In ESCAPE-TRD, esketamine nasal spray (ESK-NS) significantly increased the probability of remission at Week (Wk)8 and being relapse‑free through Wk32 after remission at Wk8 versus (vs) quetiapine extended-release (QTP-XR), in patients (pts) with treatment resistant depression (TRD). Safety data were consistent with established profiles of each treatment, with no new safety signals identified (Reif et al. DGPPN 2022; P-01-04).

To explore weight changes and their impact on treatment discontinuation in ESCAPE-TRD.

ESCAPE‑TRD (NCT04338321) was a randomised, open-label, rater-blinded, phase IIIb trial comparing efficacy and safety of ESK-NS vs QTP-XR in pts with TRD. Safety analyses were conducted on pts who received ≥1 dose of study treatment. Treatment-emergent adverse events (TEAEs) were defined as occurring at or after the first dose of study treatment and within 14 days/30 days (non-serious/serious) of the last dose. A ≥7% increase/decrease in weight from screening was considered for evaluation as a TEAE. Weights were measured and are reported as observed, with no missing data imputation.

336 and 340 pts were randomised to ESK-NS and QTP-XR; 334 and 336 were included in the safety population. Over the 32-week study, a TEAE of weight increase was reported in fewer pts treated with ESK-NS than QTP-XR (9 [2.7%] vs 42 [12.5%]), leading to treatment discontinuation in 0 vs 6 (1.8%) pts, respectively. Incidences of weight increase TEAEs were balanced across pts categorised as normal, overweight or obsese by baseline body mass index (BMI; Figure). A weight decrease TEAE was reported in 7 pts (2.1%) in the ESK-NS arm vs 0 pts in the QTP-XR arm. Mean (standard deviation [SD]) weight at baseline was 76.4 (16.2) kg (ESK-NS; n=334) vs 79.1 (16.9) kg (QTP-XR; n=336). At Wk32, mean weight was maintained (76.5 [16.3] kg) in ESK-NS treated pts (n=249; mean [SD] change from baseline: 0.1 [4.0] kg) and increased (80.7 [15.6] kg) in QTP-XR treated pts (n=203; mean [SD] change from baseline: 2.5 [5.1] kg).

Image:

Increase in weight was uncommon with ESK-NS; weight increases were more common with QTP-XR and resulted in more treatment discontinuations. Weight increase was independent from baseline BMI.

We thank the patients who participated. Funding: Janssen, medical writing: Costello Medical, UK

None Declared

Persistent negative symptoms of schizophrenia are generally considered difficult to treat or treatment resistant. A large number of investigational drugs developed and or tested for the treatment of persistent negative symptoms failed to show efficacy leading to pessimism in treatment and disinvestment in treatment research of negative symptoms.

1. To demonstrate, that available treatment methods – both pharmacological and non-pharmacological - are in fact effective for the treatment of negative symptoms of schizophrenia 2. To shortly summarize new drug research in this field.

Review of research data.

The overall estimate for the placebo effect had a medium effect size, with a Cohen’s d value of 0.6444 (SE = 0.091).1 The estimates for the placebo effect were similar in the add-on and monotherapy studies. Amisulprid was superior to placebo, cariprazine was superior to risperidone, and “direct comparisons of antipsychotics in patients with predominant negative symptoms indicated no significant difference between amisulpride and olanzapine and between asenapine and olanzapine…”2 . Various nonpharmacological interventions improved negative symptoms in randomized controlled trials relative to treatment as usual (e.g. social skills training, music therapy, non-invasive brain stimulation, mindfulness, and exercise-based interventions) 3 There is a progress in research with non-dopaminergic agents for the treatment of negative symptoms (e.g. pimavanserin, roluperidon, ulotaront).

For medication classes other than antipsychotics and antidepressants, we found no reliable support for evidence-based recommendations for using these agents in the treatment of negative symptoms in clinical practice. Effect sizes for psychosocial interventions range from small to moderate. The use of placebo has shown a clinically significant positive effect on negative symptoms, a finding that warrants further research and provides a sense of optimism regarding potential therapeutic benefits.

