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.

How do victims of bullying develop depression? Testing interpersonal style to explain the victimization-depression link.

This study tested to what extent the relation between bullying victimization and future symptoms of depression could be explained by victims being more hostile and less assertive than non-involved individuals. Data came from waves 2-4 of the Dutch TRacking Adolescents' Individual Lives Survey (TRAILS). Participants' bullying experiences were assessed at age 13, interpersonal style at age 16, and depression symptoms at age 19. Mediation analyses were performed primarily on 274 self-reported victims and 1498 non-involved peers. Self-reported victims had an increased risk for depression symptoms. About a third of that risk could be explained by victims' hostile style, which was also higher than those of non-involved peers. Although victims also reported lower levels of assertiveness than non-involved peers, this interpersonal style did not mediate the link between bullying victimization and depression. Our findings suggest that high hostility, but not low assertiveness, partly explains the increased depression risk of self-reported victims. Therefore, interventions could focus on addressing hostility, to help reduce the likelihood that adolescents who have experienced bullying victimization will have more interpersonal conflicts and mental health problems in the future. Supplementary materials also include analyses for bullies and bully-victims, and for peer-reported measures.

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.

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.

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.

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.

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.

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.

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.

Formal representation of ambulatory assessment protocols in HTML5 for human readability and computer execution.

Ambulatory assessment (AA) is a research method that aims to collect longitudinal biopsychosocial data in groups of individuals. AA studies are commonly conducted via mobile devices such as smartphones. Researchers tend to communicate their AA protocols to the community in natural language by describing step-by-step procedures operating on a set of materials. However, natural language requires effort to transcribe onto and from the software systems used for data collection, and may be ambiguous, thereby making it harder to reproduce a study. Though AA protocols may also be written as code in a programming language, most programming languages are not easily read by most researchers. Thus, the quality of scientific discourse on AA stands to gain from protocol descriptions that are easy to read, yet remain formal and readily executable by computers. This paper makes the case for using the HyperText Markup Language (HTML) to achieve this. While HTML can suitably describe AA materials, it cannot describe AA procedures. To resolve this, and taking away lessons from previous efforts with protocol implementations in a system called TEMPEST, we offer a set of custom HTML5 elements that help treat HTML documents as executable programs that can both render AA materials, and effect AA procedures on computational platforms.

Intra- and Interindividual Variability in the Behavioral, Affective, and Perceptual Effects of Alcohol Consumption in a Social Context.

BACKGROUND: We examined the influence of interindividual differences in alcohol use on the intraindividual associations of drinking occurrence with interpersonal behaviors, affect, and perceptions of others during naturally occurring social interactions. METHODS: For 14 consecutive days, 219 psychology freshmen (55% female; Mage  = 20.7 years, SD = 2.18) recorded their behaviors, affect, and perceptions in social interactions soon after an interpersonal event occurred. Interpersonal behaviors and perceptions were assessed in terms of dominance-submissiveness and agreeableness-quarrelsomeness. Participants also reported the number of alcoholic drinks consumed within 3 hours of each interaction. We considered the intraindividual associations of (i) having a drinking episode and (ii) the number of drinks during an episode with behaviors, affect, and perceptions and examined interindividual differences in drinking frequency and intensity during social interactions as potential moderators of these associations. RESULTS: Social drinking frequency and intensity moderated the associations between drinking episode and behaviors, affect, and perceptions in social interactions. During a drinking episode, more frequent social drinkers perceived others as more dominant than less frequent social drinkers. During a drinking episode in which more alcohol was consumed than usual, more frequent social drinkers also reported behaving more dominantly and experiencing less pleasant affect. CONCLUSIONS: As more frequent social drinkers had different interpersonal responses to drinking than less frequent social drinkers, including when they had consumed larger amounts of alcohol than usual, our results suggest a differential susceptibility to the effects of alcohol during naturally occurring social interactions among drinkers with varying drinking frequency.

The Reciprocity of Prosocial Behavior and Positive Affect in Daily Life.

OBJECTIVE: To examine whether prosocial behaviors help sustain a positive mood, we tested the dynamic reciprocal associations between prosocial behavior and positive affect (PA) in daily life. A second aim was to examine whether the personality traits Neuroticism and Extraversion moderate these associations. METHOD: The study included a community sample (N = 553). Participants completed an electronic diary assessing prosocial behavior and PA three times a day over 30 days. A subsample of 322 participants filled out the NEO Five-Factor Inventory to assess Neuroticism and Extraversion. Multilevel autoregressive models were performed to examine the within-person bidirectional associations between prosocial behavior and PA and possible moderation by Neuroticism and Extraversion. RESULTS: Within individuals, more PA was followed by more prosocial behavior at the next assessment, and more prosocial behavior was followed by more PA. The effect of prosocial behavior on PA was stronger for individuals high on Neuroticism. Extraversion did not moderate the associations under study. CONCLUSIONS: The findings indicate that prosocial behavior and PA reinforce each other in daily life. Prosocial behavior seems most beneficial for individuals high on Neuroticism.

No Menstrual Cyclicity in Mood and Interpersonal Behaviour in Nine Women with Self-Reported Premenstrual Syndrome.

BACKGROUND/AIMS: Before diagnosing premenstrual dysphoric disorder (PMDD), 2 months of prospective assessment are required to confirm menstrual cyclicity in symptoms. For a diagnosis of premenstrual syndrome (PMS), this is not required. Women with PMDD and PMS often report that their symptoms interfere with mood and social functioning, and are said to show cyclical changes in interpersonal behaviour, but this has not been examined using a prospective approach. We sampled cyclicity in mood and interpersonal behaviour for 2 months in women with self- reported PMS. METHODS: Participants met the criteria for PMS on the Premenstrual Symptoms Screening Tool (PSST), a retrospective questionnaire. For 2 menstrual cycles, after each social interaction, they used the online software TEMPEST to record on their smartphones how they felt and behaved. We examined within-person variability in negative affect, positive affect, quarrelsomeness, and agreeableness. RESULTS: Participants evaluated TEMPEST as positive. However, we found no evidence for menstrual cyclicity in mood and interpersonal behaviour in any of the individual women (n = 9). CONCLUSION: Retrospective questionnaires such as the PSST may lead to oversampling of PMS. The diagnosis of PMS, like that of PMDD, might require 2 months of prospective assessment.

Oral ketamine for the treatment of pain and treatment-resistant depression†.

BACKGROUND: Recent studies with intravenous (i.v.) application of ketamine show remarkable but short-term success in patients with MDD. Studies in patients with chronic pain have used different ketamine applications for longer time periods. This experience may be relevant for psychiatric indications. AIMS: To review the literature about the dosing regimen, duration, effects and side-effects of oral, intravenous, intranasal and subcutaneous routes of administration of ketamine for treatment-resistant depression and pain. METHOD: Searches in PubMed with the terms 'oral ketamine', 'depression', 'chronic pain', 'neuropathic pain', 'intravenous ketamine', 'intranasal ketamine' and 'subcutaneous ketamine' yielded 88 articles. We reviewed all papers for information about dosing regimen, number of individuals who received ketamine, number of ketamine days per study, results and side-effects, as well as study quality. RESULTS: Overall, the methodological strength of studies investigating the antidepressant effects of ketamine was considered low, regardless of the route of administration. The doses for depression were in the lower range compared with studies that investigated analgesic use. Studies on pain suggested that oral ketamine may be acceptable for treatment-resistant depression in terms of tolerability and side-effects. CONCLUSIONS: Oral ketamine, given for longer time periods in the described doses, appears to be well tolerated, but few studies have systematically examined the longer-term negative consequences. The short- and longer-term depression outcomes as well as side-effects need to be studied with rigorous randomised controlled trials.

The Effects of Tryptophan on Everyday Interpersonal Encounters and Social Cognitions in Individuals with a Family History of Depression.

BACKGROUND: Individuals with a family history of depression show subtle abnormalities in the processing of social stimuli. This could negatively affect their interpersonal functioning and contribute to their depression risk. Repeated administration of the serotonin precursor tryptophan has previously been shown to increase agreeable behavior and reduce quarrelsome behavior in irritable people, who are also considered at risk for depression. METHODS: To examine the effects of tryptophan on social functioning in individuals with a family history of depression, 40 men and women with at least one first-degree relative with depression received tryptophan (1g three times a day) and placebo for 14 days each in a double-blind crossover design and recorded their social behavior and mood during everyday interpersonal encounters. Participants also provided daily ratings of their positive and negative cognitions concerning their social functioning. RESULTS: Tryptophan improved mood. Unexpectedly, tryptophan increased quarrelsome behavior and reduced agreeable behavior, specifically during interactions at home. The behavioral effects of tryptophan were not moderated by mood or by the interaction partner. Negative social cognitions were lower when tryptophan was given second and lower during placebo when placebo was given second. CONCLUSION: Overall, tryptophan may not alter social behavior in individuals with a family history of depression as it does in irritable people. However, the behavioral effects of tryptophan at home might be seen as a way for individuals with a family history of depression to achieve more control. Over time, this may positively influence the way they feel and think about themselves in a social context.

Possible role of more positive social behaviour in the clinical effect of antidepressant drugs.

Increasing serotonin decreases quarrelsome behaviours and enhances agreeable behaviours in humans. Antidepressants, even those whose primary action is not on serotonin, seem to increase serotonin function. We suggest that antidepressants act in part by effects on social behaviour, which leads to a gradual improvement in mood. We review the evidence supporting the idea that antidepressants may be moving behaviour from quarrelsome to agreeable. The more positive social responses of interaction partners would initiate a cycle of more positive social behaviour, and this iterative process would result in a clinically significant improvement in mood.

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.

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.

Dopamine and light: dissecting effects on mood and motivational states in women with subsyndromal seasonal affective disorder.

BACKGROUND: Despite evidence that bright light can improve mood, the neurobiology remains poorly understood. Some evidence implicates the catecholamines. In the present study, we measured the effects of transiently decreasing dopamine (DA) synthesis on mood and motivational states in healthy women with mild seasonal mood changes who were tested in either bright or dim light. METHODS: On 2 test days, participants slept overnight in a light-controlled room. On the morning of each session, half of the participants awoke to gradual increases of bright light, up to 3000 lux, and half to dim light (10 lux). For all participants, DA was reduced on 1 of the test days using the acute phenylalanine/tyrosine depletion (APTD) method; on the other day, they ingested a nutritionally balanced control mixture (BAL). Beginning 4 hours postingestion, participants completed subjective mood questionnaires, psychological tests and a progressive ratio breakpoint task during which they worked for successive units of $5. RESULTS: Thirty-two women participated in our study. The APTD lowered mood, agreeableness, energy and the willingness to work for monetary reward. The effects on energy and motivation were independent of light, while the effects on mood and agreeableness were seen in the dim condition only, being prevented by bright light. LIMITATIONS: Acute phenylalanine/tyrosine depletion might affect systems other than DA. The sample size was small. CONCLUSION: These results suggest that increased DA function may be responsible for some of the beneficial effects of light, while adding to the evidence that the neurobiology of mood and motivational states can be dissociated.