Antidepressant Treatment In Major Depression Research Articles

AT1 -R is involved in the development of long-lasting, region-dependent and oxidative stress-independent astrocyte morphological alterations induced by Ketamine.

Astrocytes play an essential role in the genesis, maturation and regulation of the neurovascular unit. Multiple evidence support that astrocyte reactivity has a close relationship to neurovascular unit dysfunction, oxidative stress and inflammation, providing a suitable scenario for the development of mental disorders. Ketamine has been proposed as a single-use antidepressant treatment in major depression, and its antidepressant effects have been associated with anti-inflammatory properties. However, Ketamine long-lasting effects over the neurovascular unit components remain unclear. Angiotensin II AT1 receptor (AT1 -R) blockers have anti-inflammatory, antioxidant and neuroprotective effects. The present work aims to distinguish the acute and long-term Ketamine effects over astrocytes response extended to other neurovascular unit components, and the involvement of AT1 -R, in prefrontal cortex and ventral tegmental area. Male Wistar rats were administered with AT1 -R antagonist Candesartan/Vehicle (days 1-10) and Ketamine/Saline (days 6-10). After 14days drug-free, at basal conditions or after Ketamine Challenge, the brains were processed for oxidative stress analysis, cresyl violet staining and immunohistochemistry for glial, neuronal activation and vascular markers. Repeated Ketamine administration induced long-lasting region-dependent astrocyte reactivity and morphological alterations, and neuroadaptative changes observed as exacerbated oxidative stress and neuronal activation, prevented by the AT1 -R blockade. Ketamine Challenge decreased microglial and astrocyte reactivity and augmented cellular apoptosis, independently of previous treatment. Overall, AT1 -R is involved in the development of neuroadaptative changes induced by repeated Ketamine administration but does not interfere with the acute effects supporting the potential use of AT1 -R blockers as a Ketamine complementary therapy in mental disorders.

Qualitative treatment-subgroup interactions in the antidepressant treatment of major depression: Application of QUINT to individual participant data from seven placebo-controlled randomized controlled trials

BackgroundPersonalized medicine in depression has been much discussed but has seen little success so far. We applied Qualitative interaction trees (QUINT), a recently developed method that focuses on qualitative, rather than quantitative, treatment-subgroup interactions, to identify subgroups of patients for whom efficacy of antidepressants may vary. MethodsWe had direct access to four placebo-controlled randomized trials of antidepressants and remote access to three trials. We applied QUINT to the first half of the first four trials (the derivation set, n = 704). We used 15 baseline demographic or clinical variables as candidate effect modifiers. We then tested the temporal validity of the obtained subgroups with the second half of the first four trials (the temporal validation set, n = 778), and their external validity with the remaining three trials (the external validation set, n = 1321). Results“Years since onset” and “Sex” were retained in the final model. The antidepressants were significantly inferior to placebo among men with recent onset of depression, not significantly so among women with recent onset, but was significantly superior among men and women whose onset of depression was one or more years before treatment commencement. The ordering of the subgroups in terms of antidepressant efficacy was replicated in the temporal validation set but was poorly replicated in the external validation set. ConclusionTime since illness onset and sex may be important effect modifiers. However, the models need external validation. To advance personalized medicine in psychiatry, concerted efforts are called for to obtain larger datasets with common key measurements.

Exploratory analyses of effect modifiers in the antidepressant treatment of major depression: Individual-participant data meta-analysis of 2803 participants in seven placebo-controlled randomized trials

