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Abstract: Interactions between serotonergic and the endogenous opioid systems have been suggested to be involved in the etiopathogenesis of depression and in the mechanism of action of antidepressants. Activation of serotonin 5-HT1A receptors has been shown to increase plasma β-endorphin (β-END) levels in animal studies and in healthy humans. Objectives: To assess interaction abnormalities between 5-HT1A receptors and the endogenous opioid system in patients with major depression and the possible modulating effect of citalopram. Methods: The β-END response to the 5-HT1A receptor agonist, buspirone (30 mg), was measured in 30 patients with major depression and in 30 age- and sex-matched healthy controls before and after an 8-week treatment with citalopram. Pre-treatment score of the Hamilton Rating Scale for Depression (HRSD) was ≥17. Antidepressant response was defined by a 50% decrease in the HRSD. Pre- and post-treatment maximum peak response (Δmax) and the area under the curve (AUC) of β-END response were compared. Three time points were measured (60, 90 and 120 min). We also examined the correlations between the β-END response and the antidepressant response. Buspirone plasma levels were not measured. Results: At baseline, β-END response was similar in patients and controls. After 8 weeks of citalopram treatment depressed patients showed a significant decrease in the β-END response (Δmax: p <.001; AUC: p <.001). A significant correlation between the β-END reduction in the response and the reduction in the HRSD score (r =.656; p <.001) was observed. Conclusions: Changes in interaction between 5-HT1A receptor system and the endogenous opioid system may play a role both in the mechanism of action and response to antidepressant drugs. [Copyright &y& Elsevier]

Objective In an earlier report, response inhibition predict antidepressant non-response in late-life depression (Sneed et al., 2007). The purpose of this study was to ascertain whether this effect is specific to response inhibition or whether impairment in other cognitive domains also predicts non-response. Method Older depressed patients (n = 84) enrolled in an 8-week trial of citalopram were classified as impaired or non-impaired relative to the sample on mental status, psychomotor speed, reaction time, spatial judgment, and memory, and contrasted with regard to antidepressant response. Results Patients who were impaired relative to the sample on digit symbol performance did not respond as quickly to citalopram as those who were unimpaired. By the end of the 8-week trial, however, both groups reached the same level of response. Impairment in other domains had no impact on antidepressant response. Conclusions Non-response was not attributable to impairment on any of the neuropsychological tests suggesting that antidepressant non-response is specific to impaired response inhibition. Copyright © 2007 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Gender differences in the treatment response to fluvoxamine (selective serotonin re-uptake inhibitor) and milnacipran (serotonin/norepinephrine re-uptake inhibitor) were investigated in Japanese major depressive patients. A total of 125 Japanese patients was included in the present study. Sixty-six patients received fluvoxamine treatment. The daily dose was 50 mg/day for the first week and increased to 100 mg after 1 week, up to 200 mg after another week. Fifty-nine patients were given milnacipran. The daily dose was 50 mg/day for the first week, and up to 100 mg/day thereafter. Patients were divided into three groups: younger women (<44 years of age), older women (≥44 years of age) and men. Depressive symptoms were evaluated using the Montgomery and Åsberg Depression Rating Scale (MADRS) before treatment and at 1, 2, 4 and 6 weeks after the beginning of the study. In comparison with other groups, younger women treated with fluvoxamine demonstrated a significant difference in the time course of MADRS score change. However, these gender/age-related differences of antidepressant response were not observed in the patients treated with milnacipran. The results suggest that fluvoxamine is more effective in younger female patients than older female patients and male patients, while milnacipran is generally effective irrespective of gender or age. [ABSTRACT FROM AUTHOR]

Abstract: The aim of this study is to prospectively evaluate the antidepressant response to SSRIs in depressed post-menopausal women with or without hormonal therapy (HT), and to analyze the possible influence of basal serum levels of gonadotropins and sexual hormones on the antidepressant response. 170 post-menopausal women with a depressive episode (DSM-IV criteria) – 47 on HT and 123 not on HT – started the treatment with an SSRI. Depressive symptoms were assessed at baseline and 7 weeks thereafter by raters blind to treatment regimen. Response rates were 63.2% in the group without HT and 83.7% in the HT group (p =0.013). An inverse correlation emerged between the basal levels of LH and the improvement in HRSD scores (p =0.001) in the group without HT. In conclusion, HT appeared to improve the antidepressant response to SSRIs. Furthermore, in post-menopausal women, LH basal levels may be taken into account as possible predictor of response. [Copyright &y& Elsevier]

