The effect of deep repetitive transcranial magnetic stimulation with an H1 coil on hopelessness in patients with major depressive disorder: A randomized controlled trial.

OBJECTIVES: To assess the efficacy of repetitive transcranial magnetic stimulation (rTMS) with an H1 coil as a treatment for hopelessness in patients with major depressive disorder (MDD). METHODS: We conducted a randomised controlled trial in a tertiary psychiatric institution in Croatia, including patients diagnosed with MDD without psychotic symptoms and with clinically relevant hopelessness. High-frequency (18 Hz) rTMS with an H1 coil was administered over four weeks on the left dorsolateral prefrontal cortex. We examined changes in the Beck Hopelessness Scale (BHS) scores. RESULTS: We randomly assigned 51 participants to the intervention group (rTMS plus standard therapy) and 52 to the control group (standard therapy). The mean (SD) ages were 50 (12.3) and 50 (10.4) years, and 47% and 52% of the participants were females in the intervention and control groups, respectively. Following treatment, the BHS scores decreased (unadjusted bivariate analysis, p = 0.043; false discovery rate (FDR) >5%). Multivariate analysis revealed that the BHS score was reduced by 10.8% (95% confidence interval (CI: -17.8% to -3.9%) in the rTMS group and 0.7% (95% CI: 7.5% -6.1%) in the control group (p = 0.037; FDR < 5%). CONCLUSIONS: rTMS with an H1 coil improved the symptoms of hopelessness in patients with MDD.

Current Status of Repetitive Transcranial Magnetic Stimulation (rTMS) in Croatia and in University Psychiatric Hospital Sveti Ivan.

This article reviews the history, evolution, and current status of repetitive transcranial magnetic stimulation (rTMS) in Croatia. University Psychiatric Hospital Sveti Ivan experts performed the first rTMS in 2015 as a first treatment and research group in Croatia. In addition to being a leading center for rTMS in clinical trials and in treating depression, University Psychiatric Clinic Sveti Ivan TMS center continues to research rTMS for depression and other neuropsychiatric disorders and conditions, exploring novel stimulation parameters and individualized treatment protocols. Since 2017 rTMS treatment for MDD in Croatia has been reimbursed by the National Insurance Fund and has been available to hospital and ambulatory patients by indication, and now is widely used in other health centers in Croatia, to treat depression and other neuropsychiatric disorders and conditions, especially when drugs are ineffective or produce harmful side effects.

Overview of Studies on the Efficacy of Repetitive Transcranial Magnetic Stimulation on the Severity of Symptoms of Major Depressive Disorder, Conducted in University Psychiatric Hospital Sveti Ivan 2016-2022.

This brief report presents the studies on HF rTMS efficacy on major depressive disorder (MDD) symptoms conducted in University Psychiatric Hospital Sveti Ivan from 2016 to 2022. We assessed the clinically relevant effects of rTMS delivered by H1-coil and the figure-8-coil on MDD symptoms severity in the pooled sample of patients. During the last seven years, we enrolled in the studies on MDD 336 patients with a median (interquartile range; IQR) age of 53 (45-61) years, 181 (54%) of them women. We performed interventions with two different coils (8-coil and H1-coil) at 120% of the motor threshold, approximately half with 10 and half with 18 Hz frequency, and > 90% with one daily session during 20 workdays. We offer considerations on how the bulk of our research informed the future direction of our laboratory's studies and clinical work.

Antipsychotics-induced hyperprolactinemia and screening for macroprolactin.

INTRODUCTION: High prolactin (PRL) concentrations are found in laboratory test results of patients on majority of antipsychotic drugs. Prevalence rates and degrees of severity of hyperprolactinemia (HPRL) based on PRL concentration may depend on the presence of macroprolactin in the serum. The aim of the study was to investigate the difference between PRL concentrations before and after precipitation of macroprolactin and to examine if there were any changes in the categorization of HPRL between samples prior and after precipitation. MATERIALS AND METHODS: Total of 98 female patients (median age 33; range 19-47 years) diagnosed with a psychotic disorder, proscribed antipsychotic drugs, and with HPRL were included. Total PRL concentration and PRL concentration after macroprolactin precipitation with polyethylene glycol (postPEG-PRL) were determined by the chemiluminometric method on the Beckman Coulter Access2 analyser. RESULTS: Total PRL concentrations (median 1471; IQC: 1064-2016 mlU/L) and postPEG-PRL concentrations (median 1453; IQC: 979-1955 mlU/L) were significantly correlated using intraclass correlation coefficient for single measurements (mean estimation 0.96; 95%CI 0.93-0.97) and average measurement (mean estimation 0.98; 95%CI 0.96-0.99), and all investigated female patient had HPRL according to PRL and postPEG-PRL concentration. The median PRL recovery following PEG precipitation was 95; IQC: 90-100%. There was substantial agreement (kappa test = 0.859, 95% CI: 0.764-0.953) between the categories of HPRL severity based on total PRL concentrations and postPEG-PRL concentrations. CONCLUSION: The study demonstrated that HPRL was present in all subjects using the reference interval for total PRL concentration and postPEG-PRL concentration with no significant impact of macroprolactin presence in the serum on the categorization of patients according to severity of HPRL.

