Liposomal Bupivacaine Injection for Analgesia During Minimally Invasive Supracervical Hysterectomy.

Objective: To evaluate the efficacy of intracervical injection of liposomal bupivacaine for postoperative pain control among women undergoing minimally invasive supracervical hysterectomy. Methods: A randomized double-blinded placebo-controlled trial of intracervical injection of combination liposomal bupivacaine and bupivacaine for postoperative pain among patients undergoing laparoscopic and robotic supracervical hysterectomy. Patients were enrolled between October 1, 2018 and April 30, 2019. The primary outcome was pain at 12 hours postoperatively using a numeric rating scale from zero to 10. Pain scores were also recorded pre-operatively, immediately postoperatively, at 12, 24, and 48 hours postoperatively. The secondary outcome was the number of patients who required opioid analgesic medications up to 48 hours postoperatively. Results: Sixty participants were randomized into the control (n = 30) and intervention (n = 30) groups. Pain scores were 1 and 1.75 (p = 0.89) immediately postoperatively, 3 and 3.5 (p = 0.85) at 12 hours, 3.5 and 5 (p = 0.22) at 24 hours, and 2.75 and 4 (p = 0.18) at 48 hours for the control and intervention groups, respectively. Within the first 24 hours, 10 patients in the control and 14 patients in the intervention group used narcotics (p = 0.37). From the 24 to 48 hours window, 6 and 8 patients in the control and intervention groups used narcotics (p = 0.74), respectively. Conclusion: There was no statistically significant difference in pain scores between patients receiving combination liposomal bupivacaine and bupivacaine intracervical block and those receiving placebo in the first 48 hours after surgery. There was no difference in analgesic use between the two study groups.

Cause of increased size of acipenseriform eggs infected with Polypodium hydriforme.

Eggs of acipenseriform fish infected with the parasite Polypodium hydriforme become enlarged during later stages of development. This study examined if the increase in size is due to the increase in nutrients or water in the infected eggs and if the polypodium eggs affect the nutrient levels of the neighbouring eggs in the ovary. Infected and uninfected eggs were collected from parasitized Paddlefish, Polyodon spathula, hosts and unparasitized individuals. Levels of water, protein, carbohydrates, lipids and amino acids were determined for each egg. Although there were nutritional differences between eggs infected with P. hydriforme and uninfected eggs there was no indication that there was an increase in resource allocation to the infected eggs. The amount of water was much higher in infected eggs, suggesting the size increase was due to a greater influx of water. Levels of free amino acids were much higher in infected eggs and we hypothesize they could be used to increase the solute concentration to increase the influx of water, a mechanism that is also used by marine teleosts.

Routinely accessible parameters of mineralocorticoid receptor function, depression subtypes and response prediction: a post-hoc analysis from the early medication change trial in major depressive disorder.

OBJECTIVES: Previous studies indicated a relationship between aldosterone, the mineralocorticoid receptor (MR), and antidepressant treatment outcome. Physiological indicators of MR function (blood pressure and electrolytes) are easily accessible and may therefore serve as useful predictors. Thus, our aim was to investigate the predictive value of peripheral MR-related markers for antidepressant treatment outcomes. METHODS: 826 MDD patients who had participated in the randomised-controlled Early Medication Change (EMC) trial were analysed. Depression severity and MR-related markers were assessed weekly. In 562 patients, genetic variation of five MR-related genes was determined. RESULTS: Patients with blood pressure <120mmHg showed higher depression severity (p = 0.005) than patients with blood pressure ≥120mmHg. Patients with a melancholic subtype had significantly lower blood pressures (p = 0.004). Na+/K+ ratio was positively and K+-concentration was negatively correlated to depression severity and to relative changes in HAMD from baseline to day 14, and 56 respectively (p < 0.001). For none of the MR-related genes, genetic variation was associated with treatment outcomes. CONCLUSIONS: We confirmed early observations of an altered peripheral MR sensitivity, reflected by lower blood pressure, low K+ or high Na+/K+ ratio in patients with more severe depression. These routinely collected biomarkers may potentially be useful for risk stratification in an early stage of treatment. Trial Registration: clinicaltrials.gov Identifier: NCT00974155; https://www.clinicaltrials.gov/ct2/results?term=NCT00974155.