1. 1. Czobor, P., Kakuszi, B. and Bitter, I., 2022. Placebo response in trials of negative symptoms in schizophrenia: a critical reassessment of the evidence. Schizophrenia Bulletin, 48(6), pp.1228-1240. 2. Czobor, P., Bitter I. Pharmacologic treatment of negative symptoms: Focus on efficacy. In: Bitter I. (ed): Managing Negative Symptoms of Schizophrenia, Oxford University Press, 2020, p. 67

2. 2. Savill, M. Psychosocial/non-pharmacologic treatment of negative symptoms: focus on efficacy. In: Bitter I. (ed): Managing Negative Symptoms of Schizophrenia, Oxford University Press, 2020, p. 87

None Declared

Becoming a psychiatrist, clinical psychologist or psychotherapist involves a complex set of skills that require extensive training. Clinical practice development and professional and personal identity formation are closely intertwined and continue throughout one’s career. Individual and environmental factors influence dropout. The beginning stages of training are incredibly challenging for trainees and can be a time of vulnerability as they face early professional hurdles. We propose that certain educational factors, such as inadequate practical training and insufficient emotional support during professional dilemmas, play a crucial role in manifesting burnout or other symptoms, potentially leading to stagnation in one’s career.

The main objective of our study is to identify causes of disruption and/or discontinuation of the training/residency programs in psychiatry, clinical psychology, and psychotherapy. Our study also aims to highlight the causes of chronic exhaustion among trainees in mental health professions.

The research team has developed a comprehensive questionnaire including two validated psychometric scales, the Effort-Reward Imbalance Questionnaire (ERI, Siegrist et al. Soc Sci Med 2004; 58 1483-99, Salavecz et al. J Men Psychosom 2006; 7 231–246) and the Mental Health Test (MHT, Vargha et al. J Men Psychosom 2020; 21 281–322). A quantitative analysis (Braun et al. Qual. Res. Psychol. 2006; 3 77–101) will be performed on the responses, following which interviews will be conducted with previous volunteers who participated in the study. The interviews will be evaluated through content analysis. Our survey is prepared with the involvement of all significant training centers in Hungary. The study was approved by the United Ethical Review Committee for Research in Psychology (EPKEB, approval numbers: 2021-109, 2023-101).

The participants’ main characteristics and the questionnaires’ results will be summarized with standard statistical methods, while the interviews will be analyzed with the help of qualitative methods.

Based on the results of the described study, we aim to investigate the educational system’s impact on the career development and commitment of psychiatrists, psychologists, and psychotherapists in Hungary. Additionally, the research will yield valuable perspectives on how these factors affect the mental well-being of these professionals. Ultimately, the results could help address areas of concern and improve mental health professionals’ training.

* Presenting author

** The two authors contributed equally.

None Declared

Autism spectrum disorder (ASD) is a childhood onset neurodevelopmental condition, that leads to permanent disability in a high proportion of cases. ASD is associated with a heterogeneous symptom presentation, which - besides social interaction and communication difficulties - encompasses altered sensory reactivity, including excessive hyper-sensitivity to stimuli, especially in the visual domain. Meta-analyses of fMRI studies revealed increased reactivity in visual task conditions in the temporal and occipital brain regions. Neural oscillations in the EEG gamma band are viewed as a candidate neurobiological marker for higher order sensory and perceptual processes, and social interactions.

We investigated changes in gamma activity in the EEG in the eyes open (EO) vs. eyes closed (EC) condition in order to identify the neurobiological underpinning of the enhanced sensitivity to visual input in ASD as compared to typically developing (TD) subjects.

