Ongoing Antidepressant Treatment Research Articles

Heterogeneity in Antidepressant Treatment and Major Depressive Disorder Outcomes Among Clinicians

While abundant work has examined patient-level differences in antidepressant treatment outcomes, little is known about the extent of clinician-level differences. Understanding these differences may be important in the development of risk models, precision treatment strategies, and more efficient systems of care. To characterize differences between outpatient clinicians in treatment selection and outcomes for their patients diagnosed with major depressive disorder across academic medical centers, community hospitals, and affiliated clinics. This was a longitudinal cohort study using data derived from electronic health records at 2 large academic medical centers and 6 community hospitals, and their affiliated outpatient networks, in eastern Massachusetts. Participants were deidentified clinicians who billed at least 10 International Classification of Diseases, Ninth Revision (ICD-9) or Tenth Revision (ICD-10) diagnoses of major depressive disorder per year between 2008 and 2022. Data analysis occurred between September 2023 and January 2024. Heterogeneity of prescribing, defined as the number of distinct antidepressants accounting for 75% of prescriptions by a given clinician; proportion of patients who did not return for follow-up after an index prescription; and proportion of patients receiving stable, ongoing antidepressant treatment. Among 11 934 clinicians treating major depressive disorder, unsupervised learning identified 10 distinct clusters on the basis of ICD codes, corresponding to outpatient psychiatry as well as oncology, obstetrics, and primary care. Between these clusters, substantial variability was identified in the proportion of selective serotonin reuptake inhibitors, selective norepinephrine reuptake inhibitors, and tricyclic antidepressants prescribed, as well as in the number of distinct antidepressants prescribed. Variability was also detected between clinician clusters in loss to follow-up and achievement of stable treatment, with the former ranging from 27% to 69% and the latter from 22% to 42%. Clinician clusters were significantly associated with treatment outcomes. Groups of clinicians treating individuals diagnosed with major depressive disorder exhibit marked differences in prescribing patterns as well as longitudinal patient outcomes defined by electronic health records. Incorporating these group identifiers yielded similar prediction to more complex models incorporating individual codes, suggesting the importance of considering treatment context in efforts at risk stratification.

Heterogeneity in Antidepressant Treatment and Major Depressive Disorder Outcomes Among Clinicians.

While abundant work has examined patient-level differences in antidepressant treatment outcomes, little is known about the extent of clinician-level differences. Understanding these differences may be important in the development of risk models, precision treatment strategies, and more efficient systems of care. To characterize differences between outpatient clinicians in treatment selection and outcomes for their patients diagnosed with major depressive disorder across academic medical centers, community hospitals, and affiliated clinics. This was a longitudinal cohort study using data derived from electronic health records at 2 large academic medical centers and 6 community hospitals, and their affiliated outpatient networks, in eastern Massachusetts. Participants were deidentified clinicians who billed at least 10 International Classification of Diseases, Ninth Revision (ICD-9) or Tenth Revision (ICD-10) diagnoses of major depressive disorder per year between 2008 and 2022. Data analysis occurred between September 2023 and January 2024. Heterogeneity of prescribing, defined as the number of distinct antidepressants accounting for 75% of prescriptions by a given clinician; proportion of patients who did not return for follow-up after an index prescription; and proportion of patients receiving stable, ongoing antidepressant treatment. Among 11 934 clinicians treating major depressive disorder, unsupervised learning identified 10 distinct clusters on the basis of ICD codes, corresponding to outpatient psychiatry as well as oncology, obstetrics, and primary care. Between these clusters, substantial variability was identified in the proportion of selective serotonin reuptake inhibitors, selective norepinephrine reuptake inhibitors, and tricyclic antidepressants prescribed, as well as in the number of distinct antidepressants prescribed. Variability was also detected between clinician clusters in loss to follow-up and achievement of stable treatment, with the former ranging from 27% to 69% and the latter from 22% to 42%. Clinician clusters were significantly associated with treatment outcomes. Groups of clinicians treating individuals diagnosed with major depressive disorder exhibit marked differences in prescribing patterns as well as longitudinal patient outcomes defined by electronic health records. Incorporating these group identifiers yielded similar prediction to more complex models incorporating individual codes, suggesting the importance of considering treatment context in efforts at risk stratification.

