RESUMEN

Substantial clinical evidence has unravelled the superior antidepressant efficacy of ketamine: in comparison to traditional antidepressants targeting the monoamine systems, ketamine, as an N-methyl-d-aspartate receptor (NMDAR) antagonist, acts much faster and more potently. Surrounding the antidepressant mechanisms of ketamine, there is ample evidence supporting an NMDAR-antagonism-based hypothesis. However, alternative arguments also exist, mostly derived from the controversial clinical results of other NMDAR inhibitors. In this article, we first summarize the historical development of the NMDAR-centred hypothesis of rapid antidepressants. We then classify different NMDAR inhibitors based on their mechanisms of inhibition and evaluate preclinical as well as clinical evidence of their antidepressant effects. Finally, we critically analyse controversies and arguments surrounding ketamine's NMDAR-dependent and NMDAR-independent antidepressant action. A better understanding of ketamine's molecular targets and antidepressant mechanisms should shed light on the future development of better treatment for depression. This article is part of a discussion meeting issue 'Long-term potentiation: 50 years on'.

Asunto(s)

RESUMEN

(R, S)- and (S)-ketamine have made significant progress in the treatment of treatment-resistant depression (TRD) and have become a research focus in recent years. However, they both have risks of psychomimetic effects, dissociative effects, and abuse liability, which limit their clinical use. Recent preclinical and clinical studies have shown that (R)-ketamine has a more efficient and lasting antidepressant effect with fewer side effects compared to (R, S)- and (S)-ketamine. However, a recent small-sample randomized controlled trial found that although (R)-ketamine has a lower incidence of adverse reactions in adult TRD treatment, its antidepressant efficacy is not superior to the placebo group, indicating its antidepressant advantage still needs further verification and clarification. Moreover, an increasing body of research suggests that (R)-ketamine might also have significant applications in the prevention and treatment of medical fields or diseases such as cognitive disorders, perioperative anesthesia, ischemic stroke, Parkinson's disease, multiple sclerosis, osteoporosis, substance use disorders, inflammatory diseases, COVID-19, and organophosphate poisoning. This article briefly reviews the mechanism of action and research on antidepressants related to (R)-ketamine, fully revealing its application potential and development prospects, and providing some references and assistance for subsequent expanded research.

RESUMEN

BACKGROUND: Antidepressants are licensed for use in depressive disorders, but non-response and poor adherence to treatment affect a considerable number of patients. Pre-clinical and clinical evidence suggest that statins can augment the effects of antidepressants. However, the acceptability and tolerability of combining statins with antidepressants are unclear, and their add-on efficacy has only been shown in small, short-term clinical trials. Observational data can provide complementary information about treatment effects on larger samples over longer follow-ups. In this study, we therefore assessed the real-world acceptability, tolerability, and efficacy of concomitant antidepressant and statin treatment in depression. METHODS: We conducted a population-based cohort study investigating QResearch primary care research database, which comprises the anonymised electronic healthcare records of 35 + million patients over 1574 English general practices. Patients aged 18-100 years, registered between January 1998 and August 2020, diagnosed with a new episode of depression, and commencing an antidepressant were included. Using a between-subject design, we identified two study groups: antidepressant + statin versus antidepressant-only prescriptions. Outcomes of interest included the following: antidepressant treatment discontinuations due to any cause (acceptability) and due to any adverse event (tolerability) and effects on depressive symptoms (efficacy) measured as response, remission, and change in depression score on the Patient Health Questionnaire-9. All outcomes were assessed at 2, 6, and 12 months using multivariable regression analyses, adjusted for relevant confounders, to calculate adjusted odds ratios (aORs) or mean differences (aMDs) with 99% confidence intervals (99% CIs). RESULTS: Compared to antidepressant-only (N 626,335), antidepressant + statin (N 46,482) was associated with higher antidepressant treatment acceptability (aOR2months 0.88, 99% CI 0.85 to 0.91; aOR6months 0.81, 99% CI 0.79 to 0.84; aOR12months 0.78, 99% CI 0.75 to 0.81) and tolerability (aOR2months 0.92, 99% CI 0.87 to 0.98; aOR6months 0.94, 99% CI 0.89 to 0.99, though not long term aOR12 months 1.02, 99% CI 0.97 to 1.06). Efficacy did not differ between groups (range aOR2-12 months 1.00 and 1.02 for response and remission, range aOR2-12 months - 0.01 and - 0.02 for change in depression score). CONCLUSIONS: On real-world data, there is a positive correlation between antidepressant treatment adherence and statin use, partly explained by fewer dropouts due to adverse events. The main limitation of our study is its observational design, which restricts the potential to make causal inferences.

