Functional connectivity in autism spectrum disorder evaluated using rs-fMRI and DKI.

We evaluated functional connectivity (FC) in patients with adult autism spectrum disorder (ASD) using resting-state functional MRI (rs-fMRI) and diffusion kurtosis imaging (DKI). We acquired rs-fMRI data from 33 individuals with ASD and 33 healthy controls (HC) and DKI data from 18 individuals with ASD and 17 HC. ASD showed attenuated FC between the right frontal pole (FP) and the bilateral temporal fusiform cortex (TFusC) and enhanced FC between the right thalamus and the bilateral inferior division of lateral occipital cortex, and between the cerebellar vermis and the right occipital fusiform gyrus (OFusG) and the right lingual gyrus, compared with HC. ASD demonstrated increased axial kurtosis (AK) and mean kurtosis (MK) in white matter (WM) tracts, including the right anterior corona radiata (ACR), forceps minor (FM), and right superior longitudinal fasciculus (SLF). In ASD, there was also a significant negative correlation between MK and FC between the cerebellar vermis and the right OFusG in the corpus callosum, FM, right SLF and right ACR. Increased DKI metrics might represent neuroinflammation, increased complexity, or disrupted WM tissue integrity that alters long-distance connectivity. Nonetheless, protective or compensating adaptations of inflammation might lead to more abundant glial cells and cytokine activation effectively alleviating the degeneration of neurons, resulting in increased complexity. FC abnormality in ASD observed in rs-fMRI may be attributed to microstructural alterations of the commissural and long-range association tracts in WM as indicated by DKI.

Acceptability of transdermal antipsychotic patches by patients who refuse oral medication and their effectiveness in preventing recurrence of delirium: a retrospective observational study.

Injectable antipsychotics had been used for patients who refuse oral medications in delirium practice. The objectives were to investigate acceptability of transdermal antipsychotic patches by patients who refuse oral medications and their effectiveness in preventing recurrence of delirium. In this retrospective observational study, data were collected between October 2019 and December 2021. The sample was represented by patients hospitalized because of acute diseases or elective surgery who had delirium on the night before the consultation and had refused oral therapy after consultation. Delirium has been diagnosed according to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition. Instead, a transdermal patch of blonanserin, a second-generation antipsychotic drug, was tried. The primary outcome was the rate of patients who accepted it. The secondary outcome was recurrence rates of delirium. As much as 95.1% of patients who refused oral medications (98/103 patients) accepted to receive the transdermal patch. Of these, 24 patients developed delirium again, whereas all five patients who refused it developed delirium again [24.5% (24/98) vs. 100% (5/5); P = 0.0014]. The present findings suggest that transdermal antipsychotic patches are more likely to be accepted by patients who refuse oral medications. Prospective studies are needed.

Chronic primary musculoskeletal pain: a new concept of nonstructural regional pain.

The concept that a regional musculoskeletal pain may occur in the absence of identifiable tissue abnormality may be puzzling. Previously these regional complaints were generally categorized as myofascial pain syndromes, or prior to the formalization of the nociplastic pain concept, as musculoskeletal pain with a neuropathic component, and treatments were anatomically focussed. Chronic primary musculoskeletal pain is now identified under the chronic primary pain stem category with the mechanistic descriptor of nociplastic pain. It is possible that many patients previously diagnosed with myofascial pain do in fact suffer from chronic primary musculoskeletal pain, requiring a paradigm shift in management towards more centrally directed treatment strategies. Many questions remain, including validation of the proposed examination techniques, prevalence, ideal treatment, and uptake and acceptance by the healthcare community. This new classification should be welcomed as an explanation for regional pain conditions that previously responded poorly to physically focussed treatments.

Association Between Step Count Measured With a Smartphone App (Pain-Note) and Pain Level in Patients With Chronic Pain: Observational Study.