Omega-3 fatty acids for inflamed depression – A match/mismatch study

Despite decades of research on the pathophysiology of depression, the development of new therapeutic interventions has been slow, and no biomarkers of treatment response have been clinically implemented. Several lines of evidence suggest that the clinical and biological heterogeneity among patients with major depressive disorder (MDD) has hampered progress in this field. MDD with low-grade inflammation – “inflamed depression” – is a subtype of depression that may be associated with a superior antidepressant treatment response to anti-inflammatory compounds. Omega-3 fatty acid eicosapentaenoic acid (EPA) has anti-inflammatory properties, and preliminary data suggest that it may be particularly efficacious in inflamed depression. In this study we tested the hypothesis that add-on EPA has greater antidepressant efficacy in MDD patients with high baseline high-sensitivity C-reactive protein (hs-CRP) compared to MDD patients with low hs-CRP. All subjects received 2.2 g EPA, 400 mg docosahexaenoic acid and 800 mg of other fatty acids daily for 8 weeks, added to stable ongoing antidepressant treatment. The primary outcome was change in the 17-item Hamilton Depression Rating Scale (HAMD-17). Patients and raters were blind to baseline hs-CRP status. In an intention-to-treat analysis including all subjects with at least one post baseline visit (n = 101), ahs-CRPcut-off of ≥1 mg/L, but not ≥3 mg/L, was associated with a greater improvement in HAMD-17 total score. In addition to a general antidepressant effect among patients with hs-CRP ≥ 1 mg/L, adjuvant EPA treatment improved symptoms putatively related to inflamed depression such as fatigue and sleep difficulties. This adds to the mounting evidence that delineation of MDD subgroups based on inflammation may be clinically relevant to predict treatment response to anti-inflammatory interventions.

Cariprazine augmentation in patients with treatment resistant unipolar depression who failed to respond to previous atypical antipsychotic add-on. A case-series

Among individuals receiving an adequate pharmacological treatment for Major Depressive Disorder (MDD), only 30% reach a full symptom recovery; the remaining 70% will experience either a pharmacological response without remission or no response at all thus configuring treatment resistant depression (TRD). After an inadequate response to an antidepressant, possible next step options include optimizing the dose of the current antidepressant, switching to a different antidepressant, combining antidepressants, or augmenting with a non-antidepressant medication. Augmentation strategies with the most evidence-based support include atypical antipsychotics (AAs). Few data are available in literature about switching to another antipsychotic when a first augmentation trial has failed. We present a case-series of patients with unipolar treatment resistant depression who were treated with a combination of antidepressant and low dose of cariprazine after failing to respond to a first augmentation with another AA. We report data about ten patients affected by unipolar depression, visited at the outpatients unit of Mental Health Department of ASL CN2 of Bra and NA1 of Napoli (Italy). All patients failed to respond to conventional antidepressant therapy. A low dose of AA (aripiprazole, risperidone or brexpiprazole) was added for one month to the ongoing antidepressant treatment without clinical improvement. A second augmentation trial was then made with cariprazine. Seven out of ten patients were responders at the end of period, of them 1 patient reached responder status by week 2. HAM-D mean scores decreased from 23.9 ± 3.9 (baseline) to 14.8 ± 5.3 (4 weeks). Cariprazine was well tolerated, no severe side effect was observed during the trial. Our sample of treatment resistant unipolar patients showed good response to augmentation with cariprazine. Failure to a first AA-augmentation trial does not preclude response to a second one. This preliminary result requires confirmation through more rigorous studies conducted over greater samples.

Adjunctive Cariprazine in Patients With Major Depressive Disorder: Post Hoc Analysis of Efficacy by Baseline Antidepressant Response