BackgroundIt is clinically important to know who are likely to respond more or less to antidepressants. However, meaningful effect modifiers (variables associated with differential response depending on the treatment) are yet to be identified. MethodsWe conducted individual participant data (IPD) meta-analysis and meta-regression to explore effect modifiers in placebo-controlled antidepressant trials conducted so far in Japan. ResultsWe obtained access to IPD from seven placebo-controlled trials comparing bupropion, duloxetine, escitalopram, mirtazapine, paroxetine or venlafaxine with placebo in the acute phase treatment of major depression (total n = 2803). The higher the guilt subscale score of the baseline Hamilton Rating Scale for Depression (HRSD), the greater the difference in reduction in depression severity between the antidepressants and placebo at week 6, while the older the current age or the age at onset, the smaller the difference. At week 8, the guilt subscale score of HRSD and presence of suicidal ideation at baseline predicted greater, and the anhedonia subscale and insomnia subscale scores of HRSD and early response at week 2 predicted smaller, difference in reduction. LimitationsDifferent studies measured different sets of baseline variables and we were able to analyze only a limited set of candidate variables for effect modification. ConclusionAge, age at onset, several HRSD subscales including guilt, anhedonia and insomnia, presence of suicidal ideation at baseline and early response are potential effect modifiers for response to antidepressants in the acute phase antidepressant treatment of major depression. Future trials need to measure these and additional variables in concerted efforts to enable matching of treatments with individual characteristics in depression.

Early change in reward and punishment sensitivity as a predictor of response to antidepressant treatment for major depressive disorder: a CAN-BIND-1 report.

In an effort to optimize patient outcomes, considerable attention is being devoted to identifying patient characteristics associated with major depressive disorder (MDD) and its responsiveness to treatment. In the current study, we extend this work by evaluating whether early change in these sensitivities is associated with response to antidepressant treatment for MDD. Participants included 210 patients with MDD who were treated with 8 weeks of escitalopram and 112 healthy comparison participants. Of the original 210 patients, 90 non-responders received adjunctive aripiprazole for an additional 8 weeks. Symptoms of depression and anhedonia were assessed at the beginning of treatment and 8 weeks later in both samples. Reward and punishment sensitivity were assessed using the BIS/BAS scales measured at the initiation of treatment and 2 weeks later. Individuals with MDD exhibited higher punishment sensitivity and lower reward sensitivity compared with healthy comparison participants. Change in reward sensitivity during the first 2 weeks of treatment was associated with improved depressive symptoms and anhedonia following 8 weeks of treatment with escitalopram. Similarly, improvement in reward responsiveness during the first 2 weeks of adjunctive therapy with aripiprazole was associated with fewer symptoms of depression at post-treatment. Findings highlight the predictive utility of early change in reward sensitivity during antidepressant treatment for major depression. In a clinical setting, a lack of change in early reward processing may signal a need to modify a patient's treatment plan with alternative or augmented treatment approaches.

Comparative effects of antidepressant medications and untreated major depression on pregnancy outcomes: a systematic review.

Psychopharmacological treatment of pregnant women is an area of continued controversy; extensive observational research on the use of antidepressant medications in pregnancy has found these medications to be associated with increased risk of spontaneous abortion, preterm delivery, and low birth weight. However, depression itself has also been associated with increased risk of those same outcomes, and only recently have researchers begun trying to compare treated with untreated depression. The purpose of this study was to conduct a systematic review of the literature to integrate those comparative studies and compare risks and benefits. PubMed, PsycInfo, and CINAHL searches; study selection; and data extraction were carried out using PRISMA guidelines. Eleven prospective observational and case-control studies were selected for final inclusion. Risk of low birth weight and related outcomes do not differ between antidepressant-treated pregnant women and untreated depressed women. Average gestational lengths tend to be slightly shorter with antidepressant use but it is unclear whether these differences are clinically meaningful or extend to preterm delivery. Very limited research on spontaneous abortion did not allow conclusions to be drawn regarding that outcome. The low number of studies meeting criteria highlights the need for further research to aid in risk-benefit analysis for women considering antidepressant use in pregnancy. While further research is necessary, discontinuing antidepressant treatment of major depression in pregnancy due to concerns about length of gestation, birth weight, or spontaneous abortion is not supported by the evidence available at this time.

