Antidepressant Treatment Outcome Research Articles

Gender differences in 12-week antidepressant treatment outcomes for a naturalistic secondary care cohort: The CRESCEND study

This study aimed to determine whether men and women with depression differ in socio-demographic, treatment-related characteristics, and in their responses to treatment with antidepressants, as well as to explore differences in treatment outcomes by menopausal status. From a nationwide sample of 18 hospitals in South Korea, 723 depressive patients were recruited. After baseline evaluation, they received naturalistic clinician-determined antidepressant interventions. Assessment scales for evaluating depression (HAMD), anxiety (HAMA), global severity (CGI-s), and functioning (SOFAS) were administered at baseline and re-evaluated at 1, 2, 4, 8, and 12 weeks later. At baseline, women were older, less educated, less likely to be employed, had lower income, were more likely to be married, and had longer illness duration than men. There were no gender differences in the treatment-regime received. After adjustment for baseline status, women were more likely to achieve HAMD remission (OR = 1.51), HAMD response (OR = 1.64), and HAMA response (OR = 1.61). Women also experienced shorter times to HAMD response, HAMA response, and CGI-s remission. Postmenopausal women showed higher HAMA response with newer dual action antidepressants than premenopausal women. Women were found to have better outcomes following antidepressant treatment than men, and postmenopausal women had a better response on anxiety symptoms with newer dual action antidepressants.

MRI‐defined vascular depression: a review of the construct

To review the construct of MRI-defined vascular depression and to examine the substantive and methodological issues that bear on its validity as a distinct subtype of depression in late life. Literature review. We identified three areas that are critical to establishing the validity of MRI-defined vascular depression: (1) understanding and delineating the relationship between MRI hyperintensities, executive dysfunction, and antidepressant treatment outcome; (2) understanding the relationship between, and establishing the validity of, qualitative and quantitative approaches to the measurement of MRI hyperintensities (the primary feature of the proposed subtype); (3) establishing the clinical presentation and course of the subtype in the context of other late-life disorders. Despite considerable data supporting the validity of MRI-defined vascular depression, there are a number of critical issues that remain, including establishing a causal relationship between cerebrovascular disease and late-life depression, establishing consistent diagnostic criteria, determining the importance of lesion type and location, and understanding the course of the disorder.

Examining antidepressant drug response by smoking status: why is it important and how often is it done?

Despite an increasingly recognized relationship between depression and smoking, little is known about the degree to which treatment studies for depression consider the impact of smoking on outcomes. The aim of this study is to examine the extent to which smoking is considered in current antidepressant treatment research. We conducted a MEDLINE search of recent randomized clinical trials of pharmacotherapy for depression published between 1 January and 31 December 2007, and a search of current pharmacological intervention studies for depression using www.ClinicalTrials.gov. Only 5% of the 107 pharmacological trials for depression published in 2007 reported the smoking status of their samples. Two studies (1.9%) controlled for smoking in the analyses and no studies analyzed outcomes by smoking status. Excluding the eight studies of combined treatment for depression and nicotine dependence, no other study on www.ClinicalTrials.gov (total n = 920) reported an intention to analyze outcomes by smoking status. Emerging data link smoking and depression, however, little attention has been directed toward the effects of smoking on antidepressant treatment outcomes. Conducting research to understand how nicotine and smoking affect responsiveness to antidepressants would advance our understanding of the neurobiology of depression and the development of new and targeted treatments.

Genome-wide association studies of antidepressant outcome: A brief review

Genome-wide association studies (GWAS) of antidepressant treatment outcome have been at the forefront of psychiatric pharmacogenetics. Such studies may ultimately help match medications with patients, maximizing efficacy while minimizing adverse effects. The hypothesis-free approach of the GWAS has the advantage of interrogating genes that otherwise would have not been considered as candidates due to our limited understanding of their function, and may also uncover important regulatory variation within the large regions of the genome that do not contain protein-coding genes. Three independent samples have so far been studied using a genome-wide approach: The Sequenced Treatment Alternatives to Relieve Depression sample (STAR*D) (n=1953), the Munich Antidepressant Response Signature (MARS) sample (n=339) and the Genome-based Therapeutic Drugs for Depression (GENDEP) sample (n=706). None of the studies reported results that achieved genome-wide significance, suggesting that larger samples and better outcome measures will be needed. This review discusses the published GWAS studies, their strengths, limitations, and possible future directions.