EEGs were obtained in EC and EO condition in ASD (N=23) and TD subjects (N=24) in an ongoing study. For EEG recording we used a high-density 128-channel BioSemi system, with 0.5 Hz frequency resolution. The spectral power in the gamma band (30-100Hz) was quantified by the power spectral density. To investigate whether changes in the gamma band were linked to changes in arousal instead of enhanced visual processing, we also examined alterations in the alpha band (8-13Hz) in the EO condition. Spectral power changes were determined for each EEG channel by computing the difference between the EC and EO conditions (EO-EC).

Spectral power in the gamma band showed changes in the opposite direction in the two study groups: ASD subjects manifested significant (p<0.05) increase, while TD subjects had a decrease in the EO vs. EC condition in the temporal and occipital brain regions. By contrast, the changes in the alpha band were similar, with both groups exhibiting a spectral power decrease in the EO compared to the EC condition.

In ASD, an enhancement of gamma activity is present in the EO as compared to the EC condition in the posterior brain areas. These brain areas are involved in the processing of visual information, and gamma activity is considered as a measure of perceptual processes. Thus, the gamma alterations in the EO vs. EC condition may underlie the hyper-sensitivity symptoms to visual stimuli in ASD, and EEG can offer a simple to use tool to delineate the neurobiological foundation of the symptom presentation.

Funding statement: Hungarian Brain Research program,#NAP2022-I-4/2022

None Declared

Comprehensive care programs, which include individually planned pharmacotherapy are associated with higher rates of recovery1 and better long-term prognosis2. However, there are barriers to individually optimised antipsychotic treatment both from both the patients and treatment teams perspectives.

To summarize the potential contribution of adequate long-term antipsychotic treatment to recovery or better outcomes in schizophrenia.

Review of research data.

Results A shorter duration of untreated psychosis, a lower number of relapses, and the absence of a chronic course of psychosis are associated with higher rates of recovery and a better prognosis. The OPUS early intervention program was associated with better outcomes for up to 10 years, but not for more than 20 years3. Second generation antipsychotics are associated with lower mortality rates, including suicides in young people with schizophrenia.4

Higher doses of antipsychotics are associated with poorer outcomes and with potential structural brain changes, while adequate (lower) doses of antipsychotics are associated with lower side effect burden and better overall outcomes5. A significant proportion of patient may benefit from polypharmacy (combination of 2 antipsychotics)6. Antipsychotic treatment discontinuation strategies are associated with the development of treatment resistance.7

Adequate (low dose) antipsychotic treatment is part of the complex early intervention programs and long term treatment of schizophrenia, which are associated with higher rates of recovery and good outcomes. The role of polypharmacy (combination of 2 antipsychotics) may need a reconsideration in the treatment guidelines of schizophrenia.

1. 1. Kane JM et al. The Journal of clinical psychiatry. 2015 Mar 25;76(3):16590.

2. 2. Posselt CM et al. 2021. American Journal of Psychiatry, 2021, 178(10):941-951

3. 3. Hansen HG et al. 2023. JAMA Psychiatry, 2023, 80(4): 371-379.

4. 4. Correll CU et al. World Psychiatry. 2022 Jun;21(2):248-71.

5. 5. Andreasen NC et al. 2013 Jun;170(6):609-15.

6. 6. Katona L et al. 2014 Jan 1;152(1):246-54.

7. 7. Emsley R et al2013 Feb 1;33(1):80-3.

None Declared

Autism is neurodevelopmental disorder with a heterogeneous presentation of symptoms, which include disturbances in sensory, motor and cognitive processes, among which social cognitive impairments and social interaction difficulties play prominent role. Despite the fact that these impairments can lead to lifelong disability and difficulties in everyday functioning, their neurobiological basis remains largely unknown. Neural oscillations in the gamma band have been shown to be an important candidate neurobiological marker of higher order cognitive processes and social interactions. Yet, alterations of gamma oscillations in ASD have received little attention in the literature.

The aim of the current study was to investigate resting state gamma oscillations in the EEG in order to delineate alterations in ASD as compared to typically developing (TD) subjects in the intrinsic activity of the neural networks that have been linked to social cognitive functioning.