PS82. Does Serum Amyloid ß-Protein predict the Response to Antidepressant treatment in Major Depression?

PS82. Does Serum Amyloid ß-Protein predict the Response to Antidepressant treatment in Major Depression?

Brain Structural Effects of Antidepressant Treatment in Major Depression.

Depressive disorder is a very frequent and heterogeneous syndrome. Structural imaging techniques offer a useful tool in the comprehension of neurobiological alterations that concern depressive disorder. Altered brain structures in depressive disorder have been particularly located in the prefrontal cortex (medial prefrontal cortex and orbitofrontal cortex, OFC) and medial temporal cortex areas (hippocampus). These brain areas belong to a structural and functional network related to cognitive and emotional processes putatively implicated in depressive symptoms. These volumetric alterations may also represent biological predictors of response to pharmacological treatment. In this context, major findings of magnetic resonance (MR) imaging, in relation to treatment response in depressive disorder, will here be presented and discussed.

A Serum Analysis before and after Antidepressant Treatment in Major Depression: A Pilot Study

We investigated the serum protein profiles of subjects with major depressive disorder (MDD), with (n = 4) and without clinical improvement (n = 4), at the initiation of antidepressant treatment (venlafaxine) (T0) and 4 weeks later (T28), by difference gel electrophoresis in two dimensions (2D-DIGE) and mass spectrometry. The nine proteins displaying differences in composition between the two time points in the group with clinical improvement between T0 and T28 included gelsolin, clusterin, and the activated fragment of complement C3 (C3a). We then analyzed serum samples from MDD subjects receiving different antidepressants between T0 and T28. Subjects were classified into two groups, with (n = 17) or without (n = 14) clinical improvement (>50% decrease in baseline Hamilton Depression Rating Scale score), at T28. Clusterin levels did not differ between groups at either time point. Gelsolin and C3a levels differed between T0 and T28 only in the group presenting clinical improvement. A comparison with serum samples from controls suggested that the levels of these two proteins changed during MDD and were potentially modified after successful antidepressant treatment. Despite the small sample size, the results of this pilot study suggest that several changes in the expression of some serum proteins occur in association with the clinical relevance of the treatment, and indicate changes to general pathways requiring further study.

Placebo for depression: we need to improve the quality of scientific information but also reject too simplistic approaches or ideological nihilism.

The placebo response plays a major role in psychiatry, particularly in depression. A new network meta-analysis investigates whether the effects of placebo vary in studies comparing fluoxetine and venlafaxine, two widely prescribed antidepressants. Even though data from this article indicate that the effects of placebos do not differ, publication bias cannot be ruled out. The authors use their finding to criticise the paradigm of evidence-based medicine, questioning whether there is anything certain in psychiatry and, more precisely, in the field of antidepressant treatment for major depression. This study stimulates the debate about validity of scientific knowledge in medicine and highlights the importance of considering things from a different perspective. However, the authors’ view should be considered with caution. As clinicians, we make decisions every day, integrating individual clinical expertise and patients’ preferences and values with the best, up-to-date research data. The quality of scientific information must be improved, but we still think that valid conclusions to help clinical practice can be drawn from a critical and cautious use of the best available, if flawed, evidence.Please see related articles: http://www.biomedcentral.com/1741-7015/11/230 and http://www.biomedcentral.com/1741-7015/12/106.

Race, Genetic Ancestry and Response to Antidepressant Treatment for Major Depression