Relationship between Baseline Severity of Depression and Antidepressant Treatment Outcome

Assessment of depression severity is of key importance, since several clinical guidelines recommend choice of treatment dependent on the depression severity grade. Using different tools to assess baseline severity may result in different outcomes. This paper describes the results of a multicentre, naturalistic study investigating the relationship between depression symptom severity (using 4 different measures of symptom severity) and clinical outcome among patients hospitalised for depression (N=1 014). Moreover, the impact of differences between methods of measuring depression severity has been investigated. Statistical analyses (univariate measurements, logistic regression models) were conducted to detect coherences and differences between the various methods of severity categorisation. Results revealed different associations between outcome and classification methods. Response or remission rates varied if baseline severity was assessed by different instruments. Moreover, the number of responders increased with higher baseline severity grades of depression, whereas the number of remitters decreased. Additional analyses dependent on outcome criteria using continuous instead of categorical data revealed similar results. Baseline severity may be only one of many other important clinical variables that mediate clinical outcome, but it is surely an important one deserving further research and consideration.

Treatment with paroxetine, but not amitriptyline, lowers levels of lipoprotein(a) in patients with major depression

High lipoprotein(a) (Lp(a)) levels constitute a major risk factor for vascular mortality. Major depression also increases the risk of cardiovascular disease. We measured the concentrations of Lp(a) in depressed patients and controls and studied the effects of antidepressant treatment and treatment outcome. Lp(a) levels were analysed at baseline in 35 in-patients with DSM-IV major depression who were then treated in a randomized double-blind manner with amitriptyline (n = 14) or paroxetine (n = 21), as well as in 33 healthy controls. Lp(a) levels were re-assessed after 4 weeks of treatment. We found a significant decrease in Lp(a) in patients treated with paroxetine, but not in those treated with amitriptyline. Our results suggest that antidepressant treatment with paroxetine might contribute to a decrease in vascular mortality risk irrespective of treatment outcome.

Do Efficacy and Effectiveness Samples Differ in Antidepressant Treatment Outcome?

Because of strict inclusion and exclusion criteria, results drawn from placebo-controlled randomized antidepressant efficacy trials may not be transferable to real-world patients. This study was performed from March 2000 to September 2005 as a prospective, multicenter follow-up. Patients were recruited from February 2000 to June 2005. All patients were hospitalized (N = 1,014) and met DSM-IV criteria for major depressive episode. Assessments with the 21-item Hamilton Depression Rating Scale were conducted biweekly until discharge. According to the most commonly applied exclusion criteria in randomized controlled antidepressant efficacy trials, patients were retrospectively divided into 2 groups: (1) patients not fulfilling exclusion criteria and therefore eligible for a randomized placebo-controlled trial, referred to as "efficacy sample," and (2) patients fulfilling at least 1 exclusion criterion, not being eligible for inclusion in an efficacy trial ("nonefficacy sample"). The efficacy sample was compared with the nonefficacy sample in terms of sociodemographic and clinical baseline variables and outcome measures, such as remission and response rates, 17-item Hamilton Depression Rating Scale mean scores, time to remission, and time to response. Significant differences were found, with the efficacy sample being older (P = .03) and being more often treated at a university hospital (P = .02). The efficacy sample demonstrated superior outcome only in significantly higher mean Global Assessment of Functioning scores at discharge (P = .03). There were no differences regarding remission (P = .68) and response (P = .06) rates, length of hospital stay (P = .49), 17-item Hamilton Depression Rating Scale total score at discharge (P = .13), or time to response (P = .39) or remission (P = .16). Both groups differed significantly in several baseline measures and final Global Assessment of Functioning scores but not in any other outcome measure. Challenging current beliefs, our findings show that results from efficacy antidepressant trials might be more generalizable than previously thought.

An investigation of EEG, genetic and cognitive markers of treatment response to antidepressant medication in patients with major depressive disorder: A pilot study

The aim of this study was to investigate if biomarkers in QEEG, genetic and neuropsychological measures are suitable for the prediction of antidepressant treatment outcome in depression. Twenty-five patients diagnosed with major depressive disorder were assessed twice, pretreatment and at 8-wk follow-up, on a variety of QEEG and neuropsychological tasks. Additionally, cheek swab samples were collected to assess genetic predictors of treatment outcome. The primary outcome measure was the absolute decrease on the HAM-D rating scale. Regression models were built in order to investigate which markers contribute most to the decrease in absolute HAM-D scores. Patients who had a better clinical outcome were characterized by a decrease in the amplitude of the Auditory Oddball N1 at baseline. The ‘Met/Met’ variant of the COMT gene was the best genetic predictor of treatment outcome. Impaired verbal memory performance was the best cognitive predictor. Raised frontal Theta power was the best EEG predictor of change in HAM-D scores. A tentative integrative model showed that a combination of N1 amplitude at Pz and verbal memory performance accounted for the largest part of the explained variance. These markers may serve as new biomarkers suitable for the prediction of antidepressant treatment outcome.

