Associations between alcohol consumption and empathy in a non-clinical sample: drinking motives as a moderator.

People consume alcohol for multiple reasons. Negative motives are often associated with alcohol-related problems. These problems might be explained by negative effects of high alcohol consumption on empathy. Past studies have associated alcohol use disorder (AUD) with reduced cognitive and affective empathy. Few studies have focused on non-clinical samples and considered behavioral empathy. We examined the links between alcohol consumption and multiple aspects of empathy, and if these links were moderated by negative drinking motives. We collected online data of 520 unselected individuals. All completed the AUD Identification Test (AUDIT) and a Drinking Motives Questionnaire. Affective and cognitive empathy were assessed using the Empathy Quotient. Behavioral empathy was assessed by asking participants how likely they would help the person in each of 24 scenarios involving pain. Helping others in pain was positively predicted by affective and cognitive empathy. Higher AUDIT scores were associated with helping others less, particularly among participants who scored higher on drinking to cope with negative affect. People who drink more and do so to cope with negative affect appear to have less behavioral empathy. This supports the view that negative drinking motives contribute to AUD risk.

Oral esketamine in patients with treatment-resistant depression: a double-blind, randomized, placebo-controlled trial with open-label extension.

About one-third of patients with depression do not achieve adequate response to current treatment options. Although intravenous and intranasal administrations of (es)ketamine have shown antidepressant properties, their accessibility and scalability are limited. We investigated the efficacy, safety, and tolerability of generic oral esketamine in patients with treatment-resistant depression (TRD) in a randomized placebo-controlled trial with open-label extension. This study consisted of 1) a six-week fixed low-dose treatment phase during which 111 participants received oral esketamine 30 mg or placebo three times a day; 2) a four-week wash-out phase; and 3) an optional six-week open-label individually titrated treatment phase during which participants received 0.5 to 3.0 mg/kg oral esketamine two times a week. The primary outcome measure was change in depressive symptom severity, assessed with the Hamilton Depression Rating Scale (HDRS17), from baseline to 6 weeks. Fixed low-dose oral esketamine when compared to placebo had no benefit on the HDRS17 total score (p = 0.626). Except for dizziness and sleep hallucinations scores, which were higher in the esketamine arm, we found no significant difference in safety and tolerability aspects. During the open-label individually titrated treatment phase, the mean HDRS17 score decreased from 21.0 (SD 5.09) to 15.1 (SD 7.27) (mean difference -6.0, 95% CI -7.71 to -4.29, p < 0.001). Our results suggest that fixed low-dose esketamine is not effective in TRD. In contrast, individually titrated higher doses of oral esketamine might have antidepressant properties.

Life meaning and feelings of ineffectiveness as transdiagnostic factors in eating disorder and comorbid internalizing symptomatology - A combined undirected and causal network approach.

The field of eating disorders is facing problems ranging from a suboptimal classification system to low long-term success rates of treatments. There is evidence supporting a transdiagnostic approach to explain the development and maintenance of eating disorders. Meaning in life has been proposed as a promising key transdiagnostic factor that could potentially not only bridge between the different eating disorder subtypes but also explain frequent co-occurrence with symptoms of comorbid psychopathology, such as anxiety and depression. The present study used self-report data from 501 participants to construct networks of eating disorder and comorbid internalizing symptomatology, including factors related to meaning in life, i.e., presence of life meaning, perceived ineffectiveness, and satisfaction with basic psychological needs. In an undirected network model, it was found that ineffectiveness is a central node, also bridging between eating disorder and other psychological symptoms. A directed network model displayed evidence for a causal effect of presence of life meaning both on the core symptomatology of eating disorders and depressive symptoms via ineffectiveness. These results support the notion of meaning in life and feelings of ineffectiveness as transdiagnostic factors within eating disorder symptomatology in the general population.

Increased alcohol use to cope with COVID-19-related anxiety one year into the coronavirus pandemic.