BACKGROUND: Chronic pain is the leading cause of disability, affecting between 20% and 50% of the global population. The key recommended treatment is physical activity, which can be measured in daily life using a pedometer. However, poor adherence to pedometer use can result in incorrect measurements. Furthermore, only a few studies have investigated a possible curvilinear association between physical activity and chronic pain. OBJECTIVE: In this study, we developed the Pain-Note smartphone app to collect real-world data on step count, using the smartphone's built-in pedometer. The aims of our research are (1) to evaluate the association between daily step count and pain level among patients with chronic pain and (2) determine if the association between daily step count and pain level was curvilinear. METHODS: We conducted a cross-sectional study based on step count data collected with the app and on the results of questionnaires, which measured the duration and intensity of pain, the widespread pain index, the symptom severity score, and the insomnia severity scale, including 7 questions for symptoms of depression. We analyzed the association between step count and pain level as a nonlinear relationship using a restricted cubic spline model. A prespecified subgroup analysis was also conducted based on fibromyalgia criteria. RESULTS: Between June 1, 2018, and June 11, 2020, a total of 6138 records were identified, of which 1273 were analyzed. The mean age of the participants was 38.7 years, 81.9% (1043/1273) were female, and chronic pain was present for more than 5 years in 43.2% (550/1273) of participants. Participants in the third and fourth quartiles for step count (more than 3045 and 5668 steps a day, respectively) showed a significant positive association between higher step count and lower numerical pain rating scale (mean difference -0.43, 95% CI -0.78 to -0.08, P=.02; -0.45; 95% CI -0.8 to -0.1, P=.01, respectively) than those in the first quartile (less than or equal to 1199 steps a day). The restricted cubic spline model for the association between step count and pain scale displayed a steep decline followed by a moderate decrease as the step count increased; the inflection point was 5000 steps. However, this association was not observed among participants who met the fibromyalgia criteria (491/1273), who showed a steep positive increase below 2000 steps. Data were collected between June 1, 2018, and June 11, 2020, and were analyzed on November 18, 2021. CONCLUSIONS: Step count measured with the Pain-Note app showed a nonlinear association with pain level. Although participants with and without fibromyalgia showed a negative correlation between step count and pain level, participants who meet the criteria for fibromyalgia may present a different relationship between walking and pain perception compared to those in the general chronic pain population.

Nociplastic pain: towards an understanding of prevalent pain conditions.

Nociplastic pain is the semantic term suggested by the international community of pain researchers to describe a third category of pain that is mechanistically distinct from nociceptive pain, which is caused by ongoing inflammation and damage of tissues, and neuropathic pain, which is caused by nerve damage. The mechanisms that underlie this type of pain are not entirely understood, but it is thought that augmented CNS pain and sensory processing and altered pain modulation play prominent roles. The symptoms observed in nociplastic pain include multifocal pain that is more widespread or intense, or both, than would be expected given the amount of identifiable tissue or nerve damage, as well as other CNS-derived symptoms, such as fatigue, sleep, memory, and mood problems. This type of pain can occur in isolation, as often occurs in conditions such as fibromyalgia or tension-type headache, or as part of a mixed-pain state in combination with ongoing nociceptive or neuropathic pain, as might occur in chronic low back pain. It is important to recognise this type of pain, since it will respond to different therapies than nociceptive pain, with a decreased responsiveness to peripherally directed therapies such as anti-inflammatory drugs and opioids, surgery, or injections.

Music Intervention Reduces Persistent Fibromyalgia Pain and Alters Functional Connectivity Between the Insula and Default Mode Network.

OBJECTIVE: The aims of the present study were to examine the effects of short-term music interventions among patients with fibromyalgia (FM) and to clarify the alterations in functional connectivity and persistent pain. DESIGN: Pilot study. SETTING: All participants were evaluated at Juntendo University from November 2017 to January 2019. SUBJECTS: We enrolled female patients who had been clinically diagnosed with FM (N = 23). METHODS: All participants listened to Mozart's Duo for Violin and Viola No. 1, K. 423, in a quiet room for 17 minutes. We compared the degree of pain using resting-state functional magnetic resonance imaging and the numeric rating scale before and after listening to music. RESULTS: Pain scores were significantly reduced after listening to music. Further, we observed there was a significant difference in connectivity between the right insular cortex (IC) and posterior cingulate cortex (PCC)/precuneus (PCu) before and after listening to music. We also found that the difference between the right IC-PCu connectivity and the difference in pain scores were significantly correlated. CONCLUSIONS: We found that a short period of music intervention reduced chronic pain and altered functional IC-default mode network connectivity. Furthermore, music potentially normalized the neural network via IC-default mode network connectivity, yielding temporary pain relief in patients with FM. Further longitudinal studies with larger sample sizes are required to confirm these results.

