre-diagnosis treatment (48.4%), but was also prescribed to 28.9% during at least 1 month in the year after diagnosis. Antipsychotic monotherapy was the most common post-diagnosis treatment (36.0%). Lithium was prescribed to 18.5% within 1 year of diagnosis, with 4.0% receiving it as first-line monotherapy. Almost half (46.0%) switched medication at least once within 1 year. Males, ethnic minorities and patients residing in the most deprived areas had lower odds of receiving either lithium or antidepressant monotherapy.

Prescribing patterns for bipolar disorder in the UK are highly variable and often outside of guideline recommendations, with persistent use of antidepressant monotherapy and potential under-utilisation of lithium.

The primary effect parameter in depression trials is usually a measure of depressive symptoms, e.g. the Hamilton Depression Rating Scale (HDRS). Such measures have been criticised for not covering patient-relevant domains, such as quality of life, and hence not accurately reflecting patient-experienced efficacy.

To investigate the relation between clinician-rated depressive symptoms and patient-reported quality of life measured by the Quality-of-Life Enjoyment and Satisfaction Questionnaire Short Form (Q-LES-Q-SF).

We included data from six acute-phase trials (n = 918) comparing mirtazapine to another antidepressant (amitriptyline, fluoxetine, paroxetine or venlafaxine) where both HDRS and Q-LES-Q-SF had been administered. No study included a placebo arm. Correlations between instruments (scales, subscales and items) were assessed after six weeks. Q-LES-Q-SF outcomes for participants who were in HDRS-defined remission were contrasted to those from participants with more severe depressive symptoms.

Q-LES-Q-SF ratings correlated strongly with HDRS-17 (r = −0.73, p < 0.0001) and HDRS-6 (r = −0.72, p < 0.0001), but somewhat weaker to HDRS-11 (r = −0.64, p < 0.0001). Depressed mood (r = −0.66, p < 0.0001) and work and activities (r = −0.65, p < 0.0001) showed the strongest item-level correlations to Q-LES-Q-SF. Participants in HDRS-remission had average Q-LES-Q-SF scores on the lower end of those reported by healthy controls, whereas patients with mild depressive symptoms (or worse) had average life-quality scores corresponding to severe impairment.

HDRS and Q-LES-Q-SF showed considerable agreement in depressed study participants treated with antidepressants, suggesting that HDRS meaningfully reflects patient-reported improvement.

Selective serotonin reuptake inhibitors (SSRIs) are limited by inadequate response in a significant proportion of patients, slow onset, minimal cognitive benefit and side-effects. Preclinical studies suggest selective serotonin 4 receptor (5-HT4R) agonists may produce faster antidepressant effects via distinct mechanisms; however, there has been no experimental research in clinical populations to date.

To test whether the novel 5-HT4R partial agonist PF-04995274 produces early behavioural and neural changes in emotional cognition similar to SSRIs in patients with unmedicated major depressive disorder (MDD).

In a double-blind, placebo-controlled trial, 90 participants with MDD were randomised to 7 days of PF-04995274 (15 mg), citalopram (20 mg) or placebo. Emotional processing was assessed using a behavioural facial expression recognition task and functional magnetic resonance imaging (fMRI) of implicit emotional face processing (days 6–9). Observer- and self-reported symptoms of depression were also measured at baseline and study end.

As anticipated, citalopram reduced relative accuracy and increased relative reaction time to identify negative faces, with corresponding changes in neural activity (reduced left amygdala activation to emotional faces and valence-specific shifts in cortical regions). In contrast, PF-04995274 produced no change in behavioural negative bias or amygdala activity but increased medial-frontal cortex activation across valences. While this was not a clinical trial, both active treatments demonstrated an early treatment response with reduced observer-rated depression severity relative to placebo; PF-04995274 also reduced self-reported depression, state anxiety and negative affect.

PF-04995274 did not show the typical antidepressant profile of negative bias reductions observed with citalopram. Instead, it was associated with distinct increased medial-frontal activation during an emotional faces task, coupled with preliminary evidence of early clinical improvement, suggesting a potential alternative pathway for antidepressant effects. Findings support further clinical trials of 5-HT4R agonists and investigation of pro-cognitive and mood effects.

NCT03516604.

Cognitive neuropsychological models propose that antidepressants exert their therapeutic effects by modifying negative emotional processing biases early in treatment. However, evidence from large, long-term clinical samples is limited.

We conducted a mechanistic analysis within the Antidepressants to Prevent Relapse in Depression randomized controlled trial, which compared maintenance antidepressant treatment with placebo substitution in adults with recurrent depression who were currently well (N = 478). Participants completed a computerized facial emotion recognition task at baseline, 12 weeks, and 52 weeks, in which faces morphed from happy to sad. The primary outcome was the number of faces classified as happy (0–45). Linear and longitudinal mixed-effects models were used to compare treatment groups and examine associations with depressive (PHQ-9) and anxiety (GAD-7) symptoms.

Of the 462 participants completing at least one task, there was no evidence that discontinuing antidepressants altered performance compared with maintenance at 12 weeks (adjusted mean difference = 0.23, 95% CI –0.5 to 1.0, p = 0.5) or 52 weeks (0.29, –0.5 to 1.2, p = 0.5). Depressive symptoms were negatively associated with happy face classifications both cross sectionally (β = –0.20 per PHQ-9 point, p = 0.02) and longitudinally (β = –0.09, p = 0.05). Anxiety symptoms were positively associated with happy classifications (β = 0.11, p = 0.047).