Resting-state EEGs were obtained in an ongoing study investigating ASD (N=19) and TD subjects (N=15), based on eyes closed condition. EEGs were recorded using a 128-channel BioSemi system. EEG absolute power was investigated in the gamma 30-48Hz frequency band.

Gamma activity was significantly (p<0.05) diminished in multiple brain regions in ASD as compared TD subjects. The diminished gamma activity had a distinctive topographical distribution, which included the left and right inferior temporal gyrus, the right superior temporal gyrus, the TPJ and the right extrastriate areas. Additionally, we found a hemispheric asymmetry in the occipital brain areas with a decrease of gamma activity on the right and an increase in the left hemisphere as compared to TD.

Diminished gamma activity in the above brain areas may represent a cortical dysfunction which can be present due to a reduced capacity to process socially relevant information and a decreased capacity to omit irrelevant stimuli.

Funding: Hungarian Brain Research program,#NAP2022-I-4/2022

None Declared

Interpersonally coordinated behaviors are crucial for social interactions.The “Theory of Mind,” or mentalization capacity, of an individual is essential for the establishment of behavioral synchronization. The Reading the Mind in the Eyes Test (RMET) is used to assess mentalization, social cognition and empathy. Previous RMET studies, investigated people in isolation, not in social situations. It is unclear how the RMET predicts functioning during real-life social interactions.

To investigate the relationship between the performance measured on the RMET test and the synchronous behavior of two individuals interacting with each other during tasks requiring social collaboration.

Sample included healthy controls (HC,n=48) and patients with ADHD (n=26) or schizophrenia (SCH,n=36) from an ongoing EEG-hyperscanning study, employing a social coordination condition.We applied a Go/NoGo reaction time(RT) task performed by pairs of participants. Synchronous behavior was characterized by the correlation of participants’ RTs.We used the percent (%) correct responses from the RMET to characterize social cognition.

In HC, with better social cognitive performance, the correlation of behavioral responses was significantly (p<0.05) higher. In ADHD, better performance on the RMET was also accompanied by better behavioral synchronization, but the association did not reach significance due to the smaller sample size. In SCH, no relationship was detected.

In HC and ADHD, the mentalization ability as measured by RMET is associated with the behavioral synchronization between individuals in social interaction.The lack of association in the schizophrenia group may be due to psychopathological symptoms, which should be elucidated in future research. Funding: Supported by the Hungarian Brain Research program#2017-1.2.1-NKP-2017-0002

No significant relationships.

During the COVID-19 pandemic residents of the central region of Hungary also had to adapt to several challenges such as changes of hospitals’ specialty profiles and delegation of health care workers to COVID wards.

Hungarian residents have their practical training in various hospitals, while their psychiatric academic training is organised in groups.

Our aim is to share our personal experiences about how our work and training have changed during the pandemic and it’s effect on our patients.

Participants of the study were the authors of the poster. Responses to open questions were structured based on the following topics: competencies in internal medicine, infectious diseases and psychiatry, our collaboration with other medical disciplines, psychiatric training and attitudes towards mental health patients.

We worked min 2 weeks max 8 months at COVID wards and also treated COVID-19 infected psychiatric patients, thus gaining a greater experience in general medicine. In psychiatric work, acute care became prominent, communication in PPE and restricted contact with patients’ relatives were particularly difficult. Our relationship with other specialists has improved, consultation became easier. Increased use and misuse of psychiatric consultation requests led to further pressure. Restrictions, stigmatisation and discrimination increased against psychiatric patients, including difficult access to care. Psychiatric training in the hospitals became limited, however seminars organized by the university continued online with our active participation.

During the pandemic we gained greater experience in general medicine. Psychiatric care and our training was negatively affected, however the latter was mitigated by online seminars.

No significant relationships.

During the last decades, a renewed interest for negative symptoms (NS) was brought about by the increased awareness that they interfere severely with real-life functioning, particularly when they are primary and persistent.

In this guidance paper, we provide a systematic review of the evidence and elaborate several recommendations for the conceptualization and assessment of NS in clinical trials and practice.

