Relationship between plasma risperidone concentrations and clinical features in chronic schizophrenic patients in China.

BACKGROUND: Prior studies have noted great variability in the plasma levels of risperidone (RIS). Plasma concentrations of RIS and its active moiety are highly variable and depend on absorption, metabolism, and other predictors of metabolic dysregulation; however, these factors are poorly understood and the association between metabolic change and change in psychopathology is uncertain. AIM: To ascertain the characteristics of chronic schizophrenic patients treated with RIS, and to assess their relationship with plasma RIS levels. METHODS: This was a descriptive cross-sectional study of 50 patients with a diagnosis of schizophrenic psychosis treated with RIS in a psychiatric service. The plasma concentrations of RIS and its metabolite 9-hydroxyrisperidone were determined by high performance liquid chromatography. The patients' demographic and clinical characteristics, and psychopathologies were assessed, and the associations between clinical variables and plasma levels of RIS were explored. RESULTS: Male patients received higher doses of RIS than female ones, but plasma concentrations of RIS and risperidone + 9-hydroxyrisperidone (active moiety) were higher in female patients. Age and the mean scores of the general psychopathology subscale of the Positive and Negative Syndrome Scale (PANSS) were significantly positively correlated with plasma concentrations of risperidone + 9-hydroxyrisperidone adjusted for weight and dose in all 50 subjects. In male subjects, we found a statistically significant positive correlation between the concentrations of risperidone + 9-hydroxyrisperidone in plasma/(dose × kg) and age, mean PANSS negative subscale scores, mean PANSS general psychopathology subscale scores, and mean PANSS total scores. CONCLUSION: Long-term use of RIS should be closely monitored in older patients and females to minimize the risk of high concentrations which could induce side effects.

Direct and indirect effects of error monitoring on social functioning in a cohort with high-risk and first-episode psychosis.

Error monitoring plays a key role in people's adjustment to social life. This study aimed to examine the direct (DE) and indirect effects (IDE) of error monitoring, as indicated by error-related negativity (ERN), on social functioning in a clinical cohort from high-risk (APS) to first-episode psychosis (FEP). This study recruited 100 outpatients and 49 healthy controls (HC). ERN was recorded during a modified flanker task; social functioning was evaluated using the social scale of global functioning. The path analysis was executed using the "lavaan" package. When controlling for age and education, the clinical cohort had a smaller ERN than the HC group (F1, 145 = 19.58, p < 0.001, partial η2 = 0.12, 95%CI: 0.04-0.22). ERN demonstrated no substantial direct impact on current social functioning; however, it manifested indirect influences on social functioning via the disorganization factor of the Positive and Negative Syndrome Scale, both with (standardized IDE: -0.139, p = 0.009) and without (standardized IDE: -0.087, p = 0.018) accounting for the diagnosis, defined as a dummy variable (FEP = 1 and APS = 0) and included as a covariate. These findings suggest that error monitoring, as indicated by ERN, may serve as a potential prognostic indicator of social functioning in patients with psychosis.

Impaired insight and error-monitoring deficits among outpatients with attenuated psychosis syndrome and first-episode psychosis.

We aimed to determine the relationship between electrophysiological signatures of error monitoring and clinical insight among outpatients with attenuated psychosis syndrome (APS) and first-episode psychosis (FEP). Error-related negativity (ERN), error positivity (Pe), and correct response negativity (CRN) were recorded during a modified flanker task for patients with FEP (n = 32), APS individuals (n = 58), and healthy controls (HC, n = 49). Clinical insight was measured using the Schedule of Assessment of Insight (SAI) and included awareness of illness (SAI-illness), relabeling of specific symptoms (SAI-symptoms), and treatment compliance (SAI-treatment). Compared with HC, patients with FEP showed smaller ERN (p < 0.001) and Pe (p = 0.011) amplitudes and individuals with APS showed smaller ERN amplitude (p = 0.009). No significant difference in CRN amplitude was observed among the groups. A smaller negative amplitude of ERN correlated with a lower score on SAI-symptoms (b = -0.032, 95% CI: 0.062 to -0.002, p = 0.035) and a decreased total score of SAI (b = -0.096, 95% CI: 0.182 to -0.010, p = 0.029). This links were adjusted for age, education, and diagnosis (a dummy variable with FEP = 1 and APS = 0), and was independent of positive symptoms. SAI-illness was predominantly influenced by diagnosis, whereas SAI-treatment was additionally affected by disorganized communications. Neither Pe nor CRN amplitude exhibited an association with clinical insight. Unconscious error detection, as indicated by ERN, may aid individuals at the preliminary stage of psychosis in recognizing the unusual symptoms.