Maintenance antidepressant treatment did not sustain positive emotional processing biases as indexed by facial emotion recognition, despite robust associations between such biases and depressive symptoms. These findings challenge the generalizability of laboratory evidence on emotional bias modification to long-term clinical treatment and highlight the need for further mechanistic research on antidepressant action.

Antidepressants are pivotal in treating major depressive disorder and other psychiatric conditions. However, despite their widespread use, evidence regarding the serious adverse effects of prolonged antidepressant use and withdrawal in complex older-adult populations remains limited.

We aimed to investigate the association between phases of antidepressant treatment with emergency hospital admission and hospital admissions related to adverse drug reactions in older adults with polypharmacy in English primary care.

We conducted a case–control study using linked primary and secondary care electronic health record data from the Clinical Practice Research Databank GOLD and Aurum. We included individuals aged 65–100 years with polypharmacy (i.e. those who were prescribed five or more medicines). We used conditional logistic regression to investigate the associations between the phases of antidepressant treatment and hospital admission risks.

We found 626 199 emergency hospital admission cases and matched with 3 639 740 controls. The initiation phase of antidepressants was associated with the greatest increase in the risk of emergency hospital admission (adjusted odds ratio 2.30, 95% CI 2.23–2.38), followed by short treatment gap or early discontinuation after short-term use (adjusted odds ratio 1.41, 95% CI 1.37–1.45). We found that patients had a higher risk of serotonin-related symptoms, falls and trauma, and cardiovascular events during antidepressant use phases, and the risks tend to decrease in past exposure phases for most conditions.

Individuals who are on the initiation and short treatment gap or early discontinuation after short-term use of antidepressant treatment are associated with a higher risk of hospital admission. This study highlights the need for vigilant monitoring of antidepressant initiation and withdrawal in older-adult polypharmacy patients.

Psychotropic medication use has been shown to be associated with decreased bone mineral density (BMD) and quality, and increased fracture risk. Less is known about psychotropic use and associated bone loss over time.

To determine the association between psychotropic medication use and bone loss in men.

Data from 940 men (aged ≥20 years) participating in the Geelong Osteoporosis Study were used in this longitudinal study. BMD (g/cm2) at the spine and hip were measured with dual-energy X-ray absorptiometry at baseline, and 5 and 15 years post-baseline. Body mass index (BMI) was calculated, lifestyle factors and medication use was self-reported, and socioeconomic status was determined. Mood and anxiety disorders were identified through a clinical interview. Multivariable linear regression was used to determine the associations.

Over the study period (median 13.2 years), psychotropic use was associated with change in BMD at the spine (unadjusted mean difference −0.063 g/cm2, 95% CI −0.096 to −0.031, p < 0.001) and hip (−0.038 g/cm2, 95% CI −0.059 to −0.017, p < 0.001). BMI was identified as an effect modifier. Psychotropic use was associated with spine and hip bone loss at the 25th (adjusted mean difference −0.077g/cm2 (95% CI −0.122 to −0.033); and −0.058 g/cm2 (95% CI −0.084 to −0.032), respectively) and 50th percentile (adjusted mean difference −0.053 g/cm2 (95% CI −0.089 to −0.018) and −0.038 g/cm2 (95% CI −0.059 to −0.017), respectively), but not the 75th percentile of BMI (p = 0.121 and p = 0.106, respectively).

Psychotropic use was associated with bone loss in non-obese men, highlighting the need for regular monitoring and preventive strategies to protect bone health.

Recent decades have seen a steady increase in antidepressant prescribing, but little is known about prescribing trends during and following the COVID-19 pandemic.

This preregistered systematic review, following Preferred Reporting Items for Systematic reviews and Meta-Analyses guidelines, aimed to investigate antidepressant prescribing trends for adults in the UK and Republic of Ireland during and after the pandemic. It also compared prescriptions by drug and location.

We searched six databases: APA PsycInfo, CINAHL, MEDLINE, Scopus, medRxiv and Preprints.org. The review included primary research articles reporting trends in antidepressant prescriptions, including at least one time point after March 2020 in the UK and Republic of Ireland. This review has been preregistered on PROSPERO (ID: CRD42024498503).

We identified 7,320 studies, of which ten met the search criteria for the review. Studies were grouped on the basis of time period (2020: n = 5; 2021: n = 3; 2022: n = 2), location (England, Scotland, Northern Ireland, Republic of Ireland, UK) and drug type (serotonin–noradrenaline reuptake inhibitors, selective serotonin reuptake inhibitors, tricyclics, and others (e.g. monoamine oxidase inhibitors)). Most studies (eight of ten) demonstrated increased antidepressant prescribing over time. Two studies highlighted a decrease between March and May 2020. Demographic variables reflected higher rates of prescribing for women, and the modal group receiving antidepressants comprised middle-aged adults.

The commonly reported increase in antidepressant prescribing corroborates pre-pandemic trends and may suggest further, increased demands for mental health support to meet the unique challenges of the pandemic. Future research is required to evaluate the appropriateness of treatment decisions and to explore psychosocial factors that influence individual prescribing choices.