The Sequenced Treatment Alternatives to Relieve Depression (STAR*D) Study revealed poorer antidepressant treatment response among black compared with white participants. This racial disparity persisted even after socioeconomic and baseline clinical factors were taken into account. Some studies have suggested genetic contributions to this disparity, but none have attempted to disentangle race and genetic ancestry. Here we used genome-wide single-nucleotide polymorphism (SNP) data to examine independent contributions of race and genetic ancestry to citalopram response. Secondary data analyses included 1877 STAR*D participants who completed an average of 10 weeks of citalopram treatment and provided DNA samples. Participants reported their race as White (n=1464), black (n=299) or other/mixed (n=114). Genetic ancestry was estimated by multidimensional scaling (MDS) analyses of about 500 000 SNPs. Ancestry proportions were estimated by STRUCTURE. Structural equation modeling was used to examine the direct and indirect effects of observed and latent predictors of response, defined as change in the Quick Inventory of Depressive Symptomatology (QIDS) score from baseline to exit. Socioeconomic and baseline clinical factors, race, and anxiety significantly predicted response, as previously reported. However, direct effects of race disappeared in all models that included genetic ancestry. Genetic African ancestry predicted lower treatment response in all models. Although socioeconomic and baseline clinical factors drive racial differences in antidepressant response, genetic ancestry, rather than self-reported race, explains a significant fraction of the residual differences. Larger samples would be needed to identify the specific genetic mechanisms that may be involved, but these findings underscore the importance of including more African-American patients in drug trials.

A pilot dose-finding clinical trial of creatine monohydrate augmentation to SSRIs/SNRIs/NASA antidepressant treatment in major depression

Creatine's effects on brain energy metabolism raise the possibility of developing a new therapeutic strategy in depression focusing on the treatment of metabolic hypoactive brain areas. Previous creatine augmentation studies in patients with major depression showed a beneficial effect. Eighteen patients (14 women) with major depression not responding to previous 3 weeks of antidepressant treatment were enrolled into a pilot, dose finding, 4-week double-blind parallel augmentation study where creatine monohydrate 5 or 10 g daily or placebo was added to ongoing SSRIs/SNRIs/NASA treatment. Rating scales included the Hamilton Depression Rating Scale and the Clinical Global Impression Severity scale. Overall, there was no difference between creatine administered at 5 or 10 g daily and its corresponding placebos. Two female patients on creatine augmentation, but none on the placebo, showed early improvement of more than 50% reduction in Hamilton Depression Rating Scale after 2 weeks of creatine treatment. No clinically relevant side effects were reported. This preliminary study seems to suggest that the strategy using creatine augmentation in major depressive women showing no 'real-life response' to 3 weeks of treatment with SSRIs/SNRIs/NASA treatment is of no advantage compared with placebo. However, such creatine augmentation may still induce a more rapid response in a small subgroup of these female patients.

Comments on ‘What is a rational antidepressant treatment for major depression in patients with Parkinson's disease?’

DR HAGIKURA AND COLLEAGUES successfully illustrated the potentiality of mirtazapine for treating depression in patients with Parkinson's disease (PD), providing clinically relevant action mechanisms concerning blockade of serotonin 5-HT3 and 5-HT2A receptors, which may result in less dopamine-related side-effects (e.g., loss of appetite and nausea) and extrapyramidal symptoms.1 Here, I would like to add and update biological treatment issues to the authors' suggestions. Although the first randomized controlled trial (RCT)2 has suggested the superiority of older antidepressants, such as nortriptyline, over paroxetine, and previous studies have frequently reported that selective serotonin re-uptake inhibitors (SSRIs) may be no more effective than placebo in PD patients with depression, another recent, adequately powered RCT has demonstrated comparable efficacy and safety of paroxetine in PD patients.3 In fact, even though SSRIs are commonly prescribed for PD patients with depression in clinical practice, clinical trial data favoring dual-re-uptake inhibitors (e.g., venlafaxine) over SSRIs have been increasing recently.4 Hence, large-scale subsequent studies with broader entrance criteria and antidepressants acting on multiple neurotransmitters other than serotonin are particularly needed to establish advanced treatment options for such patients.2-4 Clinical heterogeneity of depression symptom profile should also be taken into account in selection of antidepressants as some PD patients may suffer more anxiety, agitation, and disturbance in sleep, while others may feel more concentration difficulties, lack of energy/interest, feeling hopeless, and somnolence.4 Discrete consideration of the pharmacodynamic profile of individual antidepressants should also be kept in mind. In addition, we may have effective augmentation agents for antidepressants to be continuously explored in PD patients with depression. In fact, a recent RCT has clearly demonstrated the efficacy and safety of omega-3 fatty acid as augmentation treatment or monotherapy for treating depression in PD patients.5 Preliminary studies also suggest that repetitive trans-cranial magnetic stimulation (rTMS) may be effective for treating depression in PD patients, especially for such patients with tolerability issues.4 Finally, the American Academy of Neurology declared that there is insufficient evidence to recommend specific antidepressant treatments for MDD in PD patients. Therefore, currently available evidence proposes that the choice of antidepressants to treat PD patients with depression should be tailored to the individual's clinical situation, including PD medications and lifestyle characteristics, based on careful consideration of benefits and risks.