Abstract: Objective: Pilot study examining the effects of estrogen therapy (ET) on antidepressant response in postmenopausal women with major depressive disorder (MDD). Methods: Twenty-two subjects received sertraline at 50mg/day for one week, with an increase to 100mg/day at week 2 for a 10-week trial. Transdermal estrogen or placebo patches 0.1mg were randomly administered concurrent with the initiation of sertraline treatment. The 21 item Hamilton Depression Rating Scale (HDRS-21) was administered to all patients at baseline and weekly thereafter. Results: Both groups showed a similar significant reduction in HDRS-21 scores by the end of the study. There was no significant difference between the two treatment groups at the end of the 10-week trial, but the women receiving sertraline with ET showed significantly greater early improvement (weeks 2–4) compared to the women receiving sertraline with placebo. Conclusions: Sertraline is an effective antidepressant for postmenopausal women with MDD. ET does not alter the response rate to antidepressant therapy however ET may play a role in accelerating the antidepressant response. [Copyright &y& Elsevier]

Abstract: Background: Investigators have examined potential mechanisms for the observed differences between men and women in antidepressant response. However, to date no studies have measured the impact of body mass index (BMI) on men''s and women''s response to selective serotonin re-uptake inhibitors or placebo. Methods: We evaluated the response to antidepressants and placebo of 274 non-obese (BMI<30) and obese (BMI>30) depressed outpatients participating in Phase II–IV clinical trials. After categorizing men and women into their respective BMI groups, we measured the amount of change each group experienced from baseline to the final visit using the HAM-D-17 and MADRS ratings scales. Results: Compared to women, men assigned to an antidepressant had a significantly lower mean total change on both the HAM-D-17 [non-obese, F(1,88)=5.292, p =0.024; obese, F(1,39)=7.040; p =0.012] and the MADRS [non-obese, F(1,66)=4.049, p =0.048; obese, F(1,27)=8.631, p =0.007]. In fact, obese men showed the smallest difference in antidepressant-placebo response. The results of the ANCOVAs indicated significant main effects of treatment (placebo vs. antidepressant), sex of the patient, and BMI category as well as a significant interaction between all three variables. Limitations: Patients participating in clinical trials are not necessarily representative of the entire depressed population. In addition, our results include only SSRIs, not other antidepressants. Conclusion: Compared to the rest of the depressed sample the subgroup of depressed obese men (n =40) showed little or no therapeutic benefit with SSRI antidepressants. Although our findings may have important clinical implications, replication and further research is warranted in order to understand their underlying mechanisms and their pertinence to dosing strategies. [Copyright &y& Elsevier]

Recent evidence suggests that signalling cascades located downstream of monoamine receptors are altered following antidepressant treatment. Our objective was to investigate whether genetic polymorphisms in genes involved in these signalling cascades influenced antidepressant efficacy.Polymorphisms in the G-protein β subunit GNB3, the cAMP response element binding protein 1 gene (CREB1), the brain derived neurotrophic factor (BDNF) and CREB binding protein (CREBBP) were studied in well characterised unipolar (n=166) and early onset (n=102) depressive populations and correlated with treatment response.The GNB3 C825T polymorphism, which results in a 41 amino acid deletion, was significantly associated with lack of remission (OR=0.18, P=0.02) and lack of response (OR=0.26, P=0.03) following 2nd switch treatment. A cytosine deletion 16 base pairs from the start of exon 8 in CREB1 was found more frequently in remitters and responders to 2nd switch antidepressant drug therapy, although these differences failed to reach significance. Polymorphisms detected BDNF (G196A) and CREBBP (T651 C) did not appear to influence antidepressant response.These results suggest that inheritance of the GNB3C825T allele may significantly influence antidepressant response and emphasises the potential importance of polymorphisms in genes in signalling cascades activated by commonly prescribed antidepressants. [ABSTRACT FROM AUTHOR]