A pilot investigation of accelerated deep transcranial magnetic stimulation protocols in treatment-resistant depression.

Accelerated repetitive transcranial magnetic stimulation (rTMS) protocols are being increasingly studied because of their potential to provide quicker and enhanced treatment efficacy. However, there is a lack of accelerated deep TMS with H1-coil (adTMS) treatment research. This randomized pilot study investigated the efficacy and safety of adTMS protocols. Twenty-eight TRD patients received 20-min sessions twice daily for 10 or 15 days. Primary outcomes were changes in Hamilton Depression Rating Scale (HDRS) scores and discontinuation because of adverse events (AE). Secondary outcomes were response, remission, daily changes in Beck Depression Inventory-II (BDI-II) scores, and AE incidence. HDRS scores decreased by 13 (95% CI 11-17; 59%, 95% CI 45-73%) and 13 (95% CI 11-14; 62%, 95% CI 54-69%) points in the 10- and 15-day protocols, respectively. The adjusted difference between the two protocols was not significant or clinically relevant. Remission was achieved by 38% and 42% after 10-day and 15-day protocols, respectively. The intervention was discontinued because of AEs in 3/33 (9%) patients. The BDI-II decreases were significant and clinically relevant during the first 8 days. Twice-daily adTMS for 10 days seems to be safe and effective, with rapid clinical benefits during the first week of treatment. These promising results warrant further investigation in larger randomized clinical trials comparing adTMS with the standard dTMS protocol.

Bullying and Attitudes Toward Masculinity in Croatian Schools: Behavioral and Emotional Characteristics of Students Who Bully Others.

Prevention of bullying is paramount to creating a positive and welcoming school environment. This study compared the following characteristics reported by students who had perpetrated bullying in Croatian schools and those who did not: gender, type of school, family wealth, negative emotionality, behaviors that may compromise health, and endorsement of traditional masculinity. Within the framework of the "Croatian Adolescent Masculinity Study," second and third grade students of secondary schools (equivalent to tenth and eleventh grade in the United States) in the city of Zagreb (N = 4,072) completed a cross-sectional, paper-and-pencil survey. Descriptive and logistic regression analyses were conducted separately for males and females to identify constructs associated with bullying perpetration. More males (12.7%) than females (5.8%) perpetrated bullying. Compared to students who did not report bullying others, significantly more students, who perpetrated bullying reported feeling sad or hopeless, having suicidal ideation, carrying a weapon, missing school because of feeling unsafe, drinking alcohol, getting inebriated, being victims of bullying, and endorsing traditional masculinity norms. The proportion of males reporting bullying others did not vary by type of school; females were more likely to perpetrate bullying in predominantly male and mixed-gender vocational schools. Bullying prevention interventions should address the complexity of problems associated with bullying others. Students who reported bullying others were more likely to participate in other harmful behaviors and have emotional problems. Endorsement of traditional masculinity norms should be further researched in other cultures and included in investigations of bullying perpetration, given its association with increased bullying among male and female students.

Hyperprolactinemia - side effect or part of the illness.

BACKGROUND: Hyperprolactinemia is associated with side effect of antipsychotics in people suffering from psychotic disorders. However, increased prolactin levels (mlU/L) were found in patients suffering from the first psychotic episode who were not receiving antipsychotic therapy. The assumption of this study is that the abnormality in the level of prolactin is associated with the effect and influence of the disease, not the therapy that is carried out. SUBJECTS AND METHODS: Study involved 54 female patients hospitalized in Psychiatric hospital "Sveti Ivan", whose average age was 33.9 years. All patients had been diagnosed with a psychotic disorder (according to MKB-10, F20-F29). 18 patients had their first psychotic episode, while 36 patients had relapses of psychotic disorder. The methods used were: PANSS scale and measurement of prolactin concentration (Immunoanalyzer ACCESS 2, CLIA method). Arithmetic mean, standard deviations, correlation coefficient, Mann Whitney U test and the chi-squared test were used. RESULTS: 75.5% of patients had prolactin values above the reference values (min 121, max 4192 ml/L). In a sample of patients with first psychotic episode, 77.8% had elevated prolactin levels, while among re-hospitalized patients, elevated levels had 74.2%. Statistically significant results were obtained: patients with higher pronounced symptoms had higher prolactin values, especially particles on PANSS: P1 (delusions), N4 (Apathy), G15 (preoccupation) and G16 (active avoidance). CONCLUSION: Elevated prolactin in patients has been demonstrated regardless of antipsychotic therapy, therefore the question of etiology of hyperprolactinemia in psychotic disorders is questionable. The association of hyperprolactinemia with the severity of the clinical picture has also been demonstrated, higher prolactin values indicating a stronger clinical picture, which calls into question the protective role of prolactin in psychotic disorders.