AbstractIntroductionPatients with major depressive disorder (MDD) often have inadequate response to antidepressant treatment (ADT) requiring augmentation with other treatments. Cariprazine is a D3-preferring D3/D2 and serotonin 5-HT1A receptor partial agonist approved to treat schizophrenia and manic, mixed, and depressive episodes of bipolar I disorder. The efficacy of cariprazine as an adjunctive treatment for patients with MDD and inadequate response to ADT alone has been evaluated in phase 2/3 randomized, double-blind, placebo-controlled trials. Post hoc analyses of one phase 3 trial (NCT03738215) evaluated cariprazine + ADT for improving depressive symptoms in subgroups of patients categorized by 1) the level of response to ongoing ADT at baseline and 2) the number of ADTs associated with inadequate response during the current episode.MethodsPatients were randomized to placebo + ADT (n=254), cariprazine 1.5 mg/d + ADT (n=252), or cariprazine 3 mg/d + ADT (n=253) for 6 weeks of double-blind treatment. Post hoc analyses evaluated change from baseline to week 6 in MADRS total score in subgroups of patients who had ≥25%–<50% or <25% response to ongoing ADT at baseline, and in subgroups of patients who had inadequate response to 1 or ≥2 ADTs in the current episode. Analyses used a mixed-effects model for repeated measures; least squares mean differences (LSMD) versus placebo with 95% confidence interval (95% CI) were calculated.ResultsAt baseline, 65.1% (n=486) of patients had an ADT response level between 25%–<50% and 34.9% (n=261) of patients had an ADT response level <25%. Mean MADRS total score reductions were greater for cariprazine 1.5 mg/d + ADT versus placebo + ADT in both ADT response subgroups (25%–<50% ADT response: -14.8 vs -11.9, LSMD [95% CI]=-2.3 [-4.2, -0.3]; <25% response to ADT: (-14.7 vs -11.7, LSMD [95% CI]=-2.6 [-5.5, 0.3]). For cariprazine 3 mg/d + ADT, mean change in MADRS total score was numerically greater versus placebo in both response subgroups (25%–<50% response=-14.2, LSMD [95% CI]=-1.5 [-3.5, 0.4]; <25% response= -12.3, LSMD [95% CI]=-0.74 [-3.6, 2.1]). Approximately 86% (n=644) and 14% (n=105) of patients in this study had inadequate response to 1 ADT or ≥2 ADTs, respectively, during the current episode. The LSMD (95% CI) in MADRS total score change for cariprazine 1.5 mg/d + ADT versus placebo + ADT was -2.3 (-4.1, -0.6) in the subgroup of patients with 1 previous ADT and -3.2 [-7.1, 0.8]) in the subgroup of patients with ≥2 previous ADTs. For cariprazine 3 mg/d + ADT, the LSMD (95% CI) in MADRS total score change versus placebo was -0.7 (-2.5, 1.0) in the 1 previous ADT subgroup and -4.7 (-8.8, -0.6) in the ≥2 previous ADTs subgroup.ConclusionsIn these post hoc analyses, cariprazine + ADT was associated with greater reductions in MADRS total score versus placebo regardless of the level of response to ongoing ADT at baseline or number of prior ADT failures in the current episode.FundingAbbVie

The Antidepressant Effect of Ketamine Is Dampened by Concomitant Benzodiazepine Medication

The rapid antidepressant effect of ketamine has become a breakthrough in the research and treatment of depression. Although predictive and modulating factors of the response to ketamine are broadly studied, little is known about optimal concurrent medication protocols. Concerning gamma-aminobutyric acid neurotransmission being a shared target for both ketamine and benzodiazepines (BZD), we evaluated the influence of BZD on the antidepressant effect of a single ketamine infusion in depressed patients. Data from 47 patients (27 females) with major depression (MADRS ≥ 20, ≥ 1 prior nonresponse to antidepressant treatment in current episode) who participated in two previous studies (EudraCT Number: 2009-010625-39 and 2013-000952-17) entered the analysis. All of the subjects were given an infusion of a subanesthetic dose of racemic ketamine (0.54 mg per kg) as an add-on medication to ongoing antidepressant treatment. Thirteen patients (28%) reached ≥ 50% reduction in MADRS within one week after ketamine administration. Nineteen (40%) patients took concomitant benzodiazepines on a daily basis. The doses of BZDs were significantly higher in nonresponders (p=0.007). ROC analysis distinguished responders from nonresponders by a criterion of >8mg of diazepam equivalent dose (DZ equivalent) with a sensitivity of 80% and a specificity of 85% (p<0.001). RM-ANOVA revealed a different time pattern of response to ketamine between the BZD+ (>8mg of DZ equivalent) and BZD− (≤8mg of DZ equivalent) groups, with a significantly worse outcome in BZD+ on day 3 (p=0.04) and day 7 (p=0.02). The results of the study indicate that concomitant benzodiazepine treatment in higher doses may attenuate ketamine’s antidepressant effect. The pathophysiological, clinical and methodological implications of this finding should be considered in future research and ketamine treatment.