Asunto(s)

RESUMEN

Despite the increasing availability of antidepressant drugs, a high rate of patients with major depression (MDD) does not respond to pharmacological treatments. Brain-derived neurotrophic factor (BDNF)-tyrosine receptor kinase B (TrkB) signaling is thought to influence antidepressant efficacy and hippocampal volumes, robust predictors of treatment resistance. We therefore hypothesized the possible role of BDNF and neurotrophic receptor tyrosine kinase 2 (NTRK2)-related polymorphisms in affecting both hippocampal volumes and treatment resistance in MDD. A total of 121 MDD inpatients underwent 3T structural MRI scanning and blood sampling to obtain genotype information. General linear models and binary logistic regressions were employed to test the effect of genetic variations related to BDNF and NTRK2 on bilateral hippocampal volumes and treatment resistance, respectively. Finally, the possible mediating role of hippocampal volumes on the relationship between genetic markers and treatment response was investigated. A significant association between one NTRK2 polymorphism with hippocampal volumes and antidepressant response was found, with significant indirect effects. Our results highlight a possible mechanistic explanation of antidepressant action, possibly contributing to the understanding of MDD pathophysiology.

Asunto(s)

RESUMEN

Major depressive disorder (MDD) is a common and disabling psychiatric condition associated with aberrant functional activity of the default mode network (DMN). However, it is unclear how the DMN dysfunction in MDD patients is characterized by functional connectivity diversity or gradient and whether antidepressant therapy causes the abnormal functional gradient of the DMN to change toward normalization. In current work, we estimated the functional gradient of the DMN derived from resting state functional magnetic resonance imaging in MDD patients (n = 70) and matching healthy controls (n = 43) and identified MDD-related functional connectivity diversity of the DMN. The longitudinal changes of the DMN functional gradient in 36 MDD patients were assessed before and after 12-week antidepressant treatment. Compared to the healthy controls, the functional gradient of the DMN exhibited relatively relative compression along the dorsal-medial axis in MDD patients at baseline and antidepressant treatment could normalize these DMN gradient abnormalities. A regularized least-squares regression model based on DMN gradient features at baseline significantly predicted the change of Hamilton Depression Rating (HAMD) Scale scores after antidepressant treatment. The medial prefrontal cortex gradient had a more contribution to prediction of antidepressant efficacy. Our findings provided a novel insight into the neurobiological mechanism underlying MDD from the perspective of the DMN functional gradient.

Asunto(s)

RESUMEN

OBJECTIVE: Some pharmacological treatments are ineffective in parts of patients with major depressive disorder (MDD), hence this needs prediction of effective treatment responses. The study aims to examine the relationship between dynamic functional connectivity (dFC) of the hippocampal subregion and antidepressant improvement of MDD patients and to estimate the capability of dFC to predict antidepressant efficacy. METHODS: The data were from 70 MDD patients and 43 healthy controls (HC); the dFC of hippocampal subregions was estimated by sliding-window approach based on resting-state functional magnetic resonance imaging (R-fMRI). After 3 months treatment, 36 patients underwent second R-fMRI scan and were then divided into the response group and non-response group according to clinical responses. RESULTS: The result manifested that MDD patients exhibited lower mean dFC of the left rostral hippocampus (rHipp.l) compared with HC. After 3 months therapy, the response group showed lower dFC of rHipp.l compared with the non-response group. The dFC of rHipp.l was also negatively correlated with the reduction rate of Hamilton Depression Rating Scale. CONCLUSION: These findings highlighted the importance of rHipp in MDD from the dFC perspective. Detection and estimation of these changes might demonstrate helpful for comprehending the pathophysiological mechanism and for assessment of treatment reaction of MDD.