Anxious depression and early changes in the HAMD-17 anxiety-somatization factor items and antidepressant treatment outcome

The objective of this study was to assess the relationship between early changes in anxiety/somatization symptoms and treatment outcome among major depressive disorder patients during a 12-week trial of fluoxetine. We also examined the relationship between anxious depression and treatment response. Five hundred and ten major depressive disorder patients received 12 weeks of fluoxetine with flexible dosing [target dosages: 10 mg/day (week 1), 20 mg/day (weeks 2-4), 40 mg/day (weeks 4-8), and 60 mg/day (weeks 5-12)]. We assessed the relationship between early changes in 17-item Hamilton Rating Scale for Depression (HAMD-17)-anxiety/somatization factor items and depressive remission, as well as whether anxious depression at baseline predicted remission at study endpoint. Baseline HAMD-17 scores were considered as covariates and the Bonferroni correction (P < or = 0.008) was used for multiple comparisons. Adjusting for baseline HAMD-17 scores, patients who experienced greater early improvement in somatic symptoms (gastrointestinal) were significantly more likely to attain remission (HAMD-17 <8) at endpoint than those without early improvement (P=0.006). Early changes in the remaining items did not predict remission, nor did anxious depression at baseline. In conclusion, among the anxiety/somatization factor items, only early changes in somatic symptoms (gastrointestinal) predicted remission. Future studies are warranted to further investigate this relationship as well as that between anxious depression and treatment outcome.

The Pharmacogenetics of Depression: Enter the GWAS

The Pharmacogenetics of Depression: Enter the GWAS

FKBP5 polymorphisms and antidepressant response in geriatric depression

Genetic variation at the FKBP5 locus has been reported to affect clinical outcomes in patients treated with antidepressant medications in several studies. However, other reports have not confirmed this association. FKBP5 may regulate the sensitivity of the hypothalamic-pituitary-adrenal axis. We tested two FKBP5 single nucleotide polymorphisms (rs1360780 and rs3800373) in a sample of 246 geriatric patients treated for 8 weeks in a double-blind randomized comparison trial of paroxetine and mirtazapine. These two polymorphisms had previously been reported to predict efficacy in depressed patients treated with selective serotonin reuptake inhibitors such as paroxetine, and those treated with mirtazapine, an agent with both serotonergic and noradrenergic actions. However, we found no significant associations between these FKBP5 genetic variants and clinical outcomes. Neither mean Hamilton Depression Rating Scale scores nor time to remission or response were predicted by FKBP5 genetic variation. These results suggest that FKBP5 is unlikely to play a major role in determining antidepressant treatment outcomes in geriatric patients.

Research Highlights

Research Highlights

No interactions between genetic polymorphisms and stressful life events on outcome of antidepressant treatment

Genetic polymorphisms seem to influence the response on antidepressant treatment and moderate the impact of stress on depression. The present study aimed to assess, whether allelic variants and stressful life events interact on the clinical outcome of depression. In a sample of 290 systematically recruited patients diagnosed with a single depressive episode according to ICD-10, we assessed the outcome of antidepressant treatment and the presence of stressful life events in a 6-month period preceding onset of depression by means of structured interviews. Further, we genotyped nine polymorphisms in the genes encoding the serotonin transporter, brain derived neurotrophic factor, catechol-O-methyltransferase, angiotensin converting enzyme, tryptophan hydroxylase, and the serotonin receptors 1A, 2A, and 2C. We found no evidence that the effects of the genetic polymorphisms on treatment outcome were dependent on stressful life events experienced by the individual prior to onset of depression.