Longitudinal CSF proteome profiling in mice to uncover the acute and sustained mechanisms of action of rapid acting antidepressant (2R,6R)-hydroxynorketamine (HNK).

Delayed onset of antidepressant action is a shortcoming in depression treatment. Ketamine and its metabolite (2R,6R)-hydroxynorketamine (HNK) have emerged as promising rapid-acting antidepressants. However, their mechanism of action remains unknown. In this study, we first described the anxious and depression-prone inbred mouse strain, DBA/2J, as an animal model to assess the antidepressant-like effects of ketamine and HNK in vivo. To decode the molecular mechanisms mediating HNK's rapid antidepressant effects, a longitudinal cerebrospinal fluid (CSF) proteome profiling of its acute and sustained effects was conducted using an unbiased, hypothesis-free mass spectrometry-based proteomics approach. A total of 387 proteins were identified, with a major implication of significantly differentially expressed proteins in the glucocorticoid receptor (GR) signaling pathway, providing evidence for a link between HNK and regulation of the stress hormone system. Mechanistically, we identified HNK to repress GR-mediated transcription and reduce hormonal sensitivity of GR in vitro. In addition, mammalian target of rapamycin (mTOR) and brain-derived neurotrophic factor (BDNF) were predicted to be important upstream regulators of HNK treatment. Our results contribute to precise understanding of the temporal dynamics and molecular targets underlying HNK's rapid antidepressant-like effects, which can be used as a benchmark for improved treatment strategies for depression in future.

Spontaneous Bilateral Tubal Ectopic Pregnancy in a Low-Risk Patient: A Case Report with Implications for Preoperative Patient Counseling.

Bilateral tubal ectopic pregnancies (BTP) are the rarest form of ectopic pregnancy. They are difficult to diagnose preoperatively, and an evidence-based guideline for management does not exist. In this report, we discuss a 35-year-old patient who presented with suspected right tubal ectopic pregnancy. BTP was diagnosed intraoperatively, and a laparoscopic bilateral salpingectomy was performed without complication. The diagnosis was subsequently confirmed by pathology. This case highlights the importance of patient counseling and comprehensive preoperative planning. Due to the poor presurgical diagnosis of BTP, patient counseling should include the possibility of BTP, appropriate options for management, and potential loss of fertility following treatment. In addition, all cases of suspected ectopic pregnancy necessitate a thorough preoperative investigation of bilateral adnexa and intraoperative inspection of the pelvis.

Early life adversity targets the transcriptional signature of hippocampal NG2+ glia and affects voltage gated sodium (Nav) channels properties.

The precise mechanisms underlying the detrimental effects of early life adversity (ELA) on adult mental health remain still elusive. To date, most studies have exclusively targeted neuronal populations and not considered neuron-glia crosstalk as a crucially important element for the integrity of stress-related brain function. Here, we have investigated the impact of ELA, in the form of a limited bedding and nesting material (LBN) paradigm, on a glial subpopulation with unique properties in brain homeostasis, the NG2+ cells. First, we have established a link between maternal behavior, activation of the offspring's stress response and heterogeneity in the outcome to LBN manipulation. We further showed that LBN targets the hippocampal NG2+ transcriptome with glucocorticoids being an important mediator of the LBN-induced molecular changes. LBN altered the NG2+ transcriptome and these transcriptional effects were correlated with glucocorticoids levels. The functional relevance of one LBN-induced candidate gene, Scn7a, could be confirmed by an increase in the density of voltage-gated sodium (Nav) channel activated currents in hippocampal NG2+ cells. Scn7a remained upregulated until adulthood in LBN animals, which displayed impaired cognitive performance. Considering that Nav channels are important for NG2+ cell-to-neuron communication, our findings provide novel insights into the disruption of this process in LBN mice.

Early onset of depression and treatment outcome in patients with major depressive disorder.