RESUMEN

Background: The central executive network (CEN), salience network (SN), and default mode network (DMN) are the three most studied depression-related brain networks. Many studies have shown that they are related to depression symptoms and treatment effects. However, few studies have related these three networks and their activity frequency bands to depressive symptoms and treatment efficacy. Methods: Sixty-six medication-free patients with major depressive disorder (MDD) were enrolled. Magnetoencephalography (MEG) was administered at baseline to calculate imaging indicators such as the power and functional connectivity (FC) of each brain network. The Hamilton Rating Score for Depression (HRSD-17) was assessed at baseline and weekly for 4 weeks. Pearson correlation and receiver operating characteristic curves (ROC) analyses were used to explore the relationship between brain imaging indicators and antidepressant efficacy. Results: The difference between therapeutically effective and ineffective groups was mainly manifested in the beta power of the SN. The FC of beta waves between the three networks was related to antidepressant efficacy, with ROC analysis results of AUC = 0.794, P = 0.004, sensitivity = 76.7%, and specificity = 81.8%. Limitations: The sample size was small and a healthy control group was not available. Conclusions: The interaction between the three networks is related to antidepressant efficacy and the relief of depressive symptoms.

RESUMEN

BACKGROUND: Although repetitive transcranial magnetic stimulation (rTMS) and prolonged intermittent theta-burst stimulation (piTBS) can induce changes in synaptic plasticity, the influence of brain-derived neurotrophic factor (BDNF) genotypes on their antidepressant effects remain unknown. Hence, we investigated the BDNF polymorphism contribution to the antidepressant effect of different forms left-sided prefrontal stimulations in a randomized, sham-controlled study METHODS: Seventy-five patients with medication-resistant depression were randomly assigned into three monotherapy groups: piTBS, high-frequency(HF) rTMS, or sham. The acute treatment period was two weeks. 17-item Hamilton Depression Rating scale (HDRS-17) were applied at baseline, week-1, and week-2. The primary outcome was percentage changes of HDRS-17 (%HDRS-17 changes) analyzed by generalized estimating equation (GEE) model. RESULTS: The GEE analysis revealed a significant interaction between group, time, and BDNF genotypes effects on %HDRS-17 changes over time.  In patients carrying Val homozygotes, piTBS and HF-rTMS both exhibited significantly greater %HDRS reduction than sham at week-2. In Met carriers, only piTBS showed better efficacy than sham at week-2 (piTBS vs. sham, -41.1% vs.-18.9%, p=0.004). Regarding the influence of different BDNF genotypes on antidepressant efficacy in each intervention, only HF-rTMS exhibited significantly different degrees of %HDRS-17 changes between Val homozygotes and Met carriers (-68.5% vs. -26.4%, p=0.012, respectively), but piTBS delivered the consistent efficacy regardless of the BDNF polymorphism. CONCLUSIONS: This is the first study to confirm the different impacts of BDNF genotypes on the effect of different left-sided prefrontal brain stimulation. BDNF Val66Met polymorphism may play a role in the antidepressant response of piTBS and HF-rTMS. (Trial Registration Number UMIN-CTR:UMIN000020892: Registration date: Feb.4, 2016).