Continuous theta burst stimulation over the bilateral supplementary motor area in obsessive-compulsive disorder treatment: A clinical randomized single-blind sham-controlled trial.

BACKGROUND: Obsessive-compulsive disorder (OCD) can cause substantial damage to quality of life. Continuous theta burst stimulation (cTBS) is a promising treatment for OCD patients with the advantages of safety and noninvasiveness. OBJECTIVE: The present study aimed to evaluate the treatment efficacy of cTBS over the bilateral supplementary motor area (SMA) for OCD patients with a single-blind, sham-controlled design. METHODS: Fifty-four OCD patients were randomized to receive active or sham cTBS treatment over the bilateral SMA for 4 weeks (five sessions per week, 20 sessions in total). Patients were assessed at baseline (week 0), the end of treatment (week 4), and follow-up (week 8). Clinical scales included the YBOCS, HAMD24, HAMA14, and OBQ44. Three behavioral tests were also conducted to explore the effect of cTBS on response inhibition and decision-making in OCD patients. RESULTS: The treatment response rates were not significantly different between the two groups at week 4 (active: 23.1% vs. sham: 16.7%, p = 0.571) and week 8 (active: 26.9% vs. sham: 16.7%, p = 0.382). Depression and anxiety improvements were significantly different between the two groups at week 4 (HAMD24: F = 4.644, p = 0.037; HAMA14: F = 5.219, p = 0.028). There was no significant difference between the two groups in the performance of three behavioral tests. The treatment satisfaction and dropout rates were not significantly different between the two groups. CONCLUSIONS: The treatment of cTBS over the bilateral SMA was safe and tolerable, and it could significantly improve the depression and anxiety of OCD patients but was not enough to improve OCD symptoms in this study.

High frequency repetitive transcranial magnetic stimulation of dorsomedial prefrontal cortex for negative symptoms in patients with schizophrenia: A double-blind, randomized controlled trial.

Negative symptoms are the major challenge in clinical management of schizophrenia. Dorsomedial prefrontal cortex (DMPFC) has been suggested to be highly involved in the mechanisms of negative symptoms of schizophrenia. However, the effect of repetitive Transcranial Magnetic Stimulation (rTMS) over DMPFC has not yet been well studied. In this double-blind, randomized controlled rTMS clinical trial, thirty-three participants (17 in active group and 16 in sham group) were enrolled. This study includes the rTMS treatment phase (lasts for 4 weeks) and a subsequently naturalistic follow-up phase (lasts for another 4 weeks). Schizophrenia patients with prominently negative symptoms were randomly assigned to receive 10 Hz or sham rTMS intervention. The score change in Scale of Negative Symptoms (SANS) was defined as the primary outcome measure. There was a significant decrease in negative symptoms, especially affective flattening and anhedonia in schizophrenia patients after DMPFC-rTMS intervention. Moreover, the negative symptoms improvement could maintain at least another 4 weeks. In addition, no memory impairment or serious adverse reaction of rTMS emerged. Our results suggest that high frequency rTMS over DMPF may represent a safe and effective treatment for negative symptoms in patients with schizophrenia.

An Open-label Trial of Adjuvant High-frequency Left Prefrontal Repetitive Transcranial Magnetic Stimulation for Treating Suicidal Ideation in Adolescents and Adults With Depression.