Risk and risk factors for disability pension among patients with treatment resistant depression\u2013 a matched cohort study

BackgroundTreatment resistant depression (TRD) is common among patients with depression, and is associated with clinical and functional disability. However, the risk and risk factors for being granted disability pension (DP) among patients with TRD have not been investigated.MethodsAll antidepressant initiators in Sweden with a diagnosis of depression in specialized care were identified in nationwide registers 2006–2013 and followed regarding treatment trials. TRD was defined as the start of a third sequential trial. Patients with TRD who were not on DP (N = 3204) were matched by age, sex, history of depression, calendar year, and time for treatment start with 3204 comparators with depression and ongoing antidepressant treatment. A proportional Cox Regression was performed with DP as outcome, adjusted for various sociodemographic and clinical covariates.ResultsCompared to the comparison cohort, TRD was associated with a doubled risk for all-cause DP (aHR 2.07; 95%CI 1.83–2.35), DP due to depression (2.28; 1.82–2.85) and to any mental disorder (2.24; 1.95–2.57) but not due to somatic diagnoses (1.25; 0.84–1.86). Among significant risk factors for DP in TRD were female sex, being > 29 years of age, unemployment and a diagnosis of comorbid personality disorder (ICD-10 codes F60.0–9).ConclusionTRD is associated with an elevated risk for DP compared to other patients with depression, with large potential costs for the affected patients and for society. Clinical and therapeutic implications for patients with TRD who are granted DP should be further investigated. Limitation: No clinical data, e.g. type of depression or reason for treatment switch, was available for this study.

Efficacy of single and repeated administration of ketamine in unipolar and bipolar depression: a meta-analysis of randomized clinical trials

BackgroundDue to unmet clinical needs for efficient drugs with a rapid onset of antidepressant effects, we aimed to evaluate the efficacy of single-dose ketamine in different subgroups of patients with major depression and establish whether repeated ketamine administration could be a viable strategy to maintain treatment gains.MethodsElectronic databases (Medline via PubMed, Embase, Cochrane Library, Trip Database) were systematically searched until February 22, 2019, for published peer-reviewed randomized controlled trials (RCTs) concerning a single and repeated administration of ketamine in patients with major depression. All relevant RCTs were selected and critically appraised, and a meta-analysis of eligible studies was performed.ResultsA total of 20 studies were included in the meta-analysis. The largest effect of ketamine vs. controls in reducing depressive symptoms was observed at 24 h (SMD = − 0.89; 95% CI − 1.24; − 0.53; p < 0.00001); however, a significant difference was shown for up to 7 days after a single dose. Significant differences compared with controls were observed for up to 7 days in treatment-resistant patients and when ketamine was added to ongoing antidepressant treatment, while there were no significant differences at 7 days when ketamine was used as monotherapy. In patients with major depression, initial antidepressant effects of ketamine were maintained during repeated dosing. At 2–3 weeks of repeated ketamine treatment, significant reduction of depression severity scores was observed: SMD = − 0.70; 95% CI − 1.15; − 0.25 or SMD = − 0.81; 95% CI − 1.41; − 0.20 (depending on the dosing regimen used); p ≤ 0.009 vs placebo.ConclusionsOur meta-analysis revealed rapid and robust antidepressant effects of single-dose ketamine in patients with treatment-resistant depression (TRD). By pooling data from RCTs, we showed for the first time that repeated ketamine administration is effective in sustaining initial antidepressant effects observed after single dosing.

Who is willing to participate in research? A screening model for an anxiety and depression trial in the epilepsy clinic

ObjectiveAnxiety and depression in epilepsy are prevalent, associated with poor outcomes, underrecognized, undertreated, and thus a key area of need for treatment research. The objective of this study was to assess factors associated with research participation among epilepsy clinic patients who screened positive for anxiety or depression. This was accomplished by characterizing clinical and psychiatric factors among patients seen in an epilepsy clinic and evaluating which factors were associated with consent for potential research participation, via a combined clinical and research screening model. MethodsIn a pragmatic trial of anxiety and depression treatment in epilepsy, individuals with a positive screen for anxiety and/or depression at a routine epilepsy clinic visit were invited to opt-in (via brief electronic consent) to further eligibility assessment for a randomized treatment study. Information on psychiatric symptoms and treatment characteristics were collected for dual clinical care and research screening purposes. Cross-sectional association of demographic, clinical, and psychiatric factors with opting-in to research was analyzed by multiple logistic regression. ResultsAmong N = 199 unique adults with a first positive screen for anxiety and/or depression among 786 total screening events, 154 (77.4%) opted-in to further potential research assessment. Higher depression scores and current treatment with an antidepressant were independently associated with opting-in to research (depression odds ratio (OR) = 1.13 per 1-point increase in Neurological Disorders Depression Inventory-Epilepsy (NDDI-E) score, p = 0.028, 95% confidence interval (CI): 1.01–1.26; antidepressant OR = 2.37, p = 0.041, CI: 1.04–5.41). Nearly half of the 199 individuals (43.7%) with anxiety and/or depression symptoms were already being treated with an antidepressant, and 46.7% were receiving neither antidepressant therapy nor mental health specialty care. One-quarter (24.1%) reported a past psychiatric hospitalization, yet only half of these individuals were receiving mental health specialty care. SignificanceOur results demonstrate a high willingness to participate in research using a brief electronic consent approach at a routine clinic visit. Adults with persistent anxiety or depression symptoms despite antidepressant therapy and those with higher depression scores were more willing to consider a randomized treatment study. This has implications for future study design, as individuals already on treatment or those with more severe symptoms are often excluded from traditional research designs. We also found a high burden of psychiatric disease and high prevalence of persistent symptoms despite ongoing antidepressant treatment.

