Factors associated with neurofeedback and mindfulness-based combination therapy for patients with substance use disorder: A multicenter study

Background and objectives Substance use disorder (SUD) has become a major concern in public health globally, and there is an urgent need to develop an integrated psychosocial intervention. The aims of the current study are to test the efficacy of the integrated treatment with neurofeedback and mindfulness-based therapy for SUD and identify the predictors of the efficacy. Methods This study included 110 participants with SUD into the analysis. Outcome of measures includes demographic characteristics, severity of dependence, quality of life, symptoms of depression, and anxiety. Independent t test is used to estimate the change of scores at baseline and three months follow-up. Generalized estimating equations are applied to analyze the effect of predictors on the scores of dependence severity over time by controlling for the effects of demographic characteristics. Results A total of 22 (20 %) participants were comorbid with major mental disorder (MMD). The decrement of the severity in dependence, anxiety, and depression after treatment are identified. Improved scores of qualities of life in generic, psychological, social, and environmental domains are also noticed. After controlling for the effects of demographic characteristics, the predictors of poorer outcome are comorbid with MMD, lower quality of life, and higher level of depression and anxiety. Conclusion The present study implicates the efficacy of integrated therapy. Early identification of predictors is beneficial for healthcare workers to improve the treatment efficacy. (AU)

Impaired Brain-Heart Relation in Patients With Methamphetamine Use Disorder During VR Induction of Drug Cue Reactivity.

Methamphetamine use disorder (MUD) is an illness associated with severe health consequences. Virtual reality (VR) is used to induce the drug-cue reactivity and significant EEG and ECG abnormalities were found in MUD patients. However, whether a link exists between EEG and ECG abnormalities in patients with MUD during exposure to drug cues remains unknown. This is important from the therapeutic viewpoint because different treatment strategies may be applied when EEG abnormalities and ECG irregularities are complications of MUD. We designed a VR system with drug cues and EEG and ECG were recorded during VR exposure. Sixteen patients with MUD and sixteen healthy subjects were recruited. Statistical tests and Pearson correlation were employed to analyze the EEG and ECG. The results showed that, during VR induction, the patients with MUD but not healthy controls showed significant [Formula: see text] and [Formula: see text] power increases when the stimulus materials were most intense. This finding indicated that the stimuli are indiscriminate to healthy controls but meaningful to patients with MUD. Five heart rate variability (HRV) indexes significantly differed between patients and controls, suggesting abnormalities in the reaction of patient's autonomic nervous system. Importantly, significant relations between EEG and HRV indexes changes were only identified in the controls, but not in MUD patients, signifying a disruption of brain-heart relations in patients. Our findings of stimulus-specific EEG changes and the impaired brain-heart relations in patients with MUD shed light on the understanding of drug-cue reactivity and may be used to design diagnostic and/or therapeutic strategies for MUD.

Effect of light needle in the treatment of opioid use disorder: A protocol for a randomized controlled trial.

BACKGROUND: Opioid use disorder occurs worldwide and creates an increasing economic burden and public health crisis. Some problems are associated with using opioid agonists; therefore, there is a need to develop non-opioid treatments to improve acute and long-term opioid withdrawal syndromes. METHODS: We will enroll 100 participants with opioid use disorders receiving methadone maintenance treatment at an addiction treatment center and randomly allocate them to an experimental or control group. The experimental group will receive 12 sessions of light needle therapy within 4 weeks, while the control group will receive sham light needle treatment without any laser output. Urinary morphine levels were assessed before and after treatment. Participants will be asked to self-report their number of episodes or days of heroin use and heroin craving/refusal to use heroin in the previous week before and after treatment on a visual analogue scale score of 0 to 10. Quality of life will be reported using the Short Form-12v2 before and after 4 weeks of treatment. Pulse diagnosis and heart rate variability will be evaluated before and after treatment. Baseline patient characteristics will be compared between the groups using the independent t test and the χ2 test. Data between the 2 groups will be compared using generalized estimation equations, and paired t tests. OBJECTIVE: This study aims to investigate the effect of adjuvant light needle therapy in patients with opioid use disorder on methadone maintenance treatment.

Differences in orexin-A level in the functional brain network of HUD patients undergoing harm reduction therapy.