P.2.c.026 Early increase in the neuronal marker N-acetyl-aspartate with antidepressant treatment of major depression

P.2.c.026 Early increase in the neuronal marker N-acetyl-aspartate with antidepressant treatment of major depression

What is a rational antidepressant treatment for major depression in patients with Parkinson's disease?

What is a rational antidepressant treatment for major depression in patients with Parkinson's disease?

Early increase in marker of neuronal integrity with antidepressant treatment of major depression: 1H-magnetic resonance spectroscopy of N-acetyl-aspartate

Increasing interest surrounds potential neuroprotective or neurotrophic actions of antidepressants. While growing evidence points to important early clinical and neuropsychological effects of antidepressants, the time-course of any effect on neuronal integrity is unclear. This study used magnetic resonance spectroscopy to assess effects of short-term treatment with escitalopram on N-acetyl-aspartate (NAA), a marker of neuronal integrity. Thirty-nine participants with major depression were randomly assigned to receive either 10 mg escitalopram or placebo daily in a double-blind, parallel group design. On the seventh day of treatment, PRESS data were obtained from a 30×30×20 mm voxel placed in medial frontal cortex. Age and gender-matched healthy controls who received no treatment were also scanned. Levels of NAA were significantly higher in patients treated with escitalopram than in either placebo-treated patients (p<0.01) or healthy controls (p<0.01). Our findings are consistent with the proposition that antidepressant treatment in depressed patients can produce early changes in neuronal integrity.

P-514 - Wakefulness regulation and the prediction of antidepressant treatment in major depression

The vigilance regulation model of affective disorders suggests that tonically high vigilance (i.e. brain arousal) in patients with major depression (MD) induces social withdrawal and sensation avoidance as autoregulatory reactions to decrease external stimulation. A computer based algorithm (VIGALL) has been developed that allows the classification of EEG-vigilance time series. Validation studies revealed a close association of EEG-vigilance stages and autonomous nervous system (ANS) activity and proved the discriminative power of VIGALL by showing that patients with MD reveal a more stable EEG-vigilance regulation compared to healthy controls. Before this background the question raises, whether vigilance regulation patterns could also be used for treatment prediction in MD. The predictive power of three different pre-treatment EEG-vigilance regulation patterns was analyzed in 33 previously unmedicated patients with MD. Results will be presented that show differences of frequency distribution of vigilance regulation patterns in responders and non-responders, defined by a reduction more or less than 30% in Hamilton Depression Rating Scale after two weeks of treatment with an SSRI or mirtazapine. Additionally, differences of ANS activity by means of heart rate variability between responders and non-responders will be shown. The results will be discussed within the light of a possible dysregulation of cortical and autonomous arousal in MD. Also the usage of EEG-vigilance regulation patterns as a biomarker for antidepressant treatment outcome in MD will be adressed.