Early score fluctuation and placebo response in a study of major depressive disorder

Early score fluctuation in double-blind, placebo-controlled studies may affect the reliability of the baseline measurement and adversely affect the eventual study outcome. We examined the effect of early score fluctuation during a 2-week double-blind placebo lead-in period in a phase II, double-blind, placebo-controlled trial of adjunctive s-adenosyl methionine (MSI-195) in MDD subjects who had had an inadequate response to ongoing antidepressant treatment. The overall study failed to meet its specified endpoints.We examined the score trajectories of all placebo-assigned subjects during the double-blind placebo lead-in period and subsequent 6-week treatment period. Placebo-assigned subjects with ≥20% HamD17 or MADRS score fluctuations (improvement or worsening) during the double-blind placebo lead-in period (prior to randomization) had significantly higher rates of placebo response and remission at week 8 compared to subjects with <20% response. A post-hoc analysis of evaluable subjects taken from the ITT population that excluded subjects with ≥20% early score response yielded higher effect sizes for both the HamD17 and MADRS sub-groups and statistical significance for MSI-195 over placebo in the MADRS sub-group (p = 0.012) with an effect size of 0.404.A reliable baseline measure is an asset for signal detection. These post-hoc findings suggest that study designs that anticipate and attempt to manage early response prior to randomization may yield more meaningful outcome data for trials of MDD and possibly other disorders as well.

Trajectories of Acute Antidepressant Efficacy

In patients who are not responding to antidepressant pharmacotherapy, information regarding the future probability of response with the same treatment is scarce. Specifically, it is unclear at what point in time the probability to respond or remit ceases to increase, because few studies report data on response or remission at repeated time points beyond 4 or 8 weeks of treatment. Consequently, treatment recommendations in clinical practice guidelines differ widely. We systematically searched MEDLINE, Embase, PsycINFO, and CENTRAL databases through March 2014 using generic terms for depressive or affective disorders, individual drug names, and placebo (Prospero Registration: CRD42014010105). We identified double-blind, randomized studies with continuous outcome reporting from 4 weeks up to at least 12 weeks that compared antidepressant monotherapy to placebo in adult patients suffering from acute depressive disorder. Data extraction and synthesis followed Cochrane Collaboration guidelines. Primary outcome was response; secondary outcomes were remission and changes in rating scale scores in previously unresponsive patients, respectively. Of 6,043 articles screened, we selected 9 studies including 3,466 patients. Altogether, 21.6% (18.6%, 24.9%) of previously nonresponsive patients achieved response with ongoing antidepressant treatment between weeks 5 and 8, and 9.9% (7.5%, 12.7%), between weeks 9 and 12. Probability of response when taking placebo was 13.0% (9.9%, 16.5%) between weeks 5 and 8 and 2.4% (1.2%, 4.6%) between weeks 9 and 12. Differences in the probability of response between antidepressant and placebo translated into a number needed to treat of 11 after 4 weeks and 17 after 8 weeks. Heterogeneity was low to moderate, and results remained stable across subgroup and sensitivity analyses. In patients unresponsive to antidepressant pharmacotherapy, improvements in psychopathology can be expected with ongoing antidepressant treatment for up to 3 months. After 8 weeks of treatment, improvement with ongoing monotherapy is relatively small.

Early symptomatic improvement affects treatment outcome in a study of major depressive disorder

Early symptomatic improvement immediately following randomization can affect signal detection in clinical trials. The impact of early improvement of the Montgomery-Asberg depression rating scale (MADRS) on eventual treatment outcome was examined in a 6-week, double-blind, placebo-controlled trial of a putative antidepressant (CX157) versus placebo in depressed subjects with major depressive disorder (MDD) who had had an inadequate response to ongoing antidepressant treatment (NCT00739908).MADRS score changes within one week after randomization directly affected treatment outcome at the study endpoint (week 6). The response and remission rates at week 6 increased significantly as the percent of MADRS score improvement increased between baseline and week 1 regardless of treatment assignment. Less MADRS improvement or actual worsening within the first week after randomization was associated with minimal overall MADRS score changes by week 6 in either treatment assignment. Alternatively, CX157 assigned subjects who had ≥30% improvement by week 1 achieved a significantly greater treatment response rate than the matched placebo group at the study endpoint (p = 0.025) that converted the lack of signal detection in the mITT population.This post-hoc analysis highlights the potent effect that early symptomatic improvement immediately following randomization can have on treatment outcome, and is particularly relevant for antidepressant drugs with rapid onset of action. The findings compel further exploration of possible moderating and mediating factors, including the experimental condition itself that can influence early response, and the need to identify “bio-types” within the population of MDD subjects.