BACKGROUND: Repetitive transcranial magnetic stimulation (rTMS) offers promise for the treatment of depression, yet its potential impact on suicidal ideation (SI), particularly in adolescents, has not been well studied. This study aimed to investigate the efficacy of add-on rTMS for reducing SI in a large clinical sample experiencing an acute phase of depression. METHODS: This study included 146 patients with a score of ≥14 on the 17-item Hamilton Rating Scale for Depression (HAMD). Among them, 97 had a HAMD-SI (3-item) score of 1 or greater and were pooled into the analysis. Symptoms of depression and SI were measured using the HAMD total score and HAMD-SI score. Comparisons of clinical improvement for both SI and rates of remission were made between adolescent (n = 29) and adult patients (n = 68), as well as between high-frequency (HF) rTMS on the left dorsolateral prefrontal cortex (DLPFC) (80 trains, 30 pulses per train, 12 s intertrain interval, 2400 pulses per session) and low-frequency (LF) rTMS on the right DLPFC protocol (2 trains, 700 pulses per train, 1 s intertrain-interval, 1400 pulses per session), power (intensity) level of 120% of motor threshold (MT), and 5 sessions per week for 2 weeks. RESULTS: Add-on rTMS treatment showed significant clinical improvement in SI, and was also well tolerated, with no adverse events reported. The SI improvements and remission rates were more significant in adolescents treated with the HF left DLPFC rTMS protocol, compared with adults treated with the LF right DLPFC rTMS protocol (remission rates: adolescent with LF right DLPFC, 50%; adolescent with HF left DLPFC, 94%; adult with LF right DLPFC, 65%; adult with HF left DLPFC, 57%). A positive association between improvement in the HAMD total score and HAMD-SI score was found in adults, but not in adolescents. CONCLUSIONS: Add-on rTMS treatment for SI associated with depression is promising with respect to safety and feasibility. Our preliminary evidence supports an extension of the application of rTMS to adolescent patients with SI during the acute phase of depression, in addition to its use in adult treatment-resistant depression.

Comparative efficacy of add-on rTMS in treating the somatic and psychic anxiety symptoms of depression comorbid with anxiety in adolescents, adults, and elderly patients-A real-world clinical application.

BACKGROUND: Repetitive transcranial magnetic stimulation (rTMS) is an effective adjuvant treatment for depression. Many patients with depression have comorbid anxiety symptoms. However, previous rTMS studies have focused on patients with depression, and often excluded comorbid anxiety. This real-world study aimed to investigate the comparative efficacy of add-on rTMS in treating the somatic and psychic anxiety symptoms of depression comorbid with anxiety in adolescents, adults and elderly patients. METHODS: This study included 147 depression patients with anxiety symptoms who were treated with at least 10 sessions of rTMS. The symptoms of anxiety and depression were assessed with the Hamilton Rating Scale for Anxiety (HAMA) and the Hamilton Rating Scale for Depression (HAMD) at baseline and after 2 and 4 weeks of treatment. This was done to compare the improvement degree of add-on rTMS on somatic and psychic anxiety symptoms in adolescents, adults and elderly patients respectively. RESULTS: Both somatic and psychic anxiety symptoms were significantly improved after the add-on rTMS in adolescents, adults and elderly patients. The improvement of somatic anxiety was better than that of psychic anxiety after rTMS treatment in elderly patients (t2w=3.895, P<0.001; t4w=2.823, P = 0.008). LIMITATION: The overall sample was mostly composed of elderly patients, while adolescents and adult patients were fewer. CONCLUSIONS: The add-on rTMS treatment can improve somatic anxiety better than psychic anxiety in depression with anxiety symptoms, especially in elderly patients.

Antidepressant Effect of Adjunct Repetitive Transcranial Magnetic Stimulation in Inpatients 60 Years and Older.