Asunto(s)

RESUMEN

Background: Current mainstream treatment of major depressive disorder (MDD) has a disadvantage in delayed onset of efficacy, making detection of early signatures predicative of the long-term treatment efficacy urgent. Methods: MDD patients were scored with HAMD-24 and serum brain-derived neurotrophic factor (BDNF) levels were measured at different times in two independent trials: a single-arm observation of Yueju pill, a clinically approved traditional multiherbal medicine, and a two-arm random placebo-controlled trial for Yueju vs escitalopram. The ratio of the BDNF level to HAMD-24 score, or neuroplasticity index (NI), and its derived parameters were used for correlation analysis and receiver operating characteristic (ROC) analysis. Results: On both the early (4th) and final (28th) days, Yueju and escitalopram significantly reduced HAMD-24 scores, compared to baselines, but only Yueju increased BDNF at both times. For either Yueju or escitalopram treatment, NI, but not BDNF, at baseline was correlated to NIs at the early or final treatment day. NI at early time was significantly correlated to early NI enhancement from the baseline for both Yueju and escitalopram, and to final NI enhancement from the baseline for Yueju in both trials. ROC analysis supported the predictability of Yueju's final treatment efficacy from early NI enhancement. Limitations: The small sample size and 28 days of treatment time may lead to the impossibility of ROC analysis of escitalopram. Conclusion: Early NI enhancement is useful for prediction of long-term efficacy of Yueju and presumably some other antidepressants. Clinical Trial Registration: [www.ClinicalTrials.gov], identifier [ChiCTR1900021114].

RESUMEN

A dramatic increase in the prevalence of major depression and diet-related disorders in adolescents has been observed over several decades, yet the mechanisms underlying this comorbidity have only recently begun to be elucidated. Exposure to western-style diet (WSD), high in both fats (45% kcal) and carbohydrates (35% kcal): e.g., high fat diet (HFD), has been linked to the development of metabolic syndrome-like symptoms and behavioral dysregulation in rodents, as similarly observed in the human condition. Because adolescence is a developmental period highlighted by vulnerability to both stress and poor diet, understanding the mechanism(s) underlying the combined negative effects of WSDs and stress on mood and reward regulation is critical. To this end, adolescent male C57 mice were exposed to vicarious social defeat stress (VSDS), a stress paradigm capable of separating physical (PS) versus psychological/emotional (ES) stress, followed by normal chow (NC), HFD, or a separate control diet high in carbohydrates (same sucrose content as HFD) and low in fat (LFD), while measuring body weight and food intake. Non-stressed control mice exposed to 5 weeks of NC or HFD showed no significant differences in body weight or social interaction. Mice exposed to VSDS (both ES and PS) gain weight rapidly 1 week after initiation of HFD, with the ES-exposed mice showing significantly higher weight gain as compared to the HFD-exposed control mice. These mice also exhibited a reduction in saccharin preference, indicative of anhedonic-like behavior. To further delineate whether high fat was the major contributing factor to these deficits, LFD was introduced. The mice in the VSDS + HFD gained weight more rapidly than the VSDS + LFD group, and though the LFD-exposed mice did not gain weight as rapidly as the HFD-exposed mice, both the VSDS + LFD- and VSDS + HFD-exposed mice exhibited attenuated response to the antidepressant fluoxetine. These data show that diets high in both fats and carbohydrates are responsible for rapid weight gain and reduced reward sensitivity; and that while consumption of diet high in carbohydrate and low in fat does not lead to rapid weight gain, both HFD and LFD exposure after stress leads to reduced responsiveness to antidepressant treatment.