Orexins regulate the reward-seeking pathway and also play a role in drug addiction. The aim of this study was an investigation of the changes in serum level of orexin-A as well as changes in the functional brain network in heroin use disorder (HUD) patients undergoing harm reduction therapy (HRT). Twenty-five HUD patients undergoing HRT that included methadone and buprenorphine, and 31 healthy control (HC) subjects, were enrolled for this study. Serum orexin-A levels and brain-derived neurotrophic factor were measured with assay kits. The functional brain network in HUD patients and HC was investigated and assessed using seed-based analysis and functional brain MRI scans. t Tested orexin-A levels were found to be significantly higher in HUD patients undergoing HRT than in HCs (P < .05). Analysis showed the functional activity of the right ventral anterior insula (RVAI) in HUD patients to be significantly lower than in HCs (P < .05, Family-Wise Error) corrected). In addition, the internetwork functional connectivity was significantly lower in the left nucleus accumbens and left dorsal anterior insula in the HUD subjects than in HCs (P < .05, Family-Wise Error corrected). In this study, no significant correlation between orexin-A levels and functional brain networks was found. However, the results suggest that HRT might increase orexin-A levels and decrease functional activity in RVAI in HUD patients.

Laser meridian massage decreased craving in men with opioid use disorder on methadone maintenance treatment.

BACKGROUND: The incidence of opioid use disorder (OUD) is increasing worldwide, and the opioid-related overdose crisis is currently a major global challenge. This study investigated the effects of adjuvant laser meridian massage (LMM) in men with OUD undergoing methadone maintenance treatment (MMT). METHODS: A case-controlled study was conducted from February 2019 to April 2020. Fourteen men with OUD on MMT were enrolled from an addiction treatment center as an experimental group. An age-matched control group comprising 13 men was also enrolled. The experimental group received LMM on the back, including over the Bladder meridian and Governor Vessel, three times weekly for 4 weeks. The control group received only MMT. Urinary morphine levels, patients' self-reports of the number of episodes or days of heroin use, and visual analog scale scores for heroin craving/refusal to use heroin during the previous week were evaluated. Quality of life was reported using the Short Form (SF)-12v2. RESULTS: The experimental group showed a significant decrease in heroin use (p < 0.05), whereas the control group showed a significant increase in heroin craving (p < 0.05). The SF-12v2 Health Survey revealed a significant improvement in physical health in the experimental group (P < 0.05). CONCLUSION: The results of this study suggest that laser meridian massage can be considered a safe, well-tolerated, and potentially useful adjuvant intervention for opioid use disorder.

Neuronal Abnormalities Induced by an Intelligent Virtual Reality System for Methamphetamine Use Disorder.

Methamphetamine use disorder (MUD) is a brain disease that leads to altered regional neuronal activity. Virtual reality (VR) is used to induce the drug cue reactivity. Previous studies reported significant frequency-specific neuronal abnormalities in patients with MUD during VR induction of drug craving. However, whether those patients exhibit neuronal abnormalities after VR induction that could serve as the treatment target remains unclear. Here, we used an integrated VR system for inducing drug related changes and investigated the neuronal abnormalities after VR exposure in patients. Fifteen patients with MUD and ten healthy subjects were recruited and exposed to drug-related VR environments. Resting-state EEG were recorded for 5 minutes twice-before and after VR and transformed to obtain the frequency-specific data. Three self-reported scales for measurement of the anxiety levels and impulsivity of participants were obtained after VR task. Statistical tests and machine learning methods were employed to reveal the differences between patients and healthy subjects. The result showed that patients with MUD and healthy subjects significantly differed in Θ, α, and γ power changes after VR. These neuronal abnormalities in patients were associated with the self-reported behavioral scales, indicating impaired impulse control. Our findings of resting-state EEG abnormalities in patients with MUD after VR exposure have the translational value and can be used to develop the treatment strategies for methamphetamine use disorder.

Diagnostic Reliability and Validity of the Semi-Structured Assessment for Drug Dependence and Alcoholism (SSADDA) Chinese Version.