Dépression résistante : les autres stratégies thérapeutiques

Non-selective and irreversible MAOI have become as third or fourth-line strategy for the management of treatment-resistant depression. Non-selective and irreversible MAOI requires careful monitoring of drug interactions and dietary restrictions. Nutritional supplements such as omega-3 have been found to produce beneficial effects in the management of treatment-resistant depression when administered in combination with the ongoing antidepressant treatment. The glutamate antagonist ketamine has been found to produce beneficial effects in the management of treatment-resistant depression while administered alone. Dopamine and/or norepinephrine agonists, such as methylphenidate, modafinil or pramipexole, have been found to produce beneficial effects in the management of treatment-resistant depression when administered in combination with the ongoing antidepressant treatment.

Peripheral sub-inflammation is associated with antidepressant consumption in schizophrenia. Results from the multi-center FACE-SZ dataset

ObjectivesThe relation between C-reactive protein (CRP), depression and antidepressant consumption has been well explored in major depressive disorders but not in schizophrenia, which has a high rate of depression comorbidity. The objectives of this study were:– to determine the prevalence of abnormal CRP levels, depression and antidepressant consumption in a multi-center community-dwelling sample of subjects with schizophrenia;– to determine the association between abnormal CRP levels, depression and antidepressant consumption in schizophrenia.MethodTwo hundred and nineteen stable patients with schizophrenia (mean age = 31.6 years, 75.3% male gender) were systematically included in the multicentre network of FondaMental Expert Center for schizophrenia (FACE-SZ) and assessed with Calgary Depression Scale for depression. High sensitivity CRP (hs-CRP) was measured with an assay using nephelometry (Dade Behring). Abnormal CRP level was defined by levels &gt; 3 mg/L. Current medication was recorded.ResultsOverall, 63 subjects (28.8%) were found to have abnormal CRP levels, 43 (20.1%) received a diagnosis of comorbid current depression, and 51 (31.9%) had ongoing antidepressant treatment. In univariate analysis, abnormal CRP levels were found to be significantly associated with metabolic syndrome (P = 0.0011) and with antidepressant consumption (P = 0.01), while depression, psychotic symptomatology, age of onset, illness duration, sociodemographic characteristics, current tobacco or cannabis status were not (all P &gt; 0.05).In a multivariate model, abnormal CRP was highly associated with antidepressant consumption independently of other confounding variables (adjusted odd ratio = 2.9, 95% confidence interval 1.2–6.8).ConclusionAbnormal CRP levels in schizophrenia were found to be associated with antidepressant consumption, but not with depression.Disclosure of interestThe authors have not supplied their declaration of competing interest.

Peripheral sub-inflammation is associated with antidepressant consumption in schizophrenia. Results from the multi-center FACE-SZ data set