Real-World Effectiveness of Ramelteon and Suvorexant for Delirium Prevention in 948 Patients With Delirium Risk Factors.

OBJECTIVE: The aim of this study was to examine the effectiveness of ramelteon and suvorexant for delirium prevention in real-world practice. It explored whether ramelteon and/or suvorexant would affect delirium prevention among both patients at risk for but without delirium (patients at risk) and those with delirium the night before a consultation. METHODS: This multicenter, prospective, observational study was conducted by trained psychiatrists at consultation-liaison psychiatric services from October 1, 2017, to October 7, 2018. Patients who were aged 65 years or older and hospitalized because of acute diseases or elective surgery, had risk factors for delirium, and had insomnia or delirium on the night before the consultation were prescribed ramelteon and/or suvorexant. The decision to take medication was left to the discretion of each patient. The primary outcome was incidence of delirium based on the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, during the first 7 days. RESULTS: Among 526 patients at risk, those taking ramelteon and/or suvorexant developed delirium significantly less frequently than those who did not, after control for the effects of risk factors on the estimate of an independent association between the effects of ramelteon and/or suvorexant and the outcome of developing delirium (15.7% vs 24.0%; odds ratio [OR] = 0.48;, 95% CI, 0.29-0.80; P = .005). Similar results were found among 422 patients with delirium (39.9% vs 66.3%; OR = 0.36; 95% CI, 0.22-0.59; P < .0001). CONCLUSIONS: Ramelteon and suvorexant appear to be effective for delirium prevention in real-world practice.

A prospective naturalistic multicenter study on choice of parenteral medication in psychiatric emergency settings in Japan.

AIM: To provide information about psychiatric emergency situations in Japan, we examined psychiatrists' preference among parenteral medication since intramuscular (IM)-olanzapine became available and clinical characteristics in patients given IM-olanzapine compared to those given other parenteral medication. METHODS: We conducted a naturalistic study proceeding over a 1-year period in 9 psychiatric emergency departments. RESULTS: Among 197 patients, the distribution of IM-injections (n = 89) was as follows: IM-olanzapine, 66 patients (74.2%), IM-levomepromazine, 17 patients (19.1%), IM-haloperidol, 5 patients (5.6%), and IM-diazepam, 1 patient (1.1%). The distribution of intravenous (IV)-injections (n = 108) was as follows: IV-haloperidol, 78 patients (72.2%), and IV-benzodiazepines (diazepam, flunitrazepam, or midazolam), 30 patients (27.8%). Advantages of IM-olanzapine over other parenteral medications in efficacy were found as follows: less frequent needs of an additional injection despite no difference in duration until a patient became cooperative for oral administration, and less frequent needs of restraint after the injection. Furthermore, advantages of IM-olanzapine over other injections in safety were found as follows: less frequent appearance of extrapyramidal symptoms, no occurrence of ECG abnormality and other serious adverse events except a fall, less frequent needs of an adjunctive anticholinergic drug, and less frequent needs of another kind of drug additionally injected. CONCLUSIONS: Olanzapine has rapidly become the first choice of intramuscular medication in psychiatric emergency situations since it became available in Japan, probably due to the advantages in both efficacy and safety. This study reflecting psychiatric emergency practice in Japan may contribute to periodic international comparison of psychiatric emergency practice.

Retraction: Murine hypothalamic destruction with vascular cell apoptosis subsequent to combined administration of human papilloma virus vaccine and pertussis toxin.

This corrects the article DOI: 10.1038/srep36943.

The Endometriosis Fertility Index Is Useful for Predicting the Ability to Conceive without Assisted Reproductive Technology Treatment after Laparoscopic Surgery, Regardless of Endometriosis.