Frontal electroencephalogram changes in early phase antidepressant treatment predict clinical response in major depressive disorder

Evaluation of: Leuchter AF, Cook IA, Marangell LB et al.: Comparative effectiveness of biomarkers and clinical indicators for predicting outcomes of SSRI treatment in major depressive disorder: results of the BRITE-MD study. Psychiatry Res. 169, 124–131 (2009) and Leuchter AF, Cook IA, Marangell LB et al.: Effectiveness of a quantitative electroencephalographic biomarker for predicting differential response or remission with escitalopram and bupropion in major depressive disorder. Psychiatry Res. 169, 132–138 (2009). The investigators of the Biomarkers for Rapid Identification of Treatment Effectiveness in Major Depression (BRITE-MD) study calculated the Antidepressant Treatment Response (ATR) index, a biomarker of frontal quantitative electroencephalogram changes, after 1 week of escitalopram treatment and examined whether the ATR had utility as a predictor of outcome after a further 7 weeks of treatment. The ATR index predicted response and remission at week 7, whereas the symptom reduction in Hamilton Depression Rating Scale scores by week 1 only predicted response at week 7. Other markers, such as genetic polymorphisms (5-HTTLPR and 5HT2A), the clinician-rated global impression of improvement and serum drug concentrations, did not provide significant predictive utility. Notably, high ATR values predicted response to escitalopram, while low ATR values predicted response to bupropion. The findings provocatively suggest that the ATR index may be a useful predictor for short-term antidepressant outcome. These results may encourage the future work that will be necessary to evaluate the role of the ATR index and clinical measures as predictors of both short- and long-term antidepressant treatment outcomes.

Shaping brain development: Mouse communal nesting blunts adult neuroendocrine and behavioral response to social stress and modifies chronic antidepressant treatment outcome

Early experiences shape brain function and behavior and, consequently, vulnerability to psychopathology at adulthood. Here we exploited the mouse communal nest (CN) paradigm in order to investigate the effect of the early social environment on the emergence of endophenotypes of depression and on antidepressant efficacy at adulthood. CN, which consists in a single nest where three mothers keep their pups together and share care-giving behavior until weaning, is characterized by high levels of maternal behavior and peer interactions, thus representing an highly stimulating environment. Our results show that, when compared to mice reared in standard laboratory conditions (SN), adult CN mice exhibited greater sucrose preference on the first days of the test, displayed reduced anhedonia during social stress and had lower corticosterone levels after acute and prolonged social stress. Furthermore, in line with previous work, CN displayed longer immobility than SN mice in the forced swim test. Here we show that such behavioral response is differently affected by antidepressants according to early experiences. A 3-week fluoxetine treatment affected only SN mice, leading to an increase of immobility duration up to the levels showed by CN mice, while acute fluoxetine administration decreased immobility duration in both groups. These results show that being reared in a CN profoundly changes developmental trajectories, reducing the adult display of endophenotypes of depression and modifying response to antidepressants. The present findings suggest that early experiences represent one of those factors to be taken into account to identify the appropriate individual pharmacological strategy to treat depression in patients.

Pharmacogenetics Studies in STAR*D: Strengths, Limitations, and Results

Pharmacogenetics Studies in STAR*D: Strengths, Limitations, and Results

Pharmacogenetics Studies in STAR*D: Strengths, Limitations, and Results

Several lines of evidence support an important genetic contribution to the wide individual variation in therapeutic response to antidepressant medications. The Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study provided the largest cohort assembled to date of DNA from patients with nonpsychotic major depressive disorder, uniformly treated with citalopram and followed prospectively for up to 12 weeks. This pivotal study changed the face of pharmacogenetics research by increasing the sample size by an order of magnitude as well as by providing detailed prospective information about antidepressant response and tolerability. Several groups have identified markers in genes and tested the replication of previous findings of genes associated with outcome and side effects of antidepressant treatment. Variants in HTR2A, GRIK4, and KCNK2 were associated with citalopram treatment outcome. Replication was achieved in markers in the FKBP5 gene. Other findings in PDE11A and BDNF were not successfully replicated, and reports of potential confounders in previous associations with serotonin transporter variation (SLC6A4) were identified. Polymorphisms in pharmacokinetic genes involved in metabolism and transmembrane transport were also not associated with antidepressant response. Adverse events were also tested. Treatment-emergent suicidal ideation was associated with GRIK2, GRIA3, PAPLN, IL28RA, and CREB1. Sexual dysfunction was linked with variation in GRIN3A, GRIA1 GRIA3, and GRIK2. Reported and future findings of pharmacogenetics studies in STAR*D could help elucidate pathways involved in major depression and those pertinent to antidepressant outcome and side effects. Replication of these findings in independent samples could lead to the development of new treatments and to optimization of available treatments.

The role of pharmacogenetics in the treatment of depression and anxiety disorders

Although effective treatment for mood and anxiety disorders have been available for more than 40 years, 30-50% of depressed patients and 25% of patients with anxiety disorder do not respond sufficiently to first-line treatment with antidepressants. Genetic factors are supposed to play a major role in both variation of treatment response and incidence of adverse effects to medication. So far, candidate genes of pharmacokinetic and pharmacodynamic pathways of antidepressants have been investigated, and associations between several candidate genes and response to antidepressants are reported. Two functional polymorphisms of the serotonin transporter gene, 5-HTTLPR and STin2 have been investigated in a large number of pharmacogenetic studies of depression; other candidate genes include serotonin receptor genes, brain-derived neurotrophic factor, P-glycoprotein (located in the blood-brain barrier), G-proteins, TPH1 and TPH2, MAOA, the noradrenaline transporter gene, FKBP5, or cytochrome P450 (CYP450) genes. CYP450 genes play a major role in the metabolism of a substantial part of psychotropics, including antidepressants, and the first estimates of dosage adjustments for antidepressants have been provided based on metabolizer status. Genome-wide association studies that use large numbers of single-nucleotide polymorphisms to screen the entire genome for alleles that influence a trait are now feasible, and the results of the first genome-wide association studies of antidepressant treatment outcome will soon be available. The current review not only updates pharmacogenetic research in depression but also focuses on antidepressant treatment response in anxiety disorders.

Trait Anxiety and Defensive Functioning in Relation to Antidepressant Treatment Outcome

Background: Depression can occur in patients with or without trait anxiety. Although it is assumed that assessment of defenses can be useful in planning biological treatment, no studies have confirmed this hypothesis. In this study we focus on the relation between trait anxiety and defensive functioning, and on the combined influence of these personality characteristics on response to antidepressants among inpatients with a major depressive episode. Methods: Major depressive episode was diagnosed using the Schedule for Affective Disorders and Schizophrenia (SADS) and the severity of the depression was measured with the Hamilton Rating Scale for Depression (HAM-D). The level of trait anxiety was assessed using a questionnaire with 34 questions pertaining to trait anxiety. The Defense Style Questionnaire (DSQ 88) was used to assess defensive functioning followed by a weighted overall defensive functioning score (ODF). Partial correlations and multiple regression analyses were used to analyze the data. Results: The final sample included 85 patients. A significant negative effect of trait anxiety by ODF (p: 0.000) was found on the outcome score, i.e. the combination of a high score on trait anxiety and a low score on the ODF resulted in a significantly higher final score on the HAM-D. Conclusions: The most important finding in this study is that the combination of a high level of trait anxiety and immature defensive functioning evidently had a negative effect on antidepressant treatment outcome.

A Genomewide Association Study Points to Multiple Loci That Predict Antidepressant Drug Treatment Outcome in Depression

The efficacy of antidepressant drug treatment in depression is unsatisfactory; 1 in 3 patients does not fully recover even after several treatment trials. Genetic factors and clinical characteristics contribute to the failure of a favorable treatment outcome. To identify genetic and clinical determinants of antidepressant drug treatment outcome in depression. Genomewide pharmacogenetic association study with 2 independent replication samples. We performed a genomewide association study in patients from the Munich Antidepressant Response Signature (MARS) project and in pooled DNA from an independent German replication sample. A set of 328 single-nucleotide polymorphisms highly related to outcome in both genomewide association studies was genotyped in a sample of the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study. A total of 339 inpatients with a depressive episode (MARS sample), a further 361 inpatients with depression (German replication sample), and 832 outpatients with major depression (STAR*D sample). We generated a multilocus genetic variable that described the individual number of alleles of the selected single nucleotide polymorphisms associated with beneficial treatment outcome in the MARS sample ("response" alleles) to evaluate additive genetic effects on antidepressant drug treatment outcome. Multilocus analysis revealed a significant contribution of a binary variable that categorized patients as carriers of a high vs low number of response alleles in the prediction of antidepressant drug treatment outcome in both samples (MARS and STAR*D). In addition, we observed that patients with a comorbid anxiety disorder combined with a low number of response alleles showed the least favorable outcome. These results demonstrate the importance of multiple genetic factors combined with clinical features in the prediction of antidepressant drug treatment outcome, which underscores the multifactorial nature of this trait.