ObjectivesThe relation between C-Reactive Protein (CRP), depression and antidepressant consumption has been well explored in major depressive disorders but not in schizophrenia, which has a high rate of depression comorbidity. The objectives of this study were: (i) to determine the prevalence of abnormal CRP levels, depression and antidepressant consumption in a multicenter community-dwelling sample of subjects with schizophrenia (ii) to determine the association between abnormal CRP levels, depression and antidepressant consumption in schizophrenia. Method219 stable patients with schizophrenia (mean age=31.6 years, 75.3% male gender) were systematically included in the multicentre network of FondaMental Expert Center for schizophrenia (FACE-SZ) and assessed with a dedicated electronic medical record including the Structured Clinical Interview for DSM-IV Axis I Disorders and Calgary Depression Scale for depression. High sensitivity CRP (hs-CRP) was measured with an assay using nephelometry (Dade Behring). Abnormal CRP level was defined by levels >3mg/L. Current medication was recorded. ResultsOverall, 63 subjects (28.8%) were found to have abnormal CRP levels, 43 (20.1%) received a diagnosis of comorbid current depression, and 51 (31.9%) had ongoing antidepressant treatment. In univariate analysis, abnormal CRP levels were found to be significantly associated with body mass index (BMI) (p<0.0001), hypertriglyceridemia (p=0.0015), high waist circumference (p<0.0001), metabolic syndrome (p=0.0011), abdominal obesity (p<0.0001) and with antidepressant consumption (p=0.01), while depression, psychotic symptomatology, age of onset, illness duration, sociodemographic characteristics, current tobacco or cannabis status, hypertension or high fasting glucose were not (all p>0.05).In a multivariate model, abnormal CRP was associated with antidepressant consumption independently of other confounding variables (adjusted Odds Ratio=2.8, 95% confidence interval 1.22–6.62). Metabolic syndrome was also independently associated with abnormal CRP (adjusted Odds Ratio=2.6, 95% confidence interval 1.01–6.71). ConclusionAbnormal CRP levels in schizophrenia were found to be associated with antidepressant consumption, but not with depression. The potential mechanisms were discussed. Antidepressant consumption should be systematically recorded in future studies exploring inflammation in schizophrenia. Future clinical trials of interventions directed at lowering the level of CRP and other inflammatory markers are discussed.

Successful Use of Agomelatine in the Treatment of Major Depression in a Woman Taking Tamoxifen

The selective estrogen receptor modulator, tamoxifen, is extensively used for the endocrine treatment of all stages of hormone receptor-positive breast cancer. Tamoxifen is a mainly inactive prodrug, necessitating metabolism by the cytochrome P450 (CYP450) pathway, predominantly the Cytochrome P450 2D6 (CYP2D6), into the active metabolites 4-hydroxytamoxifen and, in particular, endoxifen to achieve its therapeutic effect. As several women treated with tamoxifen may experience depressive symptoms or may have a previous or actual major depressive episode with ongoing antidepressant treatment or need for a new-onset therapy, the coprescription of an antidepressant drug may be particularly problematic as several antidepressants are potent CYP2D6-inhibiting drugs. We herein report a case of a patient with major depression and concurrent tamoxifen therapy successfully treated with agomelatine monotherapy.

Aripiprazole augmentation for treatment of patients with chronic or recurrent major depressive disorder

Patients with chronic or recurrent major depressive disorder (MDD) have faced a dearth of treatment options. The present study evaluated the effectiveness and tolerability of aripiprazole augmentation for the treatment of chronic or recurrent MDD. This was the first 12-week prospective, multicentre, open-label study of the effectiveness and tolerability of flexibly dosed aripiprazole as an augmentation to ongoing antidepressant treatment in patients with chronic or recurrent MDD. The primary outcome measure for effectiveness was changes between baseline and endpoint (week 12) in total scores on the Montgomery-Asberg Depression Rating Scale. Adverse events (AEs) occurring throughout the trial are also reported. The Montgomery-Asberg Depression Rating Scale total scores decreased significantly between the baseline and the endpoint (magnitude of difference=-11.6, P<0.0001). At the endpoint, the response rate was 55.2% and the remission rate was 41.3%. Adjunctive aripiprazole treatment administered from week 1 through the endpoint was associated with remission and significant treatment responses. More than half (55.8%) of those taking adjunctive aripiprazole completed the study and relatively few patients discontinued participation because of AEs. None of the patients discontinued participation in the study because of an inadequate therapeutic response. Common AEs included headache, akathisia, insomnia and constipation. The mean dose of aripiprazole at the endpoint was 6.6 mg/day. Adjunctive aripiprazole may be effective and tolerable for patients with chronic or recurrent MDD. Adequately powered and controlled clinical trials should be conducted to confirm our open-label study findings.

Evaluation of adjunct extended-release quetiapine fumarate on sleep disturbance and quality in patients with major depressive disorder and an inadequate response to on-going antidepressant therapy