Expert consensus and systematic reviews have provided guidance for the optimal assessment of primary and persistent negative symptoms; second-generation rating scales, which provide a better assessment of the experiential domains, are available; however, NS are still poorly assessed both in research and clinical settings.

This European Psychiatric Association (EPA) guidance recommends the use of persistent negative symptoms (PNS) construct in the context of clinical trials and highlights the need for further efforts to make the definition of PNS consistent across studies in order to exclude as much as possible secondary negative symptoms. We also encourage clinicians to use second-generation scales, at least to complement first-generation ones.

The EPA guidance further recommends the evidence-based exclusion of several items included in first-generation scales from any NS summary or factor score to improve NS measurement in research and clinical settings. Self-rated instruments are suggested to further complement observer-rated scales in NS assessment.

Several recommendations are provided for the identification of secondary negative symptoms in clinical settings.

The dissemination of this guidance paper may promote the development of national guidelines on negative symptom assessment and ultimately improve the care of people with schizophrenia.

One type of the treatment interventions is the “off label” use of a drug, which may include the use of a drug in a nonapproved indication, dose range, age group, drug combination and drug formulation. Research in this field is insufficient, while the medical, financial and legal consequences of off label use maybe serious. In case of off label use of a drug the manufacturer does not have any responsibility in case of adverse or serious adverse events.

Labels (summary of product characteristics) of antipsychotic drugs have been compared for indications and examples of regulations for off label use have been collected.

Labels (summary of product characteristics) very rarely include indications for children, adolescents and for the elderly. A significant proportion of psychotic disorders listed in DSM-IV or in ICD 10 and major clinical syndromes have not been included as indications in the label of antipsychotic drugs. The same compound marketed by different companies under different names may have different labels.

The regulations for off label use of drugs vary between countries and as of today there is no common European regulation for off label drug use. In some countries off label drug prescription is not restricted, these prescriptions maybe reimbursed. Some countries restrict reimbursement of off label prescriptions and there are countries restricting the prescriptions.

More research (especially in young and old age groups) is needed in this field and some European guidelines/regulation would increase the safety of using drugs off label.

Placebo-controlled (PC) Phase 3 trials are critical for the registration of new atypical antipsychotic medications (AAP) for schizophrenia but use of placebo when efficacious treatments exist has been questioned.

To investigate evidence for the use of placebo in clinical trials of schizophrenia via a meta-analysis of large, PC trials of new AAPs.

Using the FDA Summary Basis of Approval reports, we examined outcome data from all Phase 3 clinical trials that evaluated investigational AAPs. Publications from peer-reviewed literature were also identified. The main outcome variables were: symptom improvement in individual treatment arms, clinical response, therapeutic failure.

Meta-regression indicated a highly significant difference between improvement in the placebo and the active arm (p<0.0001). Effect size (ES) estimate for the placebo arm revealed that patients in this arm obtained a statistically significant but clinically negligible symptom reduction (Cohen d: ~0.15; p<0.004) while active-treated patients displayed a substantial symptom reduction (Cohen d: ~0.70; p<0.0001). Active treatments showed a highly significant (p<0.001) superiority vs. placebo in clinical response and therapeutic failure, with failure rates often exceeding the rate of clinical response. ESs for change varied substantially across trials, with an ES range of d=0.8 for the placebo and the active arms, respectively.

Variable ESs across studies support the view that placebo control has major importance in trials of new AAPs. However, efforts should focus on finding design alternatives and to minimize the risks of PC trials so that they may be conducted in ethically acceptable manner.

Therapeutic adherence is a key issue in patients suffering from schizophrenia. The possibility of psychotic relapse is increased by the omission of medication. Relapses decrease the chance of favourable prognosis of the disorder, and this leads to further hospitalization, which entails increased social expenses. Unfortunately, medication omission, or non-compliance, is very frequent in patients with schizophrenia. Good compliance develops as a result of an interaction among multiple factors affecting the physician, the patient and his/her relatives. The objective was to define principal factors which affect compliance in persons with schizophrenia.