OBJECTIVE: The endometriosis fertility index (EFI) is a novel index for predicting pregnancy after surgery. We investigated the utility of the EFI for predicting the ability to conceive without assisted reproductive technology (ART) treatment after laparoscopic surgery. METHODS: From July 2011 through December 2012, we recruited 133 infertile patients who underwent laparoscopy, and the EFI was calculated. After surgery, 55 of 133 achieved pregnancy without ART treatment. We evaluated the factors that predicted a naturally successful pregnancy and compared them between the pregnant and non-pregnant subjects. RESULTS: On a univariate linear regression analysis, we found that a younger age, shorter duration of infertility, and higher EFI were positively associated with a successful pregnancy without ART after laparoscopic surgery (p < 0.05). According to 50th percentile EFI, the cutoff EFI predicting a successful pregnancy without ART was 7, the pregnancy rate in the high-EFI group (EFI; 8-10) was significantly higher than that in the low-EFI group (EFI ≤7; p < 0.05), but the duration to natural conception after surgery was similar between the 2 groups. CONCLUSION: The EFI possesses greater predictive power for a successful pregnancy with natural intercourse or intrauterine insemination in infertile patients, regardless of endometriosis, than the Revised-American Society of Reproductive Medicine classification.

Preventive Effects of Suvorexant on Delirium: A Randomized Placebo-Controlled Trial.

OBJECTIVE: No highly effective pharmacologic interventions to prevent delirium have been identified. We examined whether suvorexant, a potent and selective orexin receptor antagonist, is effective for the prevention of delirium. METHODS: We conducted a multicenter, rater-blinded, randomized, placebo-controlled clinical trial in intensive care units and regular acute wards between April 2015 and March 2016. Eligible patients were 65 to 89 years old, newly admitted due to emergency, and able to take medicine orally and had an expected stay or life expectancy of 48 hours or more. Seventy-two patients were randomly assigned using the sealed envelope method to receive suvorexant (15 mg/d; 36 patients) or placebo (36 patients) every night for 3 days. The primary outcome measure was incidence of delirium as determined by the DSM-5. Trained psychiatrists assessed for delirium. RESULTS: We found that delirium developed significantly less often among patients taking suvorexant than among those taking placebo (0% [n/N = 0/36] vs 17% [6/36], respectively, P = .025). Comparison by log-rank test also showed that delirium developed significantly less often among patients taking suvorexant than among those taking placebo (χ² = 6.46, P = .011). Analysis of variance revealed a tendency for main effect of treatment (F = 3.79, P = .053) on the sleep-wake cycle disturbance score (item 1) of the Japanese version of the Delirium Rating Scale-Revised-98 (DRS-R-98-J). There were no significant differences in adverse events. CONCLUSIONS: Suvorexant administered nightly to elderly patients admitted for acute care may provide protection against delirium. Larger studies are needed to show the potential of suvorexant to improve the circadian core domain of delirium. TRIAL REGISTRATION: UMIN Clinical Trials Registry identifier: UMIN000015681​.

A study of brain metabolism in fibromyalgia by positron emission tomography.

PURPOSE: The aim of the present study was to determine the brain regions with altered metabolism in patients with treatment-naïve fibromyalgia (FM). METHODS: We used [18F] fluoro-d-glucose positron emission tomography to examine a total of 18 treatment-naïve FM patients and 18 age- and sex-matched healthy controls not suffering from pain. A voxel-by-voxel group analysis was performed using statistical parametric mapping. RESULTS: No significant voxel (peak)-level results were detected in this study; however, some regions were detected as significant-size clusters. There were no significant differences in brain metabolism between FM patients and controls. However, the right thalamus and left lentiform nucleus were hypermetabolic areas in FM patients with poor prognosis compared to the healthy controls. In contrast, the left insula and left lentiform nucleus were hypometabolic areas in FM patients with good prognosis compared to the healthy controls. Compared to FM patients with good prognosis, FM patients with poor prognosis showed significant hypermetabolism in the left thalamus, bilateral lentiform nucleus, and right parahippocampal gyrus. CONCLUSION: The present findings suggest an association between the metabolism in the thalamus, lentiform nucleus, and parahippocampal gyrus and prognosis in FM patients. Further study with a larger number of patients is required to confirm this association.

High prevalence of anti-TSH receptor antibody in fibromyalgia syndrome.