RESUMEN

RATIONALE: Recently, the effects of ketamine on the circadian rhythm have suggested that ketamine's rapid antidepressant effects are associated with and without sleep disturbance improvement. OBJECTIVES: Here, we evaluated the antidepressant efficacy of repeated ketamine infusions in patients with sleep disturbances. METHODS: This study included 127 patients with major depressive disorder or bipolar disorder who received ketamine treatments during a 12-day period. Sleep quality was assessed by the 17-item Hamilton Depression Rating Scale sleep disturbance factor (SDF) (items 4, 5 and 6). Serum brain-derived neurotrophic factor (BDNF) was measured at baseline, day 13 and day 26. This study was a post-hoc analysis. RESULTS: Significant differences were found in the HAMD-17 score at 13 post-infusion time points compared to baseline, as well as the scores in SDF score at each of the 7 post-infusion (4 h after each infusion excluded) time points among all patients. Logistic regression and linear correlation analyses revealed that a greater reduction in the SDF after 24 h of the first ketamine infusion resulted in a better antidepressant effect in the last two follow-up visits. Moreover, BDNF levels were significantly higher in sleep responders than in non-responders. CONCLUSIONS: In the 127 patients, six ketamine infusions induced better therapeutic effects in sleep responders than in sleep non-responders and patients without sleep disturbances. The sleep response after repeated ketamine infusions was positively associated with high serum BDNF levels. Early sleep disturbance improvement (as early as 24 h after the first ketamine injection) may predict the antidepressant effect of repeated-dose ketamine.

Asunto(s)

RESUMEN

Perinatal depression (PND) affects approximately 15% of women, and de novo postpartum depression affects approximately 40% of PND cases. Selective serotonin reuptake inhibitors (SSRIs) are a common class of antidepressants prescribed to treat PND. However, the safety and efficacy of SSRIs have been questioned in both clinical and preclinical research. Here, using a preclinical rodent model of de novo postpartum depression, we aim to better understand neuroinflammatory cytokines and tryptophan mechanisms that may be related to SSRI efficacy. Rat dams were treated with high corticosterone (CORT; 40 mg/kg, s.c.) for 22 days in the postpartum period to simulate a depressive-like endophenotype. Concurrently, a subset of dams was treated with the SSRI, fluoxetine (FLX; 10 mg/kg, s.c.), in the postpartum period. We showed, consistent with previous studies, that although maternal FLX treatment prevented CORT-induced disturbances in maternal care behavior during the early postpartum, it failed to prevent the expression of CORT-induced passive coping behavior in the late postpartum. Furthermore, FLX treatment, regardless of CORT treatment, increased maternal hippocampal IL-1ß, plasma CXCL1, and decreased maternal plasma tryptophan, 4'-pyridoxic acid, and pyridoxal concentrations. Maternal CORT treatment reduced maternal hippocampal IFN-γ, and both hippocampal and plasma TNF-α. Our work suggests that the limited efficacy of FLX in the late postpartum may be associated with elevated levels of the proinflammatory cytokine IL-1ß in the maternal hippocampus, elevated plasma CXCL1, decreased plasma tryptophan concentration, and changes in vitamin B6 dependent tryptophan-kynurenine pathway. These findings suggest novel pathways for improving SSRI efficacy in alleviating perinatal depression.

Asunto(s)

RESUMEN

BACKGROUND/AIMS/METHODS: Electroconvulsive therapy (ECT) is still one of the most potent treatments in the acute phase of major depressive disorder (MDD) and particularly applied in patients considered treatment resistant. However, despite the frequent and widespread use of ECT for >70 years, the exact neurobiological mechanisms underlying its efficacy remain unclear. The present review aims to describe differential antidepressant and cognitive effects of ECT as well as effects on markers of neural activity and connectivity, neurochemistry, and inflammation that might underlie the treatment response and remission. RESULTS: Region- specific changes in brain function and volume along with changes in concentrations of neurotransmitters and neuroinflammatory cytokines might serve as potential biomarkers for ECT outcomes. CONCLUSIONS: However, as current data is not consistent, future longitudinal investigations should combine modalities such as MRI, MR spectroscopy, and peripheral physiological measures to gain a deeper insight into interconnected time- and modality-specific changes in response to ECT.