The Semi-Structured Assessment for Drug Dependence and Alcoholism (SSADDA) is a polydiagnostic instrument for substance use and psychiatric disorders. We translated the SSADDA English version into Chinese (SSADDA-Chinese) and report here our examination of the diagnostic reliability and validity of DSM-IV substance dependence (SD) diagnoses in a Mandarin-speaking sample in Taiwan. We recruited 125 subjects who underwent an assessment of lifetime SD diagnoses using both the SSADDA-Chinese and the Structured Clinical Interview for DSM-IV, Clinician Version (SCID-Chinese). Thirty-one subjects were retested with the SSADDA-Chinese. Cohen's κ statistic, which measures chance-corrected agreement, was used to measure the test-retest reliability and concurrent validity of the individual SD diagnoses. There was a high degree of concordance between SD diagnoses made using the SSADDA-Chinese and the SCID-Chinese, including those for dependence on alcohol (κ = 0.83), ketamine (κ = 0.97), methamphetamine (κ = 0.93), and opioids (κ = 0.95). The test-retest reliability of dependence diagnoses for ketamine (κ = 0.95), methamphetamine (κ = 0.80), and opioids (κ = 1.00) obtained using the SSADDA-Chinese was excellent, while that for alcohol dependence (κ = 0.63) and nicotine dependence (κ = 0.65) was good. We conclude that the SSADDA-Chinese is a reliable and valid instrument for the diagnosis of major SD traits in Mandarin-speaking populations.

An Intelligent Virtual-Reality System With Multi-Model Sensing for Cue-Elicited Craving in Patients With Methamphetamine Use Disorder.

Methamphetamine abuse is getting worse amongst the younger population. While there is methadone or buprenorphine harm-reduction treatment for heroin addicts, there is no drug treatment for addicts with methamphetamine use disorder (MUD). Recently, non-medication treatment, such as the cue-elicited craving method integrated with biofeedback, has been widely used. Further, virtual reality (VR) is proposed to simulate an immersive virtual environment for cue-elicited craving in therapy. In this study, we developed a VR system equipped with flavor simulation for the purpose of inducing cravings for MUD patients in therapy. The VR system was integrated with multi-model sensors, such as an electrocardiogram (ECG), galvanic skin response (GSR) and eye tracking to measure various physiological responses from MUD patients in the virtual environment. The goal of the study was to validate the effectiveness of the proposed VR system in inducing the craving of MUD patients via the physiological data. Clinical trials were performed with 20 MUD patients and 11 healthy subjects. VR stimulation was applied to each subject and the physiological data was measured at the time of pre-VR stimulation and post-VR stimulation. A variety of features were extracted from the raw data of heart rate variability (HRV), GSR and eye tracking. The results of statistical analysis found that quite a few features of HRV, GSR and eye tracking had significant differences between pre-VR stimulation and post-VR stimulation in MUD patients but not in healthy subjects. Also, the data of post-VR stimulation showed a significant difference between MUD patients and healthy subjects. Correlation analysis was made and several features between HRV and GSR were found to be correlated. Further, several machine learning methods were applied and showed that the classification accuracy between MUD and healthy subjects at post-VR stimulation attained to 89.8%. In conclusion, the proposed VR system was validated to effectively induce the drug craving in MUD patients.

Brain-derived neurotrophic factor and glutathione peroxidase as state biomarkers in alcohol use disorder patients undergoing detoxification.

The pathophysiology of alcohol use disorder (AUD) is not totally clear. The aim of this study was to investigate the serum levels of brain-derived neurotrophic factor (BDNF) and oxidative stress markers in AUD patients during alcohol detoxification. Evaluation of changes in BDNF, glutathione peroxidase (GPX), catalase, superoxide dismutase, thiobarbituric acid reactive substances, 8-hydroxy 2'-deoxyguanosine, PCC and S100B were carried out.14 AUD inpatients and 20 healthy control subjects were recruited for this study. The serum BDNF, S100B and oxidative stress markers were measured with assay kits.Serum levels of catalase, GPX, PCC and 8-hydroxy 2'-deoxyguanosine were significantly higher in the AUD group subjects than in the controls (P < .05). However, BDNF levels were lower in the AUD group than in the controls (P < .05). After alcohol detoxification treatment, the GPX levels in the AUD group dropped (P < .05) and the BDNF levels rose (P < .05).The results suggest that serum BDNF and GPX levels might be state biomarkers for AUD patients undergoing alcohol detoxification.

Adjuvant laser meridian massage in men with opioid use disorder on methadone maintenance treatment: Protocol for a case-controlled study.