Treatment response in major depression: effects of personality dysfunction and prior depression

The impact of personality dysfunction on the outcome of treatment for depression remains debated. To examine the relationship between the number of prior depressive episodes, personality dysfunction and treatment response for depression. In a large sample (n = 8229) of adult out-patients with a major depressive episode (DSM-IV), personality dysfunction was assessed using the Standardised Assessment of Personality - Abbreviated Scale (SAPAS). Potential predictors of treatment response at 6 weeks were examined via structural equation modelling. The amount of personality dysfunction and number of prior episodes of depression were both associated with poor response to treatment. Once personality dysfunction was controlled for, the number of prior episodes of depression was not associated with treatment response. Personality dysfunction is associated with impaired short-term response to antidepressant treatment in major depression. The apparent detrimental effect of prior depression on treatment response may be accounted for by pre-existing personality dysfunction.

Placebo and Antidepressant Treatment for Major Depression

Antidepressant medication is generally considered the primary treatment for major depressive disorder (MDD), but recently antidepressant treatment has approached a crisis with current trials showing shrinking specific effects and growing placebo responses. The aim of the paper is to review the placebo problem within antidepressant treatment for MDD and to draw lines to similar problems within the field of psychotherapy. Although clinicians may profit from the large placebo response in their treatment of MDD, the small differences between active treatment and placebo groups found in controlled studies should be considered a reminder that there is a need for more efficacious treatments for MDD, medical as well as psychological.

Antidepressant Treatment for Major Depression in Multiple Sclerosis

Major depressive disorder (MDD) is widely acknowledged to be an important clinical issue in multiple sclerosis (MS). Although antidepressant medications are generally regarded as efficacious, few studies have been conducted on their use in MS patients. Recently a randomized controlled trial reported negative results, raising new questions about the efficacy of these medications in this population. The objective of this review was to revisit the question of the efficacy of antidepressant medications in the treatment of MDD in MS. A literature search uncovered only three randomized controlled trials on this topic. These studies differed in their methodology, including the specific antidepressants used (desipramine, sertraline, paroxetine), the approach to the analysis (two of the three used intention-to-treat analyses), measures of depression (two defined response as a 50% reduction in the Hamilton Depression Rating Scale, and two included the Beck Depression Inventory), methodological features (two used blinding, and one included cases of dysthymia), and duration of follow-up (ranging from 1 to 4 months). Nevertheless, all of the results suggested modest therapeutic benefits for the medications evaluated. Although the current literature in this field is inadequate, the best available evidence points toward a modest positive effect of certain medications in the treatment of depression in people with MS.

Efficacy and safety of triiodothyronine supplementation in patients with major depressive disorder treated with specific serotonin reuptake inhibitors

The thyroid hormone, triiodothyronine (T3), is used as a supplement to antidepressant treatment of major depression, to accelerate and enhance response and as an augmenter in patients who have not responded. While there is support from controlled trials and meta-analyses for the use of T3 in conjunction with tricyclic antidepressants, the evidence base for supplementation of specific serotonin reuptake inhibitors (SSRIs) with T3 is more limited. We reviewed the available literature on T3 supplementation of SSRIs including open-label studies and randomized controlled trials (RCTs). Five RCTs were identified. Three were enhancement studies in which T3 was administered concurrently with the antidepressant from the start of treatment and two were augmentation studies in which T3 was added to the antidepressant treatment of patients who had not responded. Three open augmentation studies were identified. The RCTs were too disparate in methodology to allow a meta-analysis to be performed. The enhancement studies are inconclusive in that one showed strongly positive effects of T3, one showed no effect and one showed a trend. The open augmentation studies supported an effect of T3 in SSRI non-responsive patients with some support from a large RCT; a smaller, underpowered RCT did not show efficacy. T3 was well tolerated in most of the studies and adverse effects do not seem to be an impediment to clinical use. Some of the studies identified clinical and thyroid function correlates of response that require further investigation. Further research is needed before it can be definitively established whether T3 is an effective supplement to SSRIs in patients with MDD. The appropriate timing of T3 supplementation needs to be explored and also the dose and length of treatment.