Background: An increase in drinking to cope with anxiety provoked by the coronavirus was observed during the first few months of the COVID-19 pandemic. Objective: In the present study, we examined the role of drinking motives in the anxiety-alcohol link one year into the pandemic. Methods: Using a cross-sectional design, we collected data between April and May 2021: 678 participants located in Romania or the Netherlands completed an online survey on alcohol consumption in the past month (assessed using a simple quantity-frequency measure), change in drinking during the past year (assessed using a single item asking whether there had been an increase, decrease or no change), drinking motives (assessed using the Revised Drinking Motives Questionnaire), drinking-related problems (assessed using the Alcohol Use Disorder Identification Test), and COVID-19-related anxiety (assessed using the Coronavirus Anxiety Scale). Results: Compared to before the pandemic, while 42% of participants had decreased their alcohol consumption, 15% reported an increase. Participants with clinically relevant COVID-19-related anxiety (11%) were more likely to drink to cope with negative affect, enhance positive affect, and conform to others. The association between COVID-19-related anxiety and drinking-related problems was specifically moderated by drinking to cope, such that the anxiety-alcohol link was stronger in participants who endorsed this drinking motive more. Conclusion: Drinking is a maladaptive coping strategy for individuals with high levels of COVID-19-related anxiety. These individuals might benefit from interventions involving the learning of healthier skills to deal with the ongoing pandemic.

Childhood Trauma and Adult Somatic Symptoms.

OBJECTIVE: Childhood trauma is a key public health risk factor for developing physical illness. This study examined how childhood abuse and neglect predict adult somatic symptoms assessed retrospectively and in real time. METHODS: Participants in the HowNutsAreTheDutch project completed the Childhood Trauma Questionnaire-Short Form and, to assess somatic symptoms, the cross-sectional Patient Health Questionnaire ( n = 406) or a longitudinal ecological momentary assessment protocol that included responding to an item on physical discomfort 3 times a day for 30 days ( n = 290). RESULTS: As hypothesized, childhood trauma was positively associated with adult somatic symptoms assessed using the Patient Health Questionnaire ( d = 0.30) and assessed using the ecological momentary assessment item ( d = 0.31), also after adjustment for age, sex, educational level, and relationship status. Longitudinally, we also explored whether interpersonal context moderated abuse outcomes, and observed that social company dampened momentary physical discomfort among people with a history of more physical neglect ( d = 0.04). CONCLUSIONS: Childhood trauma, especially emotional and sexual abuse, predicts specific adult somatic symptoms. Future work may examine how symptom expression is influenced by the social lives of traumatized individuals.

The acute effects of alcohol on social cognition: A systematic review of experimental studies.

RATIONALE: Alcohol effects on social cognition have been studied by measuring facial emotion recognition, empathy, Theory of Mind (ToM) and other forms of information processing. OBJECTIVES: Using the PRISMA guidelines, we reviewed experimental studies that examined acute effects of alcohol on social cognition. METHODS: Scopus, PsycInfo, PubMed, and Embase were searched between July 2020 - January 2023. The PICO strategy was used for identifying participants, interventions, comparators, and outcomes. Participants (N = 2330) were adult social alcohol users. Interventions consisted of acute alcohol administration. Comparators included placebo or the lowest alcohol dose. Outcome variables were grouped into three themes: facial processing, empathy and ToM, and perceptions of inappropriate sexual behavior. RESULTS: A total of 32 studies were reviewed. Studies measuring facial processing (67%) often found no effects of alcohol on the recognition of specific emotions, facilitated emotion recognition at lower doses and worsened emotion recognition at higher doses. In studies measuring empathy or ToM (24%), lower doses were more likely to lead to improvements while higher doses were generally impairing. Within the third group of studies (9%), moderate to high alcohol doses made it more difficult to perceive sexual aggression accurately. CONCLUSIONS: Lower alcohol doses might sometimes help facilitate social cognition, but most data were in line with the idea that alcohol tends to worsen social cognition, particularly at higher doses. Future studies might focus on examining other moderators of the effects of alcohol on social cognition, particularly interpersonal characteristics such as trait emotional empathy, and participant and target gender.

Eyes on you: Ensuring empathic accuracy or signalling empathy?

The eye region is thought to play an important role in the ability to accurately infer others' feelings, or empathic accuracy (EA), which is an important skill for social interaction. However, most past studies used static pictures, including only visual information, and knowledge about the contribution of the eye region to EA when visual information is presented together with verbal content is lacking. We therefore examined whether eye gazing contributes to EA during videos of emotional autobiographical stories including both visual and verbal content. One hundred seven perceivers watched videos of targets talking about positive and negative life events and continuously rated the targets' feelings during the videos. Simultaneously, perceivers' eyes were tracked. After each video, perceivers reported on their feelings and the extent to which they empathized with and took the perspective of the targets. In contrast to studies using static pictures, we found that gazing to the eyes of targets during the videos did not significantly contribute to EA. At the same time, results on the association between the amount of gaze towards the eye region of targets and perceivers' state and trait empathy ratings suggest that eye gazing might signal empathy and social engagement to others.