BACKGROUND: Heroin addiction remains a significant public health problem worldwide, and relapse to heroin use following cessation of agonist maintenance treatment is common. The problems associated with use of opioid agonists mean that non-opioid therapies need to be developed to ameliorate acute and protracted opioid withdrawal syndromes. METHODS: Fifteen men with opioid use disorder on methadone maintenance treatment have been enrolled from an addiction treatment center as an experimental group in this case-controlled study. This group is receiving laser meridian massage on the back, including the Bladder meridian and Governor Vessel, 3 times weekly for 4 weeks. An age-matched control group that does not receive laser meridian massage has also been enrolled. Urinary morphine levels are being checked before and after 2 and 4 weeks of treatment. Subjects are requested to self-report their number of episodes or days of heroin use and 0 to 10-point visual analogue scale scores for heroin craving/refusal to use heroin during the previous week before and after 2 and 4 weeks of treatment. Quality of life will be reported using the Short Form-12v2 before and after 4 weeks of treatment. Pulse diagnosis will be recorded and heart rate variability calculated after one single treatment session. The baseline patient characteristics will be compared between the experimental and control groups using the independent t test and Chi-square test. Data are compared between the 2 groups using repeated-measures analysis of variance, generalized estimating equations, and the paired t test. OBJECTIVE: To investigate the effect of adjuvant laser meridian massage in men with opioid use disorder on methadone maintenance treatment. TRIAL REGISTRATION: ClinicalTrials.gov NCT04003077.

Decreased Level of Blood MicroRNA-133b in Men with Opioid Use Disorder on Methadone Maintenance Therapy.

Although previous animal studies have indicated that certain micro ribonucleic acids (microRNAs) play a part in the pathway of opioid addiction, whether such findings extend to human models is yet unknown. This study aims to investigate the important microRNA expressions in patients with opioid use disorder (OUD) on methadone maintenance treatment (MMT) compared to healthy controls and analyze the correlation between microRNAs and opioid characteristics among the patients. We recruited 50 patients and 25 controls, and both groups were matched regarding gender, age, and body mass index. Serum microRNAs (miR-133b, miR-23b, miR-190, miR-206, miR-210, and miR-21) were measured. The age of OUD onset, duration of MMT participation, and recent daily methadone dosage were considered the opioid characteristics. We adopted the t-test to compare the difference between patients and controls and Pearson's correlation to evaluate the association between microRNAs and opioid profiles. Only the level of miR-133b in OUD patients on MMT was significantly lower than that in healthy controls. We did not detect differences of any other microRNA expressions between the two groups. Furthermore, we found no evidence to support the association between microRNAs and opioid characteristics. This study indicates that miR-133b values may be decreased in OUD patients on MMT.

Aberrant Expression of Intracellular let-7e, miR-146a, and miR-155 Correlates with Severity of Depression in Patients with Major Depressive Disorder and Is Ameliorated after Antidepressant Treatment.

Chronic inflammation and abnormalities in Toll-like receptor (TLR) signaling pathways are associated with major depressive disorder (MDD). Our previous work reported that impaired negative regulators for the TLR pathways are associated with MDD. This study aimed to assess the association between the severity of depression and the intracellular microRNAs that regulate TLR4 signaling in both peripheral blood mononuclear cells (PBMCs) and monocytes from MDD patients. The severity of MDD before and after antidepressant treatment was determined by the 17-item Hamilton Depression Rating Scale, and quantitative RT-PCR was used to measure the levels of intracellular regulatory microRNAs, including let-7e, miR-21-5p miR-145, miR-223, miR-146a, and miR-155, in PBMCs and monocytes isolated from 43 healthy controls and 84 patients with MDD before and after treatment with antidepressants. Assays of PBMCs showed that the levels of let-7e, miR-146a, and miR-155 were lower in MDD patients than in healthy controls and were significantly higher after than before treatment in the 69 patients who completed treatment with antidepressants for four weeks. Levels of miR-146a and miR-155 in monocytes were lower in MDD patients than in controls and were increased in the former after antidepressant treatment. Multiple linear regression analyses found that let-7e and miR-146a expression before treatment was inversely correlated with severity of depression, whereas miR-155 before treatment was directly correlated with severity of depression. These findings suggest that intracellular regulatory microRNAs which regulate TLR4 signaling are aberrantly expressed in patients with MDD and that these levels are ameliorated by antidepressant treatment.

Antidepressant treatment increased serum miR-183 and miR-212 levels in patients with major depressive disorder.