Major depressive disorder (MDD) is a highly heterogeneous disorder, which may partly explain why treatment outcome using antidepressants is unsatisfactory. We investigated the onset of depression as a possible clinical marker for therapy response prediction in the context of somatic biomarkers blood pressure and plasma electrolyte concentration. 889 MDD patients were divided into early (EO, n = 226), intermediate (IO, n = 493), and late onset (LO, n = 169) patients and were analyzed for differences in socio-demographic and clinical parameters, comorbidities and treatment outcome as well as systolic blood pressure and electrolytes. EO patients more often suffered from a recurrent depression, had more previous depressive episodes, a higher rate of comorbid axis I and II disorders, and more often reported of suicidality (p < 0.001) compared to IO and LO patients. Treatment outcome was not different from IO and LO patients, although LO patients responded faster. EO patients who showed an early non-improvement of depression after 2 weeks of therapy (<20% improvement) had a 4.3-fold higher likelihood to become non-remitter as compared to LO patients with an early improvement. EO patients had significantly lower systolic blood pressure than patients with IO or LO and electrolytes in EO patients were significantly correlated with depression severity. Our results confirm other studies showing an association of an early onset of depression with a slower treatment response. The worse treatment outcome in patients with an additional early non-improvement to antidepressant therapy opens perspectives to develop and test individualized treatment approaches for EO and LO patients in the future, which may be based on differences in autonomic regulation.

A distinct transcriptional signature of antidepressant response in hippocampal dentate gyrus granule cells.

Major depressive disorder is the most prevalent mental illness worldwide, still its pharmacological treatment is limited by various challenges, such as the large heterogeneity in treatment response and the lack of insight into the neurobiological pathways underlying this phenomenon. To decode the molecular mechanisms shaping antidepressant response and to distinguish those from general paroxetine effects, we used a previously established approach targeting extremes (i.e., good vs poor responder mice). We focused on the dentate gyrus (DG), a subregion of major interest in the context of antidepressant mechanisms. Transcriptome profiling on micro-dissected DG granule cells was performed to (i) reveal cell-type-specific changes in paroxetine-induced gene expression (paroxetine vs vehicle) and (ii) to identify molecular signatures of treatment response within a cohort of paroxetine-treated animals. We identified 112 differentially expressed genes associated with paroxetine treatment. The extreme group comparison (good vs poor responder) yielded 211 differentially expressed genes. General paroxetine effects could be distinguished from treatment response-associated molecular signatures, with a differential gene expression overlap of only 4.6% (15 genes). Biological pathway enrichment and cluster analyses identified candidate mechanisms associated with good treatment response, e.g., neuropeptide signaling, synaptic transmission, calcium signaling, and regulation of glucocorticoid secretion. Finally, we examined glucocorticoid receptor (GR)-dependent regulation of selected response-associated genes to analyze a hypothesized interplay between GR signaling and good antidepressant treatment response. Among the most promising candidates, we suggest potential targets such as the developmental gene Otx2 or Htr2c for further investigations into antidepressant treatment response in the future.

Hippocampal NG2+ pericytes in chronically stressed rats and depressed patients: a quantitative study.

OBJECTIVE: The suggested link between major depression disorder (MDD) and blood-brain barrier (BBB) alterations supports an impact on the neurovascular unit in this disease condition. Here we investigate how pericytes, a major component in the neurovascular unit, respond to stress, stress hormones, proinflammatory cytokine and depression. METHOD: Hippocampal sections of chronic unpredictable stressed (CMS) rats, MDD patients and respective controls were immuno-stained against NG2, where the number of NG2+ pericytes in the molecular layer was counted. Proliferation of cultured pericytes after treatment with cortisol and IL-1ß was analyzed using radioactive-labeled thymidine. FINDINGS: The number of NG2+ pericytes was significantly higher in CMS animals than controls. Higher number of NG2+ pericytes was also detected in MDD patients, but the increase did not reach significance. IL-1ß, but not cortisol, induced a significant increase in proliferation of cultured pericytes. CONCLUSION: Our results indicate that exposure to stressful conditions affects the hippocampal pericyte population. These findings add to our knowledge about the impact of stress on the neurovascular unit, which might be relevant for understanding the alterations in BBB found in MDD patients.

Tolerability of High-Dose Venlafaxine After Switch From Escitalopram in Nonresponding Patients With Major Depressive Disorder.

BACKGROUND: Within a single depressive episode, most patients receive different antidepressants because of an inadequate response to the first-line antidepressant. A commonly used strategy is to switch from a selective serotonin reuptake inhibitor to a selective serotonin-norepinephrine reuptake inhibitor. However, little is known about the tolerability of this switch with consideration of dose and drug concentration in blood. METHODS: After 4 weeks of inadequate response to escitalopram (10-20 mg/d), medication was switched to another 4 weeks of venlafaxine (VF, 150-375 mg/d) in 234 depressed patients. Serum concentrations, depression severity, and adverse drug reactions (ADRs) were assessed weekly. RESULTS: The switch of medication led to an increase of ADRs such as reduced salivation (+11%), orthostatic dizziness (+11%), and sweating (+9.8%). The most frequent ADRs during treatment with VF were reduced salivation (28.6%), sweating (24.6%), and orthostatic dizziness (15.8%). In patients receiving high-dose VF, a significant improvement of depressive symptomatology was observed, and most ADRs decreased during the course of treatment, even in patients above the therapeutic reference range. LIMITATIONS: Patients and physicians were aware of medication, and there was no direct comparison with the herein presented switch of medication. IMPLICATIONS: This study provides important information about the tolerability of a commonly used antidepressant treatment strategy. More detailed information about putative ADRs may help clinicians increase compliance through effective patient education. Because ADRs of VF were associated with the plasma concentration, therapeutic drug monitoring is recommended to guide the therapy and manage problems of tolerability.

Paroxetine Administration Affects Microbiota and Bile Acid Levels in Mice.

Recent interest in the role of microbiota in health and disease has implicated gut microbiota dysbiosis in psychiatric disorders including major depressive disorder. Several antidepressant drugs that belong to the class of selective serotonin reuptake inhibitors have been found to display antimicrobial activities. In fact, one of the first antidepressants discovered serendipitously in the 1950s, the monoamine-oxidase inhibitor Iproniazid, was a drug used for the treatment of tuberculosis. In the current study we chronically treated DBA/2J mice for 2 weeks with paroxetine, a selective serotonin reuptake inhibitor, and collected fecal pellets as a proxy for the gut microbiota from the animals after 7 and 14 days. Behavioral testing with the forced swim test revealed significant differences between paroxetine- and vehicle-treated mice. Untargeted mass spectrometry and 16S rRNA profiling of fecal pellet extracts showed several primary and secondary bile acid level, and microbiota alpha diversity differences, respectively between paroxetine- and vehicle-treated mice, suggesting that microbiota functions are altered by the drug. In addition to their lipid absorbing activities bile acids have important signaling activities and have been associated with gastrointestinal diseases and colorectal cancer. Antidepressant drugs like paroxetine should therefore be used with caution to prevent undesirable side effects.

Bioenergetic shift and actin cytoskeleton remodelling as acute vascular adaptive mechanisms to angiotensin II in murine retina and ophthalmic artery.

Ocular vascular dysfunction is a major contributing factor to the pathogenesis of glaucoma. In recent years, there has been a renewed interest in the role of angiotensin II (Ang II) in mediating the disease progression. Despite its (patho)physiological importance, the molecular mechanisms underlying Ang II-mediated oxidative stress remain largely unexplored in the ocular vasculature. Here, we provide the first direct evidence of the alterations of proteome and signalling pathways underlying Ang II-elicited oxidative insult independent of arterial pressure changes in the ophthalmic artery (OA) and retina (R) employing an in vitro experimental model. Both R and OA were isolated from male C57Bl/6J mice (n = 15/group; n = 5/biological replicate) and incubated overnight in medium containing either vehicle or Ang II (0.1 µM) at physiological conditions. Label-free quantitative mass spectrometry (MS)-based proteomics analysis identified a differential expression of 107 and 34 proteins in the R and OA, respectively. Statistical and bioinformatics analyses revealed that protein clusters involved in actin cytoskeleton and integrin-linked kinase signalling were significantly activated in the OA. Conversely, a large majority of differentially expressed retinal proteins were involved in dysregulation of numerous energy-producing and metabolic signalling pathways, hinting to a possible shift in retinal cell bioenergetics. Particularly, Ang II-mediated downregulation of septin-7 (Sept7; p < 0.01) and superoxide dismutase [Cu-Zn] (Sod1; p < 0.05), and upregulation of troponin T, fast skeletal muscle (Tnnt3; p < 0.05) and tropomyosin alpha-3 chain (Tpm3; p < 0.01) in the OA, and significant decreased expressions of two crystallin proteins (Cryab; p < 0.05 and Crybb2; p < 0.0001) in the R were verified at the mRNA level, corroborating our proteomics findings. In summary, these results demonstrated that exogenous application of Ang II over an acute time period caused impairment of retinal bioenergetics and cellular demise, and actin cytoskeleton-mediated vascular remodelling in the OA.

Sexually Dimorphic Behavioral Profile in a Transgenic Model Enabling Targeted Recombination in Active Neurons in Response to Ketamine and (2R,6R)-Hydroxynorketamine Administration.

BACKGROUND: Rapid-acting antidepressants ketamine and (2R,6R)-hydroxynorketamine ((2R,6R)-HNK) have overcome some of the major limitations of classical antidepressants. However, little is known about sex-specific differences in the behavioral and molecular effects of ketamine and (2R,6R)-HNK in rodents. METHODS: We treated mice with an intraperitoneal injection of either saline, ketamine (30 mg kg-1) or (2R,6R)-HNK (10 mg kg-1). We performed a comprehensive behavioral test battery to characterize the Arc-CreERT2 × CAG-Sun1/sfGFP mouse line which enables targeted recombination in active populations. We performed a molecular study in Arc-CreERT2 × CAG-Sun1/sfGFP female mice using both immunohistochemistry and in situ hybridization. RESULTS: Arc-CreERT2 × CAG-Sun1/sfGFP mice showed sex differences in sociability and anxiety tests. Moreover, ketamine and (2R,6R)-HNK had opposite effects in the forced swim test (FST) depending on gender. In addition, in male mice, ketamine-treated animals were less immobile compared to (2R,6R)-HNK, thus showing a different profile of the two drugs in the FST. At the molecular level we identified Bdnf mRNA level to be increased after ketamine treatment in female mice. CONCLUSION: Arc-CreERT2 × CAG-Sun1/sfGFP mice showed sex differences in social and anxiety behavior and a different pattern between ketamine and (2R,6R)-HNK in the FST in male and female mice. At the molecular level, female mice treated with ketamine showed an increase of Bdnf mRNA level, as previously observed in male mice.

Effects of age on depressive symptomatology and response to antidepressant treatment in patients with major depressive disorder aged 18 to 65 years.

BACKGROUND: There is evidence that symptomatology in patients with major depressive disorder (MDD) changes with age. However, studies comparing depressive symptomatology between different age groups during antidepressant therapy are rare. We compared demographic and clinical characteristics in depressed patients of different age groups at baseline and during treatment. METHODS: 889 MDD inpatients were divided into four age groups (18-29, 30-39, 40-49, 50-65 yrs.). Demographic and clinical characteristics including depressive symptomatology (assessed by the Inventory of Depressive Symptoms) were assessed at baseline and weekly during treatment. RESULTS: At baseline, young patients (18-29 years) significantly more often reported cognitive symptoms like irritability, suicidality, negative self-concept and interpersonal sensitivity and more often suffered from drug abuse and comorbid personality disorders. Late middle aged patients (50-65 years) significantly more often suffered from neuro-vegetative symptoms such as reduced general interest, sexual interest and sleep disturbances and more often showed a recurrent MDD and comorbid physical disorders. During therapy, symptoms such as interpersonal sensitivity in young patients and low interest in sex in late middle aged patients persisted until the end of treatment while all other symptoms declined until day 56. LIMITATIONS: The herein presented age differences in depressive symptomatology only hold true for the study medication and are not generalizable to other antidepressants agents. CONCLUSION: There are substantial differences in the clinical presentation of depression between age groups. Whereas many of these differences disappear during treatment, some differences persisted until the end of treatment. These findings my help to more specifically tailor the treatment of depressed patients.

Identifying duration criteria for eating-disorder remission and recovery through intensive modeling of longitudinal data.

OBJECTIVE: Outcome states, such as remission and recovery, include specific duration criteria for which individuals must be asymptomatic. Ideally, duration criteria provide predictive validity to outcome states by reducing symptom-return risk. However, available research is insufficient for deriving specific recommendations for remission or recovery duration criteria for eating disorders. METHOD: We intensively modeled the relation between duration criteria length and rates of remission, recovery, and subsequent symptom return in longitudinal data from a treatment-seeking sample of women with anorexia nervosa (AN) and bulimia nervosa (BN). We hypothesized that the length of the duration criterion would be inversely associated with both rates of remission and recovery and with subsequent rates of symptom return. RESULTS: Generalized estimating equations supported our hypotheses for all investigated eating-disorder features except for symptom return when using the Psychiatric Status Rating for AN. DISCUSSION: We recommend that 6 months be used for remission definitions applied to binge eating, purging, and BN symptom composite measures, whereas no duration criteria be used for low weight and AN symptom composites. We further recommend that 6 months be used for recovery definitions applied to BN symptom composites and AN symptom composites, whereas 18 months be used for individual symptoms of binge eating, purging, and low weight. The adoption of these duration criteria into comprehensive definitions of remission and recovery will increase their predictive validity, which in turn, maximizes their utility.

A Randomized Placebo-Controlled Trial of Low-Dose Testosterone Therapy in Women With Anorexia Nervosa.

CONTEXT: Anorexia nervosa (AN) is a psychiatric illness with considerable morbidity and no approved medical therapies. We have shown that relative androgen deficiency in AN is associated with greater depression and anxiety symptom severity. OBJECTIVE: To determine whether low-dose testosterone therapy is an effective endocrine-targeted therapy for AN. DESIGN: Double-blind, randomized, placebo-controlled trial. SETTING: Clinical research center. PARTICIPANTS: Ninety women, 18 to 45 years, with AN and free testosterone levels below the median for healthy women. INTERVENTION: Transdermal testosterone, 300 µg daily, or placebo patch for 24 weeks. MAIN OUTCOME MEASURES: Primary end point: body mass index (BMI). Secondary end points: depression symptom severity [Hamilton Depression Rating Scale (HAM-D)], anxiety symptom severity [Hamilton Anxiety Rating Scale (HAM-A)], and eating disorder psychopathology and behaviors. RESULTS: Mean BMI increased by 0.0 ± 1.0 kg/m2 in the testosterone group and 0.5 ± 1.1 kg/m2 in the placebo group (P = 0.03) over 24 weeks. At 4 weeks, there was a trend toward a greater decrease in HAM-D score (P = 0.09) in the testosterone vs placebo group. At 24 weeks, mean HAM-D and HAM-A scores decreased similarly in both groups [HAM-D: -2.9 ± 4.9 (testosterone) vs -3.0 ± 5.0 (placebo), P = 0.72; HAM-A: -4.5 ± 5.3 (testosterone) vs -4.3 ± 4.4 (placebo), P = 0.25]. There were no significant differences in eating disorder scores between groups. Testosterone therapy was safe and well tolerated with no increase in androgenic side effects compared with placebo. CONCLUSION: Low-dose testosterone therapy for 24 weeks was associated with less weight gain-and did not lead to sustained improvements in depression, anxiety, or disordered eating symptoms-compared with placebo in women with AN.

Decoding the Mechanism of Action of Rapid-Acting Antidepressant Treatment Strategies: Does Gender Matter?

Gender differences play a pivotal role in the pathophysiology and treatment of major depressive disorder. This is strongly supported by a mean 2:1 female-male ratio of depression consistently observed throughout studies in developed nations. Considering the urgent need to tailor individualized treatment strategies to fight depression more efficiently, a more precise understanding of gender-specific aspects in the pathophysiology and treatment of depressive disorders is fundamental. However, current treatment guidelines almost entirely neglect gender as a potentially relevant factor. Similarly, the vast majority of animal experiments analysing antidepressant treatment in rodent models exclusively uses male animals and does not consider gender-specific effects. Based on the growing interest in innovative and rapid-acting treatment approaches in depression, such as the administration of ketamine, its metabolites or electroconvulsive therapy, this review article summarizes the evidence supporting the importance of gender in modulating response to rapid acting antidepressant treatment. We provide an overview on the current state of knowledge and propose a framework for rodent experiments to ultimately decode gender-dependent differences in molecular and behavioural mechanisms involved in shaping treatment response.

Eating disorder recovery is associated with absence of major depressive disorder and substance use disorders at 22-year longitudinal follow-up.

BACKGROUND: Psychiatric comorbidity is common in eating disorders (EDs) and associated with poor outcomes, including increased risk for relapse and premature death. Yet little is known about comorbidity following ED recovery. METHODS: We examined two common comorbidities, major depressive disorder (MDD) and substance use disorder (SUD), in adult women with intake diagnoses of anorexia nervosa and bulimia nervosa who participated in a 22-year longitudinal study. One hundred and seventy-six of 228 surviving participants (77.2%) were interviewed 22 years after study entry using the Eating Disorders Longitudinal Interval Follow-up Evaluation to assess ED recovery status. Sixty-four percent (n = 113) were recovered from their ED. The Structured Clinical Interview for DSM-IV was used to assess MDD and SUD at 22 years. RESULTS: At 22-year follow-up, 28% (n = 49) met criteria for MDD, and 6% (n = 11) met criteria for SUD. Those who recovered from their ED were 2.17 times more likely not to have MDD at 22-year follow-up (95% CI [1.10, 4.26], p = .023) and 5.33 times more likely not to have a SUD at 22-year follow-up than those who had not recovered from their ED (95% CI [1.36, 20.90], p = .008). CONCLUSION: Compared to those who had not fully recovered from their ED, those who had recovered were twice as likely not to be diagnosed with MDD in the past year and five times as likely not to be diagnosed with SUDs in the past year. These findings provide evidence that long-term recovery from EDs is associated with recovery from or absence of these common major comorbidities. Because comorbidity in EDs can predict poor outcomes, including greater risk for relapse and premature death, our findings of reduced risk for psychiatric comorbidity following recovery at long-term follow-up is cause for optimism.

Understanding and Predicting Antidepressant Response: Using Animal Models to Move Toward Precision Psychiatry.

There are two important gaps of knowledge in depression treatment, namely the lack of biomarkers predicting response to antidepressants and the limited knowledge of the molecular mechanisms underlying clinical improvement. However, individually tailored treatment strategies and individualized prescription are greatly needed given the huge socio-economic burden of depression, the latency until clinical improvement can be observed and the response variability to a particular compound. Still, individual patient-level antidepressant treatment outcomes are highly unpredictable. In contrast to other therapeutic areas and despite tremendous efforts during the past years, the genomics era so far has failed to provide biological or genetic predictors of clinical utility for routine use in depression treatment. Specifically, we suggest to (1) shift the focus from the group patterns to individual outcomes, (2) use dimensional classifications such as Research Domain Criteria, and (3) envision better planning and improved connections between pre-clinical and clinical studies within translational research units. In contrast to studies in patients, animal models enable both searches for peripheral biosignatures predicting treatment response and in depth-analyses of the neurobiological pathways shaping individual antidepressant response in the brain. While there is a considerable number of animal models available aiming at mimicking disease-like conditions such as those seen in depressive disorder, only a limited number of preclinical or truly translational investigations is dedicated to the issue of heterogeneity seen in response to antidepressant treatment. In this mini-review, we provide an overview on the current state of knowledge and propose a framework for successful translational studies into antidepressant treatment response.

Predictors of long-term recovery in anorexia nervosa and bulimia nervosa: Data from a 22-year longitudinal study.

OBJECTIVE: The objective of this study was to investigate predictors of long-term recovery from eating disorders 22 years after entry into a longitudinal study. METHOD: One hundred and seventy-six of the 228 surviving participants (77.2%) were re-interviewed 20-25 years after study entry using the Longitudinal Interval Follow-up Evaluation to assess ED recovery. The sample consisted of 100 women diagnosed with anorexia nervosa (AN) and 76 with bulimia nervosa (BN) at study entry. RESULTS: A comorbid diagnosis of major depression at the start of the study strongly predicted having a diagnosis of AN-Restricting type at the 22-year assessment. A higher body mass index (BMI) at study intake decreased the odds of being diagnosed with AN-Binge Purge type, relative to being recovered, 22 years later. The only predictor that increased the likelihood of having a diagnosis of BN at the 22-year assessment was the length of time during the study when the diagnostic criteria for BN were met. CONCLUSIONS: Together, these results indicate that the presence and persistence of binge eating and purging behaviors were poor prognostic indicators and that comorbidity with depression is particularly pernicious in AN. Treatment providers might pay particular attention to these issues in an effort to positively influence recovery over the long-term.