Clinical Challenges in Patients with First Episode Psychosis and Cannabis Use: Mini-Review and a Case Study.

The influence of cannabis use on the occurrence, clinical course and the treatment of the first psychotic episode (FEP) is well documented. However, the exact link is still not clearly established. The aim of this article is to review and report the noticed increase in the number of hospitalizations of young people with a clinical appearance of severe psychotic decompensation following cannabis consumption and to show the clinical challenges in treatment of the FEP. The case study describes the clinical course of a five selected patients with a diagnosis of the FEP and positive tetrahydrocannabinol (THC) urine test who were hospitalized in a similar pattern of events. They all have a history of cannabis consumption for at least 6 years in continuity and were presented with severe psychomotor agitation, disorganisation, confusion and aggression at admission. Although the chosen drug to treat all patients was atypical antipsychotic and benzodiazepines, the course of the disorder and the clinical response to therapy were noticeably different in each patient. The clinical presentation of FEP in cannabis users can be atypical and highly unpredictable from mild psychotic symptoms to severe substance intoxication delirium. In clinical practice clinicians treating new onset psychosis need to be watchful for cannabis and synthetic cannabinoids induced psychosis. Pharmacotherapeutic interventions include prompt and adequate use of the benzodiazepine, second-generation antipsychotic, and mood-stabilizers. Further research in the pharmacotherapy of cannabis-induced psychosis is required.

Efficacy of Center for Integrative Psychiatry Multimodal Early Intervention Services in Early-Phase Psychosis on Hospital Readmission.

BACKGROUND: Growing body of evidence has opened new opportunities to enhance treatment outcomes during early-phase psychosis (EPP). The objective of this study was to evaluate the effect of the Centre for integrative psychiatry (CIP) multimodal Early Intervention Services (EIS) on time to relapse in the patients with early-phase psychosis (EPP) during 12 and 24 month period. SUBJECTS AND METHODS: We performed a retrospective cohort study on the sample of 454 EPP patients (duration of the diagnosed disorder ≤5 years) admitted to Psychiatric Hospital "Sveti Ivan", Zagreb Croatia, from January 2, 2015, to December 5, 2018, for the acute treatment of EPP. The end of follow up was March 5, 2019. The primary outcome was the time to rehospitalization because of relapse during the 12 months from the hospital discharge. Independent variable was the EIS. RESULTS: We analyzed 454 EPP patients, 260 in EIS group and 194 in no EIS group. After the adjustment for twenty possible confounding factors using the Cox proportional hazard regression, patients who received EIS had significantly and clinically relevantly lower hazard for rehospitalization because of relapse during the first 12 months (HR=0.39; CI95% 0.21-0.61; p<0.001), and during the first 24 months from the hospital discharge (HR=0.56; CI95% 0.39-0.80; p=0.003; sequential Holm-Bonferroni corrected pcorr=0.004). CONCLUSIONS: Our study indicated efficacy of the CIP multimodal EIS in patients with EPP demonstrated through the time to the hospital readmission because of relapse during the 12 and 24 months from the hospital discharge. These results strongly support the need for implementation of multimodal EIS in all patients with EPP.

Early Intervention Services for Early-Phase Psychosis - Centre for integrative psychiatry in Psychiatric Hospital "Sveti Ivan", Croatia.

BACKGROUND: There is a growing body of evidence suggesting that early and effective management in the critical early years of schizophrenia can improve long-term outcomes. The objective of this study was to evaluate time to relapse of the patients with early-phase psychosis treated in the Centre for integrative psychiatry (CIP). SUBJECT AND METHODS: We performed a retrospective cohort study on the sample of 373 early-phase psychosis patients admitted to Psychiatric Hospital "Sveti Ivan", Zagreb Croatia: from January 1, 2015 to December 31, 2017. The primary outcome was time to relapse. RESULTS: Patients who were admitted to group psychotherapeutic program after the end of acute treatment had 70% lower hazard for relapse (HR=0.30; 95% CI 0.16-0.58). Patients who were included first in the psychotherapeutic program and then treated and controlled in the daily hospital had 74% lower hazard for relapse (HR=0.26; 95% CI 0.10-0.67). CONCLUSIONS: In early-phase psychosis, integrative early intervention service has relevant beneficial effects compare to treatment as usual. These results justified the implementation of multimodal early intervention services in treatment of patients with early-phase psychosis.