Major depressive disorder (MDD) had been associated with brain-derived neurotrophic factor (BDNF). Studies had shown that patients with MDD were associated with lower BDNF protein levels, which could be reversed by antidepressant treatment. BDNF expression had also been affected by a number of microRNAs (miRNA). BDNF and miRNA in MDD had been investigated widely in the recent years, but the relationships between miRNAs and antidepressants were less studied. From November 2015 to October 2017, inpatients diagnosed with MDD were recruited. Serum miR-16, miR-30, miR-34, miR-128, miR-132, miR-134, miR-182, miR-183, miR-185, miR-212 levels were measured before and after four weeks of antidepressant treatment of either selective serotonin reuptake inhibitor (SSRI) or serotonin-norepinephrine reuptake inhibitor (SNRI). Thirty-three patients with MDD were recruited. After treatment, miR-183 and miR-212 levels increased significantly. In patients treated with SSRI (n = 13), miR-16 levels increased significantly after treatment. Therefore, miR-183 and miR-212 levels increased significantly after four weeks of antidepressant treatment. In the SSRI group, significantly increased miR-16 levels were found, but not in SNRI group, suggesting that different types of antidepressants might affect different sets of miRNAs.

Orexin A in men with heroin use disorder undergoing methadone maintenance treatment.

Orexins have played a role in reward-seeking and addiction-related behavior. There are few reports in the literature on serum levels of orexins in patients with heroin use disorder (HUD) undergoing methadone maintenance treatment (MMT). The aim of this study was to investigate the serum levels of orexin A in HUD patients undergoing MMT. Fifty male HUD patients undergoing MMT and 25 healthy males were enrolled for this study. Serum orexin A were measured with assay kits. Using analysis of covariance (ANCOVA) with body mass index (BMI) adjustments, the serum levels of orexin A in HUD men undergoing MMT were found to be significantly higher than in healthy controls. In conclusion, our results suggest that MMT might increase orexin A levels in HUD patients.

Increased serum anti-N-methyl-D-aspartate receptor antibody immunofluorescence in psychiatric patients with past catatonia.

OBJECTIVE: Anti-N-methyl-D-aspartate receptor (NMDAR) antibody was thought to be the cause of anti-NMDAR encephalitis, with manifestations similar to catatonia and schizophrenia. Anti-NMDAR antibody in neuropsychiatric patients who had catatonia before were investigated in a follow-up evaluation. The intensity of antibody immunofluorescence was quantified and compared with healthy controls. METHOD: Nineteen patients (eight males and eleven females) agreed to be followed-up. Thirteen had the diagnosis of schizophrenia, two had the diagnosis of major depressive disorder, two had bipolar disorder, one had postpartum depression, and one had herpes simplex encephalitis. No patient had catatonia during the follow-up. Nineteen sex-matched healthy controls were recruited. RESULTS: Using Mann-Whitney U test, patients had greater intensity of anti-NMDAR antibody immunofluorescence than the healthy controls (121,979 ± 86,526 vs. 47,692 ± 26,102, p = 0.003). No correlation was found between immunofluorescence intensity and catatonia scales or symptom severity scores. Neuropsychiatric patients with past catatonia showed greater anti-NMDAR antibody response than the healthy controls. CONCLUSION: NMDAR dysfunction might play a role in the mechanism underlying catatonia. Further studies are needed to confirm this finding.

Increased serum brain-derived neurotrophic factor in male schizophrenic patients with metabolic syndrome.

Increased prevalence of metabolic syndrome was found in patients with schizophrenia. Brain-derived neurotrophic factor (BDNF) was involved in energy metabolism and the pathophysiology of schizophrenia, but differently in males and females. We aimed to investigate the serum BDNF levels in patients with schizophrenia with and without metabolic syndrome.Patients with schizophrenia were recruited. Their demographic data were collected. Metabolic profiles and serum BDNF levels were measured. Clinical symptoms were evaluated with Positive and Negative Syndrome Scale. Metabolic syndrome was determined with the criteria provided by Ministry of Health and Welfare of Taiwan. Framingham Risk Score (FRS) for estimate of 10-year risk for coronary heart disease was provided by National Institutes of Health.Of the 81 participants, 40.7% had metabolic syndrome. Those with metabolic syndrome had higher FRS. Using analysis of covariance adjusted for age and body mass index, male patients with schizophrenia with metabolic syndrome had higher serum BDNF levels than those without (4.6 ±â€Š4.7 vs 3.3 ±â€Š3.8 ng/mL, P = .022). No statistical difference was found between female patients with and without metabolic syndrome.Significant differences of serum BDNF levels were found between male patients with schizophrenia with and without metabolic syndrome, but not in females. This finding suggested the gender difference behind the mechanism of BDNF in metabolic syndrome in schizophrenia.

Decreased S100B serum levels after treatment in bipolar patients in a manic phase.

BACKGROUND: Previous studies have suggested that patients with bipolar disorder might have brain damage. The aim of this study was to investigate the serum levels of brain injury biomarkers and S100A10 in bipolar patients in a manic phase, and evaluate the changes in S100B, neuron specific enolase (NSE), heat shock protein 70 (HSP70) and S100A10 after treatment. METHOD: We consecutively enrolled 17 bipolar inpatients in a manic phase and 30 healthy subjects. Serum brain injury biomarkers and S100A10 were measured with assay kits. All patients were evaluated by examining the correlation between brain injury biomarkers and Young Mania Rating Scale (YMRS) scores. RESULT: We found significantly decreased S100B levels only in bipolar manic patients after treatment (p=0.002), but S100B levels were not significantly different from those in healthy controls (p>0.05). CONCLUSION: Our results indicate there were decreased S100B serum levels in bipolar patients in a manic phase after treatment and that increased serum S100B levels might be a possible indicator of transient disruption of the blood-brain barrier in bipolar patients in a manic phase.

The Lorazepam and Diazepam Protocol for Catatonia Due to General Medical Condition and Substance in Liaison Psychiatry.

OBJECTIVE: The lorazepam-diazepam protocol had been proved to rapidly and effectively relieve catatonia in patients with schizophrenia or mood disorder. This study aims to investigate the efficacy of lorazepam-diazepam protocol in catatonia due to general medical conditions (GMC) and substance. METHOD: Patients with catatonia that required psychiatric intervention in various settings of a medical center were included. The lorazepam-diazepam protocol had been used to treat the catatonia due to GMC or substance according to DSM-IV criteria. The treatment response had been assessed by two psychiatrists. RESULTS: Eighteen (85.7%) of 21 catatonic patients due to GMC or substance became free of catatonia after the lorazepam-diazepam protocol. Five (23.8%) of the 21 patients had passed away with various causes of death and wide range of time periods after catatonia. CONCLUSION: Our results showed that the lorazepam-diazepam protocol could rapidly and effectively relieve catatonia due to GMC and substance.

Brain-derived neurotrophic factor (BDNF) and oxidative stress in heroin-dependent male patients undergoing methadone maintenance treatment.

Brain-derived neurotrophic factor (BDNF) and oxidative stress may play a role in patients with heroin dependence. The aim of this study was to investigate the serum levels and activities of BDNF and oxidative stress markers, such as superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), thiobarbituric acid reactive substances (TBARS), protein carbonyl content (PCC), and 8-hydroxy 2'-deoxyguanosine (8-OHdG), in heroin-dependent patients undergoing methadone maintenance treatment (MMT). 60 heroin-dependent male MMT patients and 30 healthy males were recruited for this study. The serum BDNF and oxidative stress markers of these subjects were measured with assay kits. Analyses of covariance (ANCOVAs) with age and body mass index adjustments indicated that the serum levels of BDNF in the MMT patients were significantly higher than those in the healthy controls (F=5.169; p=0.026). However, there were no significant differences between the heroin-dependent patients and the healthy controls in the serum levels or activities of oxidative stress markers (p>0.05). In conclusion, our results suggest that MMT increases BDNF levels in heroin-dependent patients, and that patients undergoing MMT might be in a balanced state of reduced oxidation.

Relapses and recurrences of catatonia: 30-case analysis and literature review.

OBJECTIVE: Relieving catatonia helps identify the underlying etiology and its treatment. However, catatonia may reemerge after some time, but there are few data on the relapses and recurrences of catatonia. We aimed to investigate the characteristics of patients with relapses or recurrences of catatonia as well as the efficacy of the lorazepam-diazepam protocol on them. METHODS: Patients with catatonia who had more than one episode of catatonia and were treated with the lorazepam-diazepam protocol were identified. Their medical charts were reviewed, and interview was conducted. RESULTS: Thirty patients were identified. Nineteen (63.3%) were diagnosed with schizophrenia, five (16.7%) with major depressive disorder, two (6.7%) with bipolar disorder, and four (13.3%) with general medical conditions. In the 68 relapses and relapses the lorazepam-diazepam protocol was used, full response was reported in 54 (79.4%) of them. Twelve of 19 (63.2%) patients with schizophrenia were treated with clozapine. Twenty (66.7%) out of 30 patients were maintained on oral lorazepam by the time of discharge. Literature review showed similar prevalence of schizophrenia in patients with more than one episode of catatonia, and a wide variety of treatment options. CONCLUSION: The lorazepam-diazepam protocol was mostly effective in managing relapses and recurrences of catatonia. Maintenance clozapine and oral lorazepam were beneficial in a significant number of patients.