Sleep disturbance is common in depression and is a risk factor for recurrence and suicide. This analysis evaluated the effects of adjunct extended-release quetiapine fumarate (quetiapine XR) on sleep disturbance and quality in patients with major depressive disorder (MDD) and an inadequate response to on-going antidepressant therapy. Pooled data from two 6-wk, randomized, double-blind, placebo-controlled trials were analysed post hoc. Patients received once-daily quetiapine XR [(150 mg/d), n = 309; (300 mg/d), n = 307] or placebo (n = 303) adjunct to on-going antidepressant therapy. Analyses included: change from randomization in Montgomery-Åsberg Depression Rating Scale (MADRS) Item 4 (reduced sleep) score; Hamilton Rating Scale for Depression (HAMD) Items 4 (insomnia-early), 5 (insomnia-middle) and 6 (insomnia-late) scores; HAMD sleep disturbance factor (Items 4+5+6); Pittsburgh Sleep Quality Index (PSQI) global score. Change in MADRS total score was also evaluated in patients stratified by HAMD sleep disturbance factor score (high ≥ 4 and low < 4) at randomization. At week 6, adjunct quetiapine XR (150 and 300 mg/d) reduced MADRS Item 4, HAMD Items 4, 5 and 6, HAMD sleep disturbance factor and PSQI global scores from randomization vs. placebo (all p < 0.001). In patients with high sleep disturbance, quetiapine XR (both doses) improved depressive symptoms (MADRS total score) vs. placebo from week 1 onwards (p < 0.01). Adjunct quetiapine XR improved sleep disturbance and quality vs. placebo in patients with MDD and an inadequate response to on-going antidepressant treatment, and was effective against depressive symptoms in patients experiencing high sleep disturbance.

One-year postcollaborative depression care trial outcomes among predominantly Hispanic diabetes safety net patients

Objective The aim of this study was to determine sustained effectiveness in reducing depression symptoms and improving depression care 1 year following intervention completion. Method Of 387 low-income, predominantly Hispanic diabetes patients with major depression symptoms randomized to 12-month socioculturally adapted collaborative care (psychotherapy and/or antidepressants, telephone symptom monitoring/relapse prevention) or enhanced usual care, 264 patients completed 2-year follow-up. Depression symptoms (Symptom Checklist-20 [SCL-20], Patient Health Questionnaire-9 [PHQ-9]), treatment receipt, diabetes symptoms and quality of life were assessed 24 months postenrollment using intent-to-treat analyses. Results At 24 months, more intervention patients received ongoing antidepressant treatment (38% vs. 25%, χ 2=5.11, df=1, P=.02); sustained depression symptom improvement [SCL-20 <0.5 (adjusted odds ratio=2.06, 95% confidence interval=1.09–3.90, P=.03), SCL-20 score (adjusted mean difference −0.22, P=.001) and PHQ-9 ≥50% reduction (adjusted odds ratio=1.87, 95% confidence interval =1.05–3.32, P=.03)]. Over 2 years, improved effects were found in significant study group by time interaction for Short Form-12 mental health, Sheehan Disability Scale (SDS) functional impairment, diabetes symptoms, anxiety and socioeconomic stressors ( P=.02 for SDS; P<.0001 for all others); however, group differences narrowed over time and were no longer significant at 24 months. Conclusions Socioculturally tailored collaborative care that included maintenance antidepressant medication, ongoing symptom monitoring and behavioral activation relapse prevention was associated with depression improvement over 24 months for predominantly Hispanic patients in primary safety net care.

Efficacy, safety and tolerability of Symbyax® for acute-phase management of treatment-resistant depression

Treatment resistance is frequently encountered during the long-term care of patients with major depression. A number of ‘next step’ therapeutic options exist in such cases, including switching to an alternative antidepressant, combining antidepressants from different pharmacological classes, adding evidence-supported psychotherapies to ongoing antidepressant treatment and augmentation with a nonantidepressant drug. Augmenting antidepressants with atypical antipsychotic drugs has generated considerable clinical interest. Three atypical antipsychotics (aripiprazole, quetiapine and olanzapine) have received regulatory approval for adjunctive use with antidepressants for treatment-resistant major depression (TRD) in adults. Symbyax® (olanzapine–fluoxetine combination or OFC), the combination of olanzapine and the selective serotonin-reuptake inhibitor fluoxetine, is also approved for this indication. The short-term effectiveness of OFC for TRD is supported by results of five published randomized, controlled, acute-phase studies of generally similar design. In each study, OFC was associated with rapid reduction in depressive symptoms. In two studies, significantly greater improvement in depressive symptoms occurred in OFC-treated patients at study end point compared with those who received antidepressant monotherapy. These effects appeared to be strongest in cases where antidepressant failure was established during the current depressive episode. Although OFC was well-tolerated, increases in body weight and prolactin concentration were greater with OFC than antidepressant monotherapy, and were similar to olanzapine monotherapy. Increases in random total cholesterol levels were greatest for OFC, and were significantly greater than those of olanzapine and antidepressant monotherapy. The long-term efficacy and tolerability of OFC for TRD has not been investigated, and the comparative effectiveness of OFC versus other next-step options is unknown. As such, the exact place of OFC among the available therapeutic options for TRD is not fully understood at this time.