Objective: Much of the response to an antidepressant is the result of placebo response. The placebo response embedded in drug response confounds studies seeking to identify brain mechanisms essential for pharmacologic response. Exclusion of patients who fail to meet entry criteria at the end of a placebo lead-in phase has been inadequate to reduce the effect of placebo during pharmacologic trials. This study focused on the placebo lead-in phase and examines whether change in severity of depression during placebo lead-in predicts change in depressive symptoms during antidepressant treatment. Method: The subjects were patients aged 60-85 years with nonpsychotic unipolar major depression not attributed to dementing disorders, medical illnesses, or drugs causing depression and had a 24-item Hamilton Depression Rating Scale score of 18 or greater. After a two-week placebo lead-in, subjects with Hamilton Depression Rating Scale score of 18 or greater received 10 mg escitalopram for 12 weeks. Results: Worsening or limited change in depression during placebo treatment predicted improvement in depressive symptoms during escitalopram treatment. Limited change in anxiety, melancholia, helplessness, and paranoia during placebo treatment were the strongest predictors of improvement in depression while on escitalopram. Conclusions: These findings, if replicated, may be used to characterize depressed older patients likely to respond to the pharmacologic action of antidepressants rather than the placebo response embedded in drug trials and thus improve the methodology of biomarker studies of antidepressant response. On a clinical level, depressed older patients who improve during a prolonged evaluation may be candidates for nonpharmacologic treatments because their drug response may be limited. [ABSTRACT FROM AUTHOR]

Abstract: Rationale: Ghrelin is a peptide of 28 amino acids found in mammals that increases the release of growth hormone, food intake, and body weight. Objectives: We investigated the relationship between ghrelin and the states of anxiety and depression by giving rats either antisense DNA for ghrelin, scrambled DNA or vehicle into the lateral ventricle of rats. Results: In forced swimming tests, rats that received antisense DNA decreased the length of time that they were immobile in the water. Ghrelin antisense oligonucleotides produced an anxiolytic-like effects in the elevated plus maze test, black and white test, or conditioned fear tests. Treatment with antisense DNA for ghrelin significantly decreased rat body weight. No significant effect on general locomotor activity was seen. Conclusions: These results suggest that administration of antisense DNA for ghrelin causes an antidepressant and anxiolytic response in rats. [Copyright &y& Elsevier]

Abstract: Background: It is well established that depressive disorders are more prevalent in women; however gender differences in the pharmacological response to antidepressants are not a consistent finding in all reports. It is considered that this discrepancy can be explained by the fact that in most clinical trials drug use for comparative purposes is not completely different. In this study gender differences in antidepressant response with citalopram (CTP), a selective serotonin reuptake inhibitor and reboxetine (RBX), a selective noradrenaline reuptake inhibitor were evaluated in a group of young men and premenopausal women. Method: Eighty-six depressed patients 18 to 40 years old participated in an 8-week double-blind clinical trial. Subjects were divided in four groups according to sex and treatment assignation: females treated with CTP (n =25) or RBX (n =23), and males treated with CTP (n =19) or RBX (n =19). Response was determined using HDRS and BDI. Results: ANOVA analysis considering change in HDRS scores from baseline to last evaluation found a significant interaction between gender and type of treatment. Females treated with CTP showed a significantly greater response than females treated with RBX, while in men no differences were observed for both drugs. Limitations: Replication using larger sample size and longer treatment periods is required. Conclusions: These results support previous findings which show that premenopausal women respond better than men to serotonergic antidepressants. They also support that a plausible interaction between gonadal hormones and serotonin may explain gender differences in antidepressant response. [Copyright &y& Elsevier]

Valid and reliable methods of assessing outcome in depression are crucial to antidepressant efficacy studies but are also important for all studies that relate response to other variables. In this paper we review basic issues of reliability and validity associated with outcome measurement. We distinguish between scales or inventories designed for screening or diagnosis and those intended for outcome assessment. We note historical changes in patient selection (e.g. outpatients instead of inpatients, differentiating psychotic and non-psychotic) and how these changes affect commonly used scales such as the Hamilton Depression Rating Scale. We examine whether antidepressants with different mechanisms of action are best assessed with similar or different symptoms. And we review studies that have identified 'core' symptoms of depression and compare these findings to the magnitude of individual symptom change we found in five studies of selective serotonergic or nonadrenergic antidepressants. [ABSTRACT FROM PUBLISHER]