The antidepressant effect and safety of non-intranasal esketamine: A systematic review.

BACKGROUND: The introduction of esketamine into the field of psychiatry comes on the heels of excitement from studies on racemic ketamine. While the intranasal route has been the most studied to date, other modes of administration of esketamine may also be of interest in the management of depression. AIMS: To systematically review the literature on non-intranasal esketamine for depression in terms of its antidepressant effect and safety. METHODS: We searched PubMed, Embase, the Cochrane Library, and Google Scholar from inception up to February 2021. Search terms included a combination of Medical Subject Headings and text words indicative of esketamine and depression. We selected both controlled and uncontrolled studies examining non-intranasal esketamine for the treatment of depression. RESULTS: We identified four randomized controlled trials (RCTs) on intravenous esketamine and 15 open-label studies on intravenous (n = 80), subcutaneous (n = 73), and oral (n = 5) esketamine. We found intravenous, subcutaneous, and possibly oral administration of esketamine to be effective in reducing depressive symptoms in most patients with major depressive disorder, bipolar depression, and (severe) treatment-resistant depression. Clinical response to repeated administration of esketamine persisted over the course of treatment. Esketamine was well tolerated by most patients, but open-label data indicate marked psychotomimetic symptoms in exceptional cases. The overall quality of the controlled studies was considered high, the overall quality of the uncontrolled studies low to moderate. CONCLUSIONS: Intravenous, subcutaneous, and possibly oral esketamine may offer an effective and safe addition to the depression treatment armamentarium. However, as most included studies lacked a control group and had small sample sizes, the quality of our results is limited. Different types and formulations of ketamine remain to be compared directly.

Interpersonal responses to facial expressions of disgust, anger, and happiness in individuals with varying levels of social anxiety.

BACKGROUND AND OBJECTIVES: Facial expression recognition has been studied extensively, including in relation to social anxiety. Nonetheless, a limited number of studies examined recognition of disgust expressions. Results suggest that disgust is perceived as more threatening than anger, and thus may invite more extreme responses. However, few studies have examined responses to facial expressions. These studies have focused on approach-avoidance responses. Our primary aim was to examine to what extent anger and disgust expressions might invite interpersonal responses in terms of quarrelsomeness-agreeableness and dominance-submissiveness. As social anxiety has been previously associated with a heightened sensitivity to anger and disgust expressions, as well as with alterations in quarrelsomeness-agreeableness and dominance-submissiveness, our secondary aim was to examine whether social anxiety would moderate these responses. METHODS: Participants were 55 women and 43 men who completed social anxiety measures, including the Brief Fear of Negative Evaluation scale, and two tasks that involved "targets" expressing anger, disgust, or happiness at 0%, 50%, or 100%. Participants first indicated how quarrelsome or agreeable and how dominant or submissive they would be towards each target, and then how much they would avoid or approach each target. RESULTS: While 100% disgust and anger expressions invited similar levels of quarrelsomeness and avoidance, 50% disgust invited more quarrelsomeness and stronger avoidance than 50% anger. While these patterns were not meaningfully moderated by social anxiety, individuals with higher BFNE scores showed a relatively strong approach of happy faces. LIMITATIONS: Actual interpersonal behaviour in response to facial expressions was not assessed. CONCLUSIONS: Findings support the relevance of disgust as an interpersonal signal and suggest that, especially at mild intensity, disgust may have a stronger impact than anger on people's quarrelsomeness and avoidance responses. Findings provided no support for the view that people with social anxiety would be particularly responsive to disgust (or anger) expressions.

Rumination, worry and negative and positive affect in prolonged grief: A daily diary study.

After bereavement, a significant minority experiences severe, persistent, and disabling grief, termed prolonged grief or complicated grief. Prolonged grief treatments may be enhanced by improving understanding of malleable risk factors in post-loss psychological adaptation. Repetitive negative thought (e.g., rumination, worry) constitutes such a risk factor. Rumination and worry are both theorized to be maladaptive through interrelations with affect, yet this assumption has not been systematically investigated in the bereaved. We aimed to fill this gap in knowledge with a baseline survey and 10-day daily diary investigation among a bereaved sample. Survey between-subject analyses (N = 113) demonstrated that trait rumination and worry, trait negative affect and prolonged grief symptoms are positively related to each other and negatively related with trait positive affect. Within-subject multilevel analyses of diaries (N = 62) demonstrated that trait rumination and trait worry relate positively to daily negative affect and negatively to daily positive affect. Daily rumination and worry showed similar relationships with daily negative and positive affect. A stronger relationship emerged between daily rumination and daily negative affect in people with higher prolonged grief symptom levels. Findings consistently support interrelations between repetitive negative thought, affect, and prolonged grief symptoms. Rumination appears particularly detrimental in people with severe grief reactions. Results align with research demonstrating the effectiveness of targeting repetitive negative thought in prolonged grief treatments. Additionally, our study demonstrates the potential feasibility and usefulness of using daily diaries to study behaviours of relevance to post-loss adaptation in everyday life.

Youth Psychopathology in Daily Life: Systematically Reviewed Characteristics and Potentials of Ecological Momentary Assessment Applications.

Traditionally, symptoms of youth psychopathology are assessed with questionnaires, clinical interviews, or laboratory observations. Ecological Momentary Assessment (EMA) could be a particularly valuable additional methodology, since EMA enables examining the daily lives of youths near real-time, considering fluctuations and specific contexts of symptoms. This systematic review aimed to review the characteristics of current EMA applications and to provide a synthesis of their potential in studying youth psychopathology. Following a systematic search in PsycInfo and Medline, we identified 50 studies in clinical samples. Most studies used EMA to examine fluctuations in symptoms, affect, and behavior, and the relation with contextual factors. EMA was also used to investigate interactions between parents and their children over time, and to monitor and predict treatment response. EMA appeared feasible in youth and could provide valuable insights that contribute to understanding youth psychopathology. Benefits, gaps, and suggestions for future research and clinical practice are discussed.

Repeated, low-dose oral esketamine in patients with treatment-resistant depression: pilot study.

BACKGROUND: Intravenous infusion of ketamine can produce rapid and large symptom reduction in patients with treatment-resistant depression (TRD) but presents major obstacles to clinical applicability, especially in community settings. Oral esketamine may be a promising addition to our TRD treatment armamentarium. AIMS: To explore the safety, tolerability and potential clinical effectiveness of a 3-week treatment with repeated, low-dose oral esketamine. METHOD: Seven patients with chronic and severe TRD received 1.25 mg/kg generic oral esketamine daily, over 21 consecutive days. Scores on the Systematic Assessment for Treatment Emergent Events (SAFTEE), Community Assessment of Psychic Experiences (CAPE), Clinician Administered Dissociative States Scale (CADSS) and Hamilton Rating Scale for Depression (HRSD) instruments, as well as blood pressure and heart rate, were repeatedly assessed. RESULTS: Treatment with oral esketamine was well-tolerated. No serious side-effects occurred, and none of the participants discontinued treatment prematurely. Psychotomimetic effects were the most frequently reported adverse events. Mean HDRS score decreased by 16.5%, from 23.6 to 19.7. Three participants showed reductions in HDRS scores above the minimum clinically important difference (eight-point change), of whom two showed partial response. No participants showed full response or remission. CONCLUSIONS: These results strengthen the idea that oral esketamine is a safe and well-tolerated treatment for patients with chronic and severe TRD, but therapeutic effects were modest. Results were used to design a randomised controlled trial that is currently in progress.

Victims of Bullying: Emotion Recognition and Understanding.

Introduction: Victims of bullying often show interpersonal problems, such as having less high-quality interpersonal relationships compared to non-involved individuals. Research suggests that interpersonal struggles are associated with diminished emotional intelligence and competence and can lead to mental health problems such as depression. Therefore, we examined emotion recognition abilities, empathic accuracy, and behavioral responses to emotions in bullying victims and non-involved individuals. Based on previous research, we expected victims to show diminished skills in all three domains. Methods: Adolescents (Mage=17years; 67% female; no "other" gender participants) with (N=24) and without (N=21) a self-reported history of bullying victimization in high school completed a Virtual Reality facial emotion recognition task (ERT-VR), an empathic accuracy task (EAT) using videos of people recounting real-life autobiographical events, and a computer task in which they indicated their likely behavioral responses to facial emotions. Results: The two groups only significantly differed in recognizing emotions when taking their depression symptoms into account. Across emotions, victims had lower recognition accuracy than non-involved individuals. When examining emotion-specific differences, victims showed lower accuracy for neutral faces which they mainly mistook for angry faces. Conclusion: In contrast to expectations, adolescents with a high-school history of bullying victimization mostly showed similar emotional intelligence and competence skills as non-involved individuals. Nonetheless, we found some subtle differences regarding emotion recognition. Victims misjudged neutral as angry faces. This suggests a hostile attribution bias which might help explain victims' interpersonal problems as well as their increased risk for mental health problems.

Social Anxiety and Empathy: A Systematic Review and Meta-analysis.

OBJECTIVE: This systematic review and meta-analysis aimed to clarify the association between social anxiety and affective (AE) and cognitive empathy (CE). METHODS: 1442 studies from PsycINFO, Medline, and EMBASE (inception-January 2020) were systematically reviewed. Included studies (N = 48) either predicted variance in empathy using social anxiety scores or compared empathy scores between socially anxious individuals and a control group. RESULTS: Social anxiety and AE were statistically significantly positively associated, k = 14, r = .103 (95%CI [.003, .203]), z = 2.03, p = .043. Sex (QM (2) = 18.79, p <  .0001), and type of measures (QM (1 = 7.34, p = .007) moderated the association. Correlations were significant for male samples (rmale = .316, (95%CI [.200, .432])) and studies using self-report measures (rself-report = .162 (95%CI [.070, .254])). Overall, social anxiety and CE were not significantly associated, k = 52, r =-.021 (95%CI [-.075, .034]), z= -0.74, p = .459. Sample type moderated the association (QM (1) = 5.03, p < .0001). For clinical samples the association was negative (rclinical= -.112, (95%CI [-.201, -.017]). CONCLUSION: There was evidence for a positive association between social anxiety and AE, but future studies are needed to verify the moderating roles of sex and type of measure. Besides, low CE might only hold for patients with SAD.

Group Cognitive Behavioural Analysis System of Psychotherapy (CBASP) for persistently depressed outpatients: a retrospective chart review.

BACKGROUND: Cognitive behavioural analysis system of psychotherapy (CBASP) is an effective individual treatment for persistent depressive disorder (PDD), but evidence on group treatment (Group-CBASP) is limited. Our aim was to review the effect of Group-CBASP on self-report depression severity in outpatients with PDD, overall and by age of depression-onset. METHODS: A retrospective chart review study (November 2011-March 2017) in 54 patients with PDD (29 late-onset, 25 early-onset). Patients were previously treated by pharmacotherapy (92.6%), psychotherapy (98.1%) and/or electroconvulsive therapy (11.1%). Group-CBASP involved 24 weekly sessions during 6 months, followed by individual appointments over 6 months. The Inventory of Depressive Symptoms -self rating(IDS-SR) was used at baseline and after 3, 6, 9 and 12 months, computing mean differences and response rates. RESULTS: The mean IDS-SR score decreased significantly from 39.83 at baseline to 33.78 at 6 months: a decrease from severe to moderate depression after 24 weeks of Group-CBASP, with a medium effect size (Cohen's d = .49). At 12 months, the mean IDS-SR score was 32.81, indicating moderate symptom levels remained. At 6 and 12 months, mean IDS-SR scores were similar among late- versus early-onset patients, but at 12 months response rates were higher among late-onset patients. LIMITATIONS: Although results of our study provide valuable input for future prospective studies, limitations were the use of a retrospective design and the small group size. CONCLUSION: Group-CBASP offered to an outpatient population with PDD was associated with clinically relevant decrease in self-reported symptom severity, and with sustained response particularly in patients with late onset of depression. PRACTITIONER POINTS: Group-CBASP seems to be a good alternative for CBASP in individual setting. Patients with late age of depression-onset seem to benefit more from Group-CBASP. This study shows that clinical relevant effects of Group-CBASP, followed by individual contacts, remain at least for 6 months. Research on personalizing treatment strategies is needed to improve patient assignment for Group-CBASP.

Dynamic Interactive Social Cognition Training in Virtual Reality (DiSCoVR) for People With a Psychotic Disorder: Single-Group Feasibility and Acceptability Study.

BACKGROUND: People with a psychotic disorder commonly experience problems in social cognition and functioning. Social cognition training (SCT) improves social cognition, but may inadequately simulate real-life social interactions. Virtual reality (VR) provides a realistic, interactive, customizable, and controllable training environment, which could facilitate the application of skills in daily life. OBJECTIVE: We developed a 16-session immersive VR SCT (Dynamic Interactive Social Cognition Training in Virtual Reality [DiSCoVR]) and conducted a single-group feasibility pilot study. METHODS: A total of 22 people with a psychotic disorder and reported problems in social cognition participated. Feasibility and acceptability were assessed using a survey for participants and therapists, and by examining relevant parameters (eg, dropouts). We analyzed preliminary treatment effects on social cognition, neurocognition, and psychiatric symptoms. RESULTS: A total of 17 participants completed the study. Participants enjoyed DiSCoVR (mean 7.25, SD 2.05; range 3-10), thought it was useful for daily social activities (mean 7.00, SD 2.05; range 3-10), and enjoyed the combination of VR and a therapist (mean 7.85, SD 2.11; range 3-10). The most frequently mentioned strength of DiSCoVR was the opportunity to practice with personalized social situations (14/20, 70%). A significant improvement of emotion perception was observed (Ekman 60 Faces; t16=-4.79, P<.001, d=-0.67), but no significant change was found in other measures of social cognition, neurocognition, psychiatric symptoms, or self-esteem. CONCLUSIONS: DiSCoVR was feasible and acceptable to participants and therapists, and may improve emotion perception.

Threat-related motivational disengagement: Integrating blunted cardiovascular reactivity to stress into the biopsychosocial model of challenge and threat.

Background: The biopsychosocial model of challenge and threat specifies a challenge-threat continuum where favorable demand-resource evaluations, efficient cardiovascular responses, and superior performance characterize challenge; and maladaptive outcomes like clinical depression characterize threat states. The model also specifies task engagement, operationalized as heart rate and ventricular contractility increases, as a prerequisite for challenge and threat states. The blunted cardiovascular reactivity to stress literature describes reductions of these increases and associates them with problems like clinical depression. Objectives: To determine whether blunted cardiovascular reactivity to stress has implications for challenge and threat theory. Methods: We review and synthesize the literatures on blunted cardiovascular reactivity to stress and the biopsychosocial model. Results: Blunted cardiovascular reactivity appears not to reflect a physiological inability to respond to stress. Rather, it reflects a contextually dependent motivational dysregulation and reduced reactivity to stress consistent with deficient task engagement in the biopsychosocial model. Conclusion: We argue that blunted cardiovascular reactivity represents deficient task engagement, and more generally, motivational disengagement due to threat states. Our biopsychosocial model-based approach conceptualizes this motivational disengagement as a tendency to avoid motivated performance situations. This tendency may represent a defense mechanism against subsequent threat and might explain associations with disorders like clinical depression.

Correction to: Oral esketamine for treatment-resistant depression: rationale and design of a randomized controlled trial.

After publication of our article [1] we were notified that Figure 1 was wrongly presented.

Homesickness in social context: An ecological momentary assessment study among 1st-year university students.

Homesickness is common among university students and associated with mental health problems. Most previous studies assessed homesickness as a summary of the past weeks. However, there may be significant fluctuations across situations. At the current residence, homesickness may especially be triggered during (phone) interactions with attachment figures. Dutch and international 1st-year students (n = 92) completed the Utrecht Homesickness Scale and subsequently used a smartphone application to record social interactions for 14 days (ecological momentary assessment [EMA]). For each interaction they reported the social context (e.g. location, contact type) and their affective state, including homesickness. Homesickness in the past weeks and momentary homesickness were both higher in international students than in Dutch students. Feeling homesick was highest at participants' current residency, when interacting with parents, or when using video-chat. When participants felt more homesick, they reported less pleasant and more unpleasant affect. In conclusion, EMA provided insight in cross-situational variations in homesickness.

Oral esketamine for treatment-resistant depression: rationale and design of a randomized controlled trial.

BACKGROUND: There is an urgent need to develop additional treatment strategies for patients with treatment-resistant depression (TRD). The rapid but short-lived antidepressant effects of intravenous (IV) ketamine as a racemic mixture have been shown repeatedly in this population, but there is still a paucity of data on the efficacy and safety of (a) different routes of administration, and (b) ketamine's enantiomers esketamine and arketamine. Given practical advantages of oral over IV administration and pharmacodynamic arguments for better antidepressant efficacy of esketamine over arketamine, we designed a study to investigate repeated administration of oral esketamine in patients with TRD. METHODS: This study features a triple-blind randomized placebo-controlled trial (RCT) comparing daily oral esketamine versus placebo as add-on to regular antidepressant medications for a period of 6 weeks, succeeded by a follow-up of 4 weeks. The methods support examination of the efficacy, safety, tolerability, mechanisms of action, and economic impact of oral esketamine in patients with TRD. DISCUSSION: This is the first RCT investigating repeated oral esketamine administration in patients with TRD. If shown to be effective and tolerated, oral esketamine administration poses important advantages over IV administration. TRIAL REGISTRATION: Dutch Trial Register, NTR6161. Registered 21 October 2016.