Asunto(s)

RESUMEN

OBJECTIVE: Ketamine has been demonstrated to have robust and rapid antidepressant effects, and few studies have focused on the relationship between insomnia and the efficacy of ketamine. The objective of this study was to examine whether baseline insomnia predicted the antidepressant efficacy of repeated intravenous ketamine infusions for unipolar and bipolar depression. METHOD: Patients with high insomnia (n = 64) or low insomnia (n = 68) received six intravenous infusions of ketamine (0.5 mg/kg over 40 min) over 12 days (Monday-Wednesday-Friday). The Montgomery-Asberg Depression Rating Scale (MADRS) without sleep item was used to assess depressive symptoms. Response was defined as a MADRS total score ≥ 50%, and remission was defined as a MADRS total score ≤ 10. RESULT: There were no differences in response or remission rates between patients with high and low insomnia. However, the logistic regression model showed that high insomnia predicted an increased likelihood of response and remission. Cox proportional hazards models showed a reduced latency to respond and remit in patients with high insomnia. A linear mixed model showed that the high insomnia subgroup had greater improvement than the low insomnia subgroup (all p < 0.05). LIMITATION: The major limitation of this study is the open-label design. CONCLUSION: When given six ketamine infusions, patients with high insomnia were more likely to respond and remit than those with low insomnia. Patients with high insomnia showed not only a shorter latency to respond and remit, but also greater improvement than those with low insomnia.

Asunto(s)

RESUMEN

BACKGROUND: We previously compared the inclusion/exclusion criteria in the studies of vortioxetine to other antidepressants and found that they were significantly more restrictive in the vortioxetine studies. In the present study, we tested the hypothesis that the differences in psychiatric inclusion/exclusion criteria used in the studies of some antidepressants resulted in differences in generalizability to clinical samples. METHODS: We applied the inclusion and exclusion criteria used in 161 antidepressant efficacy trials to 1,271 patients presenting to an outpatient practice who received a principal diagnosis of major depressive disorder. The patients underwent a thorough diagnostic evaluation. We compared the percentage of patients that would be excluded in studies of different medications. RESULTS: The percentage of patients that would have been excluded was significantly higher in the vortioxetine studies than other medications. For the 15 medications that were included in at least 5 trials, we computed the mean percentage of patients that would be excluded. The values ranged from 76.0% (for fluoxetine) to 99.1% (for quetiapine). LIMITATIONS: While our calculations were based on the exclusion criteria stated in the published articles, we have no way of knowing how these criteria were actually applied. CONCLUSION: Studies of different medications vary in how representative the samples are of patients in clinical practice. The variability in the inclusion/exclusion criteria used to select samples for antidepressant efficacy trials, and the evidence that studies of different medications vary in their generalizability, makes it more difficult to interpret network analyses comparing the relative efficacy of medications.

Asunto(s)

RESUMEN

To improve understanding of treatment-resistant depression (TRD) in a large population of individuals with depression, a self-reported antidepressant efficacy survey was designed and administered to 23andMe research participants. Participants with a current depressive episode or with a depressive episode within the last 5 years were queried for the effect of pharmacotherapy during the episode. TRD was defined as non-response to at least two antidepressants taken for at least 5-6 weeks. Non-TRD (NTRD) was defined as responsive to either the first or second medication taken for at least 3-4 weeks. Participants who could not be classified as TRD or NTRD were excluded from the analysis. Approximately 56,000 participants completed the survey, among which approximately 33,000 took medication for a depressive episode. The 3409 participants with self-reported TRD tended to have younger age of onset, and a more persistent course prior to initiation of treatment (e.g., a longer prior average episode duration and residual symptoms between episodes) than the 18,511 participants classified as NTRD. This survey identified depression characteristics, comorbidities, trigger events, and early childhood trauma that distinguish TRD from NTRD.