A survey was conducted using a self-rated questionnaire to assess compliance in patients, their relatives and their physicians. Subjects participated from various geographical areas of the country in order to make a sample representative.

909 schizophrenic patients, 73 physicians and 423 relatives participated in this study. Forty-one percent of patients indicated non-compliance by their own decision. The analogous estimate from physicians was 57%. Almost half of the patients (42%) forgot to take the medication or miss it due to other cognitive dysfunctions. This problem affects more patients according to physicians' (49%) and the relatives' (55%) opinion.

Based on our estimates improvement of therapeutic adherence in patients with schizophrenia has high clinical importance, since lack of adherence is directly related to therapeutic failure, and results in an elevated risk for patients' deterioration and life-functioning.

This study assessed the efficacy of agomelatine (1,2,3), in the prevention of relapse in non-depressed out-patients with DSM-IV-TR defined Generalized Anxiety Disorder (GAD) and the tolerability.

GAD patients received open label agomelatine (25–50 mg/day). At week 4 the dose was increased for patients with insufficient improvement (blinded criteria). At week 16, responders were randomised to maintenance treatment with either agomelatine, or placebo for a 26 week period. Then, agomelatine treated-patients were re-randomised to an agomelatine arm or to a placebo arm, to confirm the lack of discontinuation symptoms (on the DESS check-list).

The primary outcome was the time to relapse (days) during the 26 week double-blind treatment period, as estimated using the Kaplan-Meier method. Relapse was defined as HAMA total score > = 15 or withdrawal for lack of efficacy (in the investigator's opinion, based on both HAM-A and CGI scores).

477 patients entered the open-label phase and 329 completed this period. 228 patients were randomly assigned to receive agomelatine (114 patients) or placebo (114 patients).

The incidence over time of relapse was significantly lower with agomelatine compared to placebo (19.7% versus 31.7% log rank test p = 0.046) during the double-blind treatment period.

During the double-blind treatment period 12.4% patients with agomelatine and 9.6% with placebo reported at least one emergent adverse event related to the study treatment. There was no discontinuation syndrome in agomelatine treated patients.

Agomelatine was efficacious in preventing relapse in GAD, with maintenance of efficacy over 6 months, and good tolerability.

Earlier studies have shown that candidate gene risk polymorphisms and psychoactive substance abuse influence the frequency and severity of psychosis.

In this study we examined whether the most studied schizophrenia risk polymorphisms and psychoactive substance abuse interact in their influence on symptom severity and neurocognition.

We analyzed the clinical data of 280 schizophrenia patients, including genotyping data of the candidate genes NRG1, DTNBP1, RGS4, G72/G30 and PIP5K2A. Patients were assessed clinically by the Positive and Negative Symptom Scale (PANSS) and information about substance abuse was based on self-report and reviewing patient charts. We tested for possible interactional effects using the General Linear Model (GLM) analysis.

15,8% of patients reported episodic or regular substance abuse, the vast majority (92%) used cannabis or the combination of cannabis and another drug. Substance abuse was associated with higher scores of the PANSS hostility/excitement factor, independent of sex, age, or genetic results (F = 4,02;p = 0,04). We found significant interactional effects of the DTNBP1 gene risk polymorphisms and substance abuse on different PANSS factors: rs2619528 and positive substance abuse interaction were associated with higher scores on the PANSS negative factor (F = 4,6;p = 0,03), and the PANSS depression factor (F = 4,75;p = 0,03). Moreover the rs3213207 - substance abuse interaction was associated with higher scores on the PANSS cognitive factor (F = 7,55;p = 0,006). Carriers of the Val allele of the COMT Val158Met polymorphism demonstrated significantly higher scores on the PANSS depression factor (F = 5,53;p = 0,02).

Our results underscore the importance of gene-environment interactions in the phenotypic heterogeneity of schizophrenia.