The introduction of selective serotonin (5-HT) reuptake inhibitors (SSRIs) has significantly improved the pharmacological treatment of a range of psychiatric disorders. Nevertheless, despite the undoubted advantages of antidepressant treatment in terms of improved tolerability to therapy while maintaining a high level of efficacy, not all patients benefit from it; an appreciable proportion do not respond adequately, while others may show adverse reactions. The necessary change of the initial treatment choice often requires extended periods for the remission of symptomatology. Such difficulties could be avoided if it should be possible to determine more quickly the most suitable drug. Several factors have been thought to influence the outcome of antidepressant therapy. Among the factors influencing the interindividual variability in response to treatment with SSRI, differences in genetic features may play a significant role. Several genetic polymorphisms have been associated with therapeutic SSRI response, including genetic variants of the 5-HT transporter, 5-HT-2A-receptor, tryptophan hydroxylase, brain-derived neurotrophic factor, G-protein beta3 subunit, interleukin-1beta and angiotensin-converting enzyme, although with conflicting results; also cytochrome P450 drug-metabolising enzymes may bear a particular importance, although further corroboration of the findings is necessary, and further key participating genes remain to be identified. The hope is that the identification of these genetic components will eventually facilitate the development of a customised SSRI treatment.The Pharmacogenomics Journal (2004) 4, 274-282. doi:10.1038/sj.tpj.6500250 Published online 27 April 2004 [ABSTRACT FROM AUTHOR]

Predicting response to antidepressant medication has been a challenge to clinicians and researchers for decades. Attention has been paid to the role of motor retardation as a putative indicator of treatment response, yet previous findings have been mixed. One reason for this inconsistency may be related to the subjective nature of motor retardation and how it is assessed. In the present study, we adopted a measure of motor programming previously shown to characterize parkinsonian bradykinesia to test whether neuromotor function could predict response to antidepressant treatment. Twenty-eight patients (14 males and 14 females with a mean age of 42.0 years) meeting DSM-IV criteria for a depressive disorder were randomized to receive 8 weeks of treatment with one of three antidepressant medications (sertraline, phenelzine, or bupropion). Treatment outcomes were assessed using the 17-item version of the Hamilton Rating Scale for Depression (HRSD). Patients were considered asymptomatic if their post-treatment HRSD total score was equal to or less than 7. Treatment responders (n=15) had significantly less baseline impairment (P=0.01) on the neuromotor measure than non-responders (n=13). There was a significant relationship between amount of improvement on the HRSD and severity of baseline neuromotor function (r=−0.51; P=0.006). No significant group effects were found for baseline psychomotor slowing or clinical ratings of motor retardation. These results demonstrate that a quantitative measure of motor programming may be a useful predictor of antidepressant non-response. [Copyright &y& Elsevier]

Previous studies have shown that changes in brain function precede clinical response to antidepressant medications. Here we examined quantitative EEG (QEEG) absolute and relative power and a new measure, cordance, for detecting regional changes associated with treatment response. Fifty-one adults with unipolar depression completed treatment trials using either fluoxetine or venlafaxine vs. placebo. Data were recorded at baseline and after 48 h and 1 week on drug or placebo. Baseline and change from baseline values were examined for specific brain regions in four subject groups (medication and placebo responders and nonresponders). No regional baseline QEEG differences were found among the groups; there also were no significant changes in theta power over time. In contrast, medication responders uniquely showed significant decreases in prefrontal cordance at 48 h and 1 week. Clinical differences did not emerge until after four weeks. Subjects with greater changes in cordance had the most complete 8-week responses. These findings implicate the prefrontal region in mediating response to antidepressant medications. Cordance may have clinical applicability as a leading indicator of individual response. [Copyright &y& Elsevier]

Background: Antidepressants are a first-line treatment for depression. However, only a third of individuals experience remission after the first treatment. Common genetic variation, in part, likely regulates antidepressant response, yet the success of previous genome-wide association studies has been limited by sample size. This study performs the largest genetic analysis of prospectively assessed antidepressant response in major depressive disorder to gain insight into the underlying biology and enable out-of-sample prediction., Methods: Genome-wide analysis of remission ( n remit  = 1852, n  = 5218) was performed. Single nucleotide polymorphism-based heritability was estimated using genome-wide complex trait analysis. Genetic covariance with eight mental health phenotypes was estimated using polygenic scores/AVENGEME. Out-of-sample prediction of antidepressant response polygenic scores was assessed. Gene-level association analysis was performed using MAGMA and transcriptome-wide association study. Tissue, pathway, and drug binding enrichment were estimated using MAGMA.nonremit  = 3299) and percentage improvement ( n  = 5218) was performed. Single nucleotide polymorphism-based heritability was estimated using genome-wide complex trait analysis. Genetic covariance with eight mental health phenotypes was estimated using polygenic scores/AVENGEME. Out-of-sample prediction of antidepressant response polygenic scores was assessed. Gene-level association analysis was performed using MAGMA and transcriptome-wide association study. Tissue, pathway, and drug binding enrichment were estimated using MAGMA., Results: Neither genome-wide association study identified genome-wide significant associations. Single nucleotide polymorphism-based heritability was significantly different from zero for remission ( h 2  = -0.018, SE = 0.032). Better antidepressant response was negatively associated with genetic risk for schizophrenia and positively associated with genetic propensity for educational attainment. Leave-one-out validation of antidepressant response polygenic scores demonstrated significant evidence of out-of-sample prediction, though results varied in external cohorts. Gene-based analyses identified h 2 as significantly associated with antidepressant response.ETV4 and DHX8 as significantly associated with antidepressant response., Conclusions: This study demonstrates that antidepressant response is influenced by common genetic variation, has a genetic overlap schizophrenia and educational attainment, and provides a useful resource for future research. Larger sample sizes are required to attain the potential of genetics for understanding and predicting antidepressant response., (© 2021 The Authors.)

Inadequate response to antidepressant treatment, in a significant proportion of patients diagnosed with Major Depressive Disorder, contributes to the large burden of disability associated with the disease; thus, predicting treatment response is one of the most important challenge for clinicians who deal with depressed patients. The cytokine hypothesis of depression suggests that altered pheripheral cytokine levels are involved in the pathophysiology of depressive disorder and in modulating response to treatment. Present meta-analysis aimed to investigate the association between cytokine levels at baseline and response to antidepressant therapies. Authors performed a systematic search of PubMed and Embase databases for studies published between 2010 and January 2021: of 3345 identified records, 31 studies met the inclusion criteria for the qualitative synthesis, whereas 19 studies were eligible for quantitative analysis. Patients who failed to respond to antidepressant had aberrant inflammatory process, namely higher baseline levels of C-Reactive Protein and Interleukine-8, which is associated with treatment outcome in Major Depressive Disorder. Despite these promising results, further investigations are needed in order to replicate the data and to examine the potential role of inflammatory marker as a novel predictive tool for pharmacological treatment of depressive disorder., (Copyright © 1964–2022 by MedWorks Media Inc, Los Angeles, CA All rights reserved. Printed in the United States.)

Background: A key challenge in the understanding and treatment of depression is identifying cell types and molecular mechanisms that mediate behavioral responses to antidepressant drugs. Because treatment responses in clinical depression are heterogeneous, it is crucial to examine treatment responders and nonresponders in preclinical studies., Methods: We used the large variance in behavioral responses to long-term treatment with multiple classes of antidepressant drugs in different inbred mouse strains and classified the mice into responders and nonresponders based on their response in the forced swim test. Medial prefrontal cortex tissues were subjected to RNA sequencing to identify molecules that are consistently associated across antidepressant responders. We developed and used virus-mediated gene transfer to induce the gene of interest in specific cell types and performed forced swim, sucrose preference, social interaction, and open field tests to investigate antidepressant-like and anxiety-like behaviors., Results: Cartpt expression was consistently upregulated in responders to four types of antidepressants but not in nonresponders in different mice strains. Responder mice given a single dose of ketamine, a fast-acting non-monoamine-based antidepressant, exhibited high CART peptide expression. CART peptide overexpression in the GABAergic (gamma-aminobutyric acidergic) neurons of the anterior cingulate cortex led to antidepressant-like behavior and drove chronic stress resiliency independently of mouse genetic background., Conclusions: These data demonstrate that activation of CART peptide signaling in GABAergic neurons of the anterior cingulate cortex is a common molecular mechanism across antidepressant responders and that this pathway also drives stress resilience., (© 2022 The Authors.)

Twenty-four hour urinary excretion of 3-methoxy-4-hydroxyphenylglycol (MHPG), the metabolite thought best to reflect brain norepinephrine metabolism, was studied longitudinally in ten depressed patients before and during the acute and chronic phases of lithium treatment. Five of the patients were identified as bipolar I (prior history of mania), 3 as bipolar II (history of hypomania) and 2 as unipolar (history of depression). During acute lithium administration (first week) there was no consistent pattern of change in MHPG. Comparing the predrug period with the third and fourth week of treatment, all of the responders showed an increase in MHPG, while the non-responders showed no change or a decrease. It is concluded that the change in clinical state is the most important variable contributing to MHPG changes in these patients. There was a tendency for the pretreatment MHPG excretion to be low in the patients who went on to show a clear-cut antidepressant response to lithium compared to those who were unequivocal non-responders. The predrug MHPG for the bipolar patients (prior history of mania) was significantly lower than the unipolar patients, a difference which apparently contributes to the lower MHPG in the lithium responders, all of whom were in the bipolar group. [ABSTRACT FROM AUTHOR]

Introduction: Major depressive disorder (MDD) constitutes the leading cause of disability worldwide. Although efficacious antidepressant pharmacotherapies exist for MDD, only about 40-60% of the patients respond to initial treatment. However, there is still a lack of robustly established and applicable biomarkers for antidepressant response in everyday clinical practice. Objectives: This study targets the assessment of the vasopressin (AVP) surrogate marker Copeptin (CoP), as a potential peripheral hypothalamic-level biomarker of antidepressant treatment response in MDD. Methods: We measured baseline and dynamic levels of plasma CoP along with plasma ACTH and cortisol (CORT) in drug-naive outpatients with MDD before and after overnight manipulation of the hypothalamic-pituitary-adrenal (HPA) axis [i.e., stimulation (metyrapone) and suppression (dexamethasone)] on three consecutive days and their association with treatment response to 4 weeks of escitalopram treatment. Results: Our findings suggest significantly higher baseline and post-metyrapone plasma CoP levels in future non-responders, a statistically significant invert association between baseline CoP levels and probability of treatment response and a potential baseline plasma CoP cut-off level of above 2.9 pmol/L for future nonresponse screening. Baseline and dynamic plasma ACTH and CORT levels showed no association with treatment response. Conclusions: This pilot study provide first evidence in humans that CoP may represent a novel, clinically easily applicable, endocrine biomarker of antidepressant response, based on a singlemeasurement, cut-off level. These findings, underline the role of the vasopressinergic system in the pathophysiology of MDD and may represent a significant new tool in the clinical and biological phenotyping of MDD enhancing individual-tailored therapies. [ABSTRACT FROM AUTHOR]

Several trials have recently shown that a poor response to antidepressant treatment predicts the emergence of new suicidal ideas and attempts. This effect seems to be associated to an excess in the antidepressant dosage and to a young age of the patients. Inversely, new data also suggests that suicidal depressed patients (independently of comorbidity and type of treatment) respond less well when an antidepressant treatment is prescribed. The role of activation syndrome, or antidepressant-induced jitteriness/anxiety syndrome, needs also to be discussed since specific symptoms seem to be particularly associated with the risk of emergent suicidal ideas or behavior. Overall, this presentation will review the evidence in clinical samples of suicidal patients about the preventive effects of antidepressant treatment. [ABSTRACT FROM AUTHOR]

• Early change in cognition was a non-significant predictor of treatment response. • Signal-to-noise ratio was low due to high heterogeneity in the cognitive data. • Future studies should stratify patients to produce more homogenous samples. • Early cognitive change may predict response in stratified MDD subpopulations. • Early change in MADRS and baseline MADRS scores were correlated with response. Antidepressant pharmacotherapy dominates current treatment in psychiatry, including treatment for major depressive disorder (MDD). However, the current trial-and-error process of medication selection contributes to treatment failure and unnecessarily exposes patients to lengthy and insufficient treatment trials. Notably, improvements in measures of cognition have been demonstrated to occur early during treatment and prior to improvements in clinical state. Cognitions have been categorized based on emotional valence (i.e., cold versus hot cognitions). Cold cognitions describe cognitive operations that are relevant to the processing of non-emotional information. The current analysis investigates whether early changes in cold cognition can predict response after 8 weeks of vortioxetine treatment in adults with MDD. This was secondary analysis of an 8-week, open-label study. Cognition was assessed at week 0 and week 2 to measure early cognitive change. Depressive symptom severity was assessed at week 0 and week 8 to measure treatment response. Eighty-one subjects were analyzed using binomial logistic regression models. Early change in cognition was a non-significant predictor of response (p = 0.845, SE = 0.599, OR = 1.124), which may have resulted from high data variability. The overall predictive accuracy of the model was low (sensitivity = 37.5%, specificity = 89.8%, PPV = 70.6%, NPV = 68.8%). Future studies should include larger samples and stratify patients based on potentially moderating variables, such as baseline cognitive impairment and occupation. Stratification would likely produce more homogenous samples, reducing the amount of variability observed for early cognitive change. [ABSTRACT FROM AUTHOR]

We tested the hypothesis that allelic variation of 5-HTT linked polymorphic region (5-HTTLPR) could influence illness onset and recurrence in 129 bipolar and 128 unipolar recurrent patients. Among bipolar patients, homozygotes for the short variant showed an earlier age at onset and a lower recurrence rate than heterozygotes and homozygotes for the long variant. Unipolar patients showed a trend toward the same difference. Data support a role for 5-HTTLPR in course of affective illness. [Copyright &y& Elsevier]

Background: Alterations in gray matter (GM) have been recognized as playing an important role in the neurobiological mechanism underlying major depressive disorder (MDD) and antidepressant responses. However, little is known about white matter (WM) connectivity in MDD, leaving an incomplete understanding of the pathophysiology of the disorder., Purpose: To examine the functional connectivity (FC) of WM, GM, and WM-GM in MDD patients and explore the relationship between FC and antidepressant response., Study Type: Longitudinal study., Subjects: In all, 129 MDD patients and 89 healthy controls (HC)., Field Strength/sequence: Whole-brain blood oxygen level-dependent (BOLD) single-shot echo planar imaging was acquired at 3.0T., Assessment: At baseline, all participants received Hamilton depression rating scale (HAMD) assessment and an fMRI scan. After 2- and 8-week antidepressant treatment, patients completed the HAMD again. The HAMD reductive rate of 2- and 8-weeks were calculated., Statistical Tests: The comparisons of age, education, HAMD scores, and FC values (false discovery rate correction) between patients and controls were calculated with a two-sample t-test. The chi-square test was employed to compare the differences of gender between these two groups. Correlations between FC and HAMD, as well as the reductive rate of HAMD, were analyzed with Pearson or Spearman correlation. Receiver operator curve analysis was performed to predict the antidepressant response., Results: Compared to HC, MDD patients exhibited widespread decreases in FC of WM-GM. Furthermore, 28 GM regions and 11 WM bundles had lower connectivity in MDD patients. At baseline, four FC of WM-GM showed negative correlations with the HAMD scores. Six FC of WM-GM correlated with the 2-week reductive rate of HAMD. Moreover, FC in GM, WM, and WM-GM also exhibited significantly positive correlations with an 8-week reductive rate of HAMD., Data Conclusion: The FC of WM-GM was decreased in MDD and may play a role in its pathophysiology and antidepressant responses., Level of Evidence: 2., Technical Efficacy Stage: 2., (© 2020 International Society for Magnetic Resonance in Medicine.)

Depression is a leading cause of disability worldwide and improving its treatment is a core research priority for future programmes. A change in the view of psychological and biological processes, from seeing them as separate to complementing one another, has introduced new perspectives on pathological mechanisms of depression and treatment mode of action. This review presents a theoretical model that incorporated this novel approach, the cognitive neuropsychological hypothesis of antidepressant action. This model proposes that antidepressant treatments decrease the negative bias in the processing of emotionally salient information early in the course of antidepressant treatment, which leads to the clinically significant mood improvement later in treatment. The paper discusses the role of negative affective biases in the development of depression and response to antidepressant treatments. It also discusses whether the model can be applied to other antidepressant interventions and its potential translational value, including treatment choice, prediction of response and drug development.

Functional and structural MRI of prefrontal cortex (PFC) may provide putative biomarkers for predicting the treatment response to transcranial direct current stimulation (tDCS) in depression. A recent MRI study from ELECT-TDCS (Escitalopram versus Electrical Direct-Current Theror Depression Study) showed that depression improvement after tDCS was associated with gray matter volumes of PFC subregions. Based thereon, we investigated whether antidepressant effects of tDCS are similarly associated with baseline resting-state functional connectivity (rsFC). A subgroup of 51 patients underwent baseline rsFC-MRI. All patients of ELECT-TDCS were randomized to three treatment arms for 10 weeks (anodal-left, cathodal-right PFC tDCS plus placebo medication; escitalopram 10 mg/day for 3 weeks and 20 mg/day thereafter plus sham tDCS; and placebo medication plus sham tDCS). RsFC was calculated for various PFC regions and analyzed in relation to the individual antidepressant response. There was no significant association between baseline PFC connectivity of essential structural regions, nor any other PFC regions (after correction for multiple comparisons) and patients' individual antidepressant response. This study did not reveal an association between antidepressants effects of tDCS and baseline rsFC, unlike the gray matter volume findings. Thus, the antidepressant effects of tDCS may be differentially related to structural and functional MRI measurements.