BACKGROUND: Repetitive transcranial magnetic stimulation (rTMS) is now an established, safe, and effective treatment for adults with depression. However, specific research in rTMS for use in elderly patients with acute depression is scarce. OBJECTIVE: The aim of the present study was to investigate the efficacy of add-on rTMS in a clinical sample of older adults experiencing an acute phase of depression. METHOD: This study examined 114 patients (54 elderly [aged ≥60] and 60 adults [aged 18-59]) with acute depression who were drug free at baseline. They were treated with at least 10 sessions of rTMS for 4 weeks along with 1 antidepressant. Symptoms of depression were measured using the Hamilton Rating Scale for Depression at baseline and after 2 and 4 weeks of treatment. Clinical improvement and rates of response and remission were compared across groups. RESULTS: Significant improvement was noted after 2 and 4 weeks of treatment in both adult and elderly groups. Higher remission rates were found in adult patients but with no differences in response. The stimulation intensity and course of illness were significant predictors of remission after 4 weeks of rTMS treatment in the elderly. CONCLUSIONS: The add-on rTMS treatment for elderly depression patients is promising with respect to safety and feasibility. This preliminary evidence supports the application of rTMS to this group during acute episodes.

Efficacy and safety of repetitive transcranial magnetic stimulation for generalised anxiety disorder: A meta-analysis.

BACKGROUND: Pharmacological and conventional non-pharmacological treatments are only moderately effective in treating generalised anxiety disorder (GAD). Recently, repetitive transcranial magnetic stimulation (rTMS) has attracted interest because of its potential therapeutic value. AIM: To investigate the efficacy and safety of rTMS treatment for GAD. METHODS: Literature studies published in English or Chinese were screened in 10 electronic databases up to 5 December 2018. The included studies' bias risk was assessed using Cochrane risk of bias assessment tool. Meta-analysis was performed to compute the standardised mean difference (SMD) and risk ratio (RR) along with its 95% CIs through using RevMan V.5.3. Heterogeneity was inspected by I2 and the χ2 test. We performed subgroup analysis and meta-regression to investigate heterogeneity. We used funnel plot to assess publication bias. We used the GRADE approach to assess the whole quality of evidence. RESULTS: Twenty-one studies, with a total sample size of 1481, were analysed. The risk of bias in most studies included is moderate, the majority of which are lacking of blinding methods of treatment allocation. The treatment had beneficial effects in the rTMS group compared with the control group in mean anxiety score (SMD=-0.68; 95% CI -0.89 to -0.46). None of the 21 studies included here reported severe adverse events. As for dropout rates, there are no statistically significant differences between the two groups (RR 1.14, 95% CI 0.72 to 1.82) or adverse events (RR 0.95, 95% CI 0.77 to 1.18). No particular influence on the heterogeneity of any variable was observed. The risk of publication bias was low. According to the GRADE approach, the evidence levels of primary outcome (treatment effects) and secondary outcomes (acceptability and safety) were rated as 'medium'. CONCLUSION: The use of rTMS combined with medication treatment may have a significant positive anti-anxiety effect on patients with GAD. However, we should interpret the results cautiously due to the relatively high heterogeneity of the meta-analysis. Future high-quality clinical trials are needed to confirm our results.

Add-on rTMS for the acute treatment of depressive symptoms is probably more effective in adolescents than in adults: Evidence from real-world clinical practice.

BACKGROUND: Repetitive transcranial magnetic stimulation (rTMS) is considered as an effective treatment for adults with major depressive disorder. However, it remains unknown whether rTMS has comparable or better efficacy in adolescents. OBJECTIVE: The current naturalistic study aimed to investigate the efficacy and clinical outcome of add-on rTMS in a large sample of adolescent patients compared to adult patients. METHODS: This study included 117 patients (42 adolescents vs. 75 adults) with mood or anxiety disorders who were treated with at least 10 sessions of rTMS. rTMS was applied over the left dorsolateral prefrontal cortex (10 Hz). Symptoms of depression and anxiety were measured using the Hamilton Rating Scale for Depression (HAMD) and the Hamilton Rating Scale for Anxiety (HAMA) respectively, at baseline and after 2 and 4 weeks of follow-up. Comparisons of clinical improvement and rates of response/remission were made across age groups. MAJOR FINDINGS AND CONCLUSIONS: All the age groups showed significant improvements in clinical symptoms. No safety or tolerability concerns were identified. Symptomatic improvements and response/remission rates were more significant in adolescent patients than in adults. Decrease in HAMD and HAMA scores after 2 weeks and 4 weeks of rTMS treatment were positively correlated in adolescents, but not in adults. General linear model repeated measures demonstrated significant effect of time × age group interaction on the HAMD score, in response to 10 sessions of rTMS. Add-on rTMS is feasible, tolerable, effective and more applicable to adolescents with mood or anxiety disorders. However, double-blinded and sham-controlled trials are needed for validating this conclusion.

Different levels of facial expression recognition in patients with first-episode schizophrenia: A functional MRI study.

BACKGROUND: The impairment of facial expression recognition has become a biomarker for early identification of first-episode schizophrenia, and this kind of research is increasing. AIMS: To explore the differences in brain area activation using different degrees of disgusted facial expression recognition in antipsychotic-naïve patients with first-episode schizophrenia and healthy controls. METHODS: In this study, facial expression recognition tests were performed on 30 first-episode, antipsychotic-naïve patients with schizophrenia (treatment group) and 30 healthy subjects (control group) with matched age, educational attainment and gender. Functional MRI was used for comparing the differences of the brain areas of activation between the two groups. RESULTS: The average response time difference between the patient group and the control group in the 'high degree of disgust' facial expression recognition task was statistically significant (1.359 (0.408)/2.193 (0.625), F=26.65, p<0.001), and the correct recognition rate of the treatment group was lower than that of the control group (41.05 (22.25)/59.84 (13.91, F=19.81, p<0.001). Compared with the control group, the left thalamus, right lingual gyrus and right middle temporal gyrus were negatively activated in the patients with first-episode schizophrenia in the 'high degree of disgust' emotion recognition, and there was a significant activation in the left and right middle temporal gyrus and the right caudate nucleus. However, there was no significant activation difference in the 'low degree of disgust' recognition. CONCLUSIONS: In patients with first-episode schizophrenia, the areas of facial recognition impairment are significantly different in different degrees of disgust facial expression recognition.

Meta-analysis of the Efficacy and Safety of Repetitive Transcranial Magnetic Stimulation (rTMS) in the Treatment of Depression.

BACKGROUND: Repetitive transcranial magnetic stimulation (rTMS) is a new type of physiotherapy technology that has been widely used in the research of depression. Although many clinical trials have found that compared to the placebo interventions, rTMS has a significant effect on the improvement of depressive symptoms, the outcomes remain inconsistent due to differences in rTMS treatment frequency, parameter settings, and site for stimulation. AIMS: This study systematically evaluated the safety and efficacy of rTMS combined with antidepressants for the treatment of depression in Chinese and English randomized, double-blind and sham controlled trials and explored the possible related factors affecting the efficacy and safety. METHODS: We used keywords "depression" and "transcranial magnetic Stimulaton" as filters to search for the Clinical Randomized Controlled Trials (RCTs) of rTMS treatments for depression both in Chinese electronic databases: Wan fang, Wellpresi, and China Knowledge Network and in English electronic databases: PubMed, Web of Science, Embase, PsycINFO, Cochrane Library (total 8 databases) up to January 5, 2017; assessed the quality of the included studies with Cochrane risk of bias assessment tool; and according to the trial groups performed statistical analysis of the efficacy and safety presented in the included studies with RevMan5.3 software. RESULTS: A total of 9798 articles were retrieved, and finally, 29 studies were included in this study, with a total sample size of 1659, in which the sample size of the study groups was 838, and the control group sample size was 821. After Meta-analysis, we found that treatment combined rTMS with antidepressants improves depressive symptoms in patients with depression (SDM=-0.84, 95%CI=-1.19 ~ -0.48). Based on the Cochrane risk bias Assessment tool, an assessment of the bias of the included studies was conducted, one of which was assessed as having a "high risk of bias" and others as "impossible to judge". None of the included studies reported significant adverse events, and Meta-analysis showed no statistically significant differences in dropout rate between the two groups (RR=1.27, 95%CI: 0.75~2.12, Z=0.89, p=0.37). CONCLUSION: treatment that combined rTMS with antidepressant medication for depressive symptoms has a certain therapeutic advantage versus the placebo controls, demonstrated slight side effects, and attained good acceptability, but the differences between trials remained relatively large. Clinical trials with large sample sizes are required for further exploration of the possible related factors affecting the efficacy.