Asunto(s)

RESUMEN

BACKGROUND: Antidepressants are amongst the most frequently prescribed medications. More than a decade ago, our clinical research group applied a prototypic set of inclusion/exclusion criteria used in an antidepressant efficacy trial (AET) to patients presenting for treatment in our outpatient practice and found that most patients would not qualify for the trial. In the present report from the Rhode Island Methods to Improve Diagnostic Assessment and Services (MIDAS) project, we apply the psychiatric inclusion/exclusion criteria used in 158 placebo-controlled studies to a large sample of depressed patients who presented for outpatient treatment to determine the range and extent of the representativeness of samples treated in AETs and whether this has changed over time. METHOD: We applied the inclusion and exclusion criteria used in 158 AETs to 1,271 patients presenting to an outpatient practice who received a principal diagnosis of major depressive disorder. The patients underwent a thorough diagnostic evaluation. RESULTS: Across all 158 studies, the percentage of patients that would have been excluded ranged from 44.4 to 99.8% (mean = 86.1%). The percentage of patients that would have been excluded was significantly higher in the studies published in 2010 through 2014 compared to the studies published from 1995 to 2009 (91.4 vs. 83.8%, t(156) = 3.74, p < 0.001). CONCLUSIONS: Only a minority of depressed patients seen in clinical practice are likely to be eligible for most AETs. The generalizability of AETs has decreased over time. It is unclear how generalizable the results of AETs are to patients treated in real-world clinical practice.

Asunto(s)

RESUMEN

Depression represents a global mental health concern, and disproportionally affects women as they are twice more likely to be diagnosed than men. In this review, we provide a summary of evidence to support the notion that differences in depression between men and women span multiple facets of the disease, including epidemiology, symptomology, treatment, and pathophysiology. Through a lens of biological sex, we overview depression-related transcriptional patterns, changes in neuroanatomy and neuroplasticity, and immune signatures. We acknowledge the unique physiological and behavioral demands of pregnancy and motherhood by devoting special attention to depression occurring in the peripartum period. Specifically, we discuss issues surrounding the presentation, time course, treatment, and neurobiology of peripartum depression. We write this review with the intention of highlighting the encouraging advancements in our understanding of sex differences in depression, while underscoring the gaps that remain. A more systematic consideration of biological sex as a variable in depression research will be critical in the discovery and development of pharmacotherapies that are efficacious for both men and women.

Asunto(s)

RESUMEN

BACKGROUND: Inflammation may play an important role in depression and its treatment. A previous study found that increased C-reactive protein (CRP), a marker of systemic inflammation, is associated with worse response to the serotonergic antidepressant escitalopram and better response to the noradrenergic antidepressant nortriptyline. It is unclear whether this reflects genetic disposition to inflammation. METHODS: We analyzed genotype data and weekly Montgomery-Åsberg Depression Rating Scale scores (MADRS) from 755 unrelated individuals obtained over a 12-week period in the Genome-Based Therapeutic Drugs for Depression (GENDEP) study. We calculated a polygenic risk score for CRP level based on genome-wide meta-analysis results from the CHARGE Consortium. RESULTS: A higher polygenic risk score for CRP was associated with slightly better response to escitalopram and slightly worse response to nortriptyline, reflected in a statistically significant interaction between polygenic risk score and drug (beta = 1.07, 95% CI = 0.26-1.87, p = 0.0093). DISCUSSION: A differential association between CRP-PRS and antidepressant drug that is in a direction opposite to that found with serum CRP measurement suggests that previously observed effect of inflammation on antidepressant efficacy may be driven by state factors distinct from genetic influences on systemic inflammation.

Asunto(s)

RESUMEN

A recent meta-analysis of antidepressant trials is the largest conducted to date. Although it claims to prove antidepressant effectiveness beyond dispute, the main outcome is response rates, which are derived from continuous data in a process that can inflate differences between groups. The standardised mean difference of 0.3 is in line with other meta-analyses that show small differences between antidepressants and placebo that are unlikely to be clinically significant. Other factors likely to exaggerate the effects are discussed, and evidence on associations between antidepressant effects and severity and outcomes of long-term treatment is considered. Clinicians need to have open discussions with patients about the limitations of antidepressant research, the lack of evidence that antidepressants correct a chemical imbalance or other brain abnormality, and the range of adverse effects and mental and physical alterations they can produce.

Asunto(s)