Raised pro-inflammatory immune/inflammatory setpoints, leading to an increased production of peripheral cytokines, have been associated with Major Depressive Disorder (MDD) and with failure to respond to first-line antidepressant drugs. However, the usefulness of these biomarkers in clinical psychopharmacology has been questioned because single findings did not translate into the clinical practice, where patients are prescribed treatments upon clinical need. We studied a panel of 27 inflammatory biomarkers in a sample of 108 inpatients with MDD, treated with antidepressant monotherapy for 4 weeks upon clinical need in a specialized hospital setting, and assessed the predictive effect of baseline peripheral measures of inflammation on antidepressing efficacy (response rates and time-lagged pattern of decrease of depression severity) using a machine-learning approach with elastic net penalized regression, and multivariate analyses in the context of the general linear model. When considering both categorical and continuous measures of response, baseline levels of IL-1β predicted non-response to antidepressants, with the predicted probability to respond being highly dispersed at low levels of IL-1β, and stratifying toward non-response when IL-1β is high. Significant negative effects were also detected for TNF-α, while IL-12 weakly predicted response. These findings support the usefulness of inflammatory biomarkers in the clinical psychopharmacology of depression, and add to ongoing research efforts aiming at defining reliable cutoff values to identify depressed patients in clinical settings with high inflammation, and low probability to respond., (Copyright © 2020. Published by Elsevier B.V.)

Genetic factors play a significant but complex role in antidepressant (AD) response and tolerability. During recent years, there is growing enthusiasm in the promise of pharmacogenetic/pharmacogenomic (PGx) tools for optimizing and personalizing treatment outcomes for patients with major depressive disorder (MDD). The influence of pharmacokinetic and pharmacodynamic genes on response and tolerability has been investigated, including those encoding the cytochrome P450 superfamily, P-glycoprotein, monoaminergic transporters and receptors, intracellular signal transduction pathways, and the stress hormone system. Genome-wide association studies are also identifying new genetic variants associated with AD response phenotypes, which, combined with methods such as polygenic risk scores (PRS), is opening up new avenues for novel personalized treatment approaches for MDD. This chapter describes the basic concepts in PGx of AD response, reviews the major pharmacokinetic and pharmacodynamic genes involved in AD outcome, discusses PRS as a promising approach for predicting AD efficacy and tolerability, and addresses key challenges to the development and application of PGx tests.

Background: Major depressive disorder is associated with abnormal connectivity across emotion and reward circuits as well as other established circuits that may negatively impact treatment response. The goal of this study was to perform an exploratory reanalysis of archival data from a clinical trial to identify moderators of treatment outcome of sertraline over placebo., Methods: EMBARC (Establishing Moderators and Biosignatures of Antidepressant Response in Clinical Care) study participants completed magnetic resonance imaging before randomization to either sertraline or placebo for 8 weeks (n = 279). Seed-based functional connectivity was computed using 4 bilateral seeds (2 spheres defined bilaterally): amygdala, dorsolateral prefrontal cortex (DLPFC), subcallosal cingulate cortex, and ventral striatum. Functional connectivity maps were generated, principal component analysis was performed, linear mixed effects models were used to determine moderators of treatment outcome, and post hoc analyses were used to determine level of connectivity (low and high, -1 and +1 SD from the mean) that was most sensitive to improved depression severity (baseline to week 8) based on treatment., Results: Greater mean reduction in the 17-item Hamilton Rating Scale for Depression score by 8 weeks occurred with sertraline relative to placebo when connectivity in the DLPFC was low (3-way interaction test, p = .05). Conditional on low connectivity in the DLPFC and subcallosal cingulate cortex and high connectivity in the ventral striatum and amygdala, there was on average a 4.8-point greater reduction in the 17-item Hamilton Rating Scale for Depression score with sertraline relative to placebo (p = .003)., Conclusions: The level of functional connectivity seeded in both the DLPFC and the subcallosal cingulate cortex networks may play an important role in identifying a favorable response to sertraline over placebo., (Copyright © 2020 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)