AIM: Fibromyalgia syndrome (FMS) is defined as chronic widespread pain that cannot be accounted for by any other medical disorder. Our aim was to explore the prevalence of thyroid autoimmunity in patients with FMS. METHODS: For determining thyroid function in 207 FMS patients, we tested for the titers of free tri-iodothyronine, free thyroxine, thyroid-stimulating hormone (TSH), anti-thyroid peroxidase antibody (TPOAb), anti-thyroglobulin antibody (TgAb) and anti-TSH receptor antibody (TRAb). RESULTS: Twenty-five patients who had either subclinical hyper- or hypothyroidism, or overt hypothyroidism were excluded. Sixty-nine FMS patients with autoimmune thyroid diseases (AITD) (37.9%, 69/182) were identified. The prevalence of positivity for TRAb, TgAb and TPOAb was 20.3% (n = 37), 16.5% (n = 30) and 13.2% (n = 24), respectively. Compared to control populations in previous studies, the prevalence of TRAb positivity was high, and titers of TRAb were low (1.0-1.5 IU/L). The prevalence of TPOAb and TgAb positivity was not significantly higher than that reported in FMS patients in previous studies. Clinical symptom profiles were identical for FMS patients with and without AITD. CONCLUSION: We found a high prevalence of AITD among 207 patients with clinically defined FMS, with TRAb being especially prominent among these patients. Further study is needed to evaluate changes in thyroid function among FMS patients with AITD.

Evaluation of newly-developed aniseikonia testing method based on space eikonometry.

BACKGROUND: We have developed a new aniseikonia testing method based on the space eikonometry (ATSE) principle. The purpose of this study was to compare aniseikonia obtained by the ATSE to that of the conventional new aniseikonia tests (NAT), which is commonly used in Japan. METHODS: Thirty normal subjects (mean age: 22.8 years) without ocular disease except for refractive errors were studied. All of the subjects had normal binocular single vision with stereopsis. We excluded subjects with refractive errors greater than 1.00 D cylinder or anisometropia (spherical equivalent) greater than 1.00 D. We simulated overall aniseikonia of five and 10 per cent with afocal size lenses (HOYA, Tokyo, Japan) placed in the optical path of the fully corrected right eye. We measured aniseikonia three times with either the ATSE or NAT and the averages were used for the statistical analyses. RESULTS: The mean and standard deviation (SD) of aniseikonia determined by the ATSE was 5.1 ± 0.8 per cent with the five per cent afocal lens and 10.1 ± 0.8 per cent with the 10 per cent afocal lens. Aniseikonia was 2.8 ± 1.3 per cent with the five per cent afocal lens and 6.0 ± 2.5 per cent with the 10 per cent afocal lens by the NAT. The mean error was + two per cent of the theoretical value by the ATSE and -42 per cent by the NAT for both afocal lenses. CONCLUSION: We recommend the use of the new ATSE for quantitative determination of aniseikonia, as it is more accurate than the NAT.

Murine hypothalamic destruction with vascular cell apoptosis subsequent to combined administration of human papilloma virus vaccine and pertussis toxin.

Vaccination is the most powerful way to prevent human beings from contracting infectious diseases including viruses. In the case of the human papillomavirus (HPV) vaccine, an unexpectedly novel disease entity, HPV vaccination associated neuro-immunopathetic syndrome (HANS), has been reported and remains to be carefully verified. To elucidate the mechanism of HANS, we applied a strategy similar to the active experimental autoimmune encephalitis (EAE) model - one of the most popular animal models used to induce maximum immunological change in the central nervous system. Surprisingly, mice vaccinated with pertussis toxin showed neurological phenotypes that include low responsiveness of the tail reflex and locomotive mobility. Pathological analyses revealed the damage to the hypothalamus and circumventricular regions around the third ventricle, and these regions contained apoptotic vascular endothelial cells. These data suggested that HPV-vaccinated donners that are susceptible to the HPV vaccine might develop HANS under certain environmental factors. These results will give us the new insight into the murine pathological model of HANS and help us to find a way to treat of patients suffering from HANS.

Fibromyalgia syndrome and cognitive dysfunction in elderly: a case series.

AIM: Fibromyalgia syndrome (FMS) is an extremely rare complication of neurocognitive disorders (NCDs). We experienced seven such cases, and we discuss their clinical manifestation and pathomechanisms. METHODS: Seven patients with FMS as a complication of NCD were enrolled. We used the patients' medical records to identify clinical manifestations and obtain experimental data, such as pain questionnaire scores, cognitive tests, genetics and radiological imaging of the brain. RESULTS: The seven patients were clinically diagnosed with frontotemporal NCD (n = 3) or Alzheimer's disease (n = 4). No patient presented with any organic disorder that would explain their chronic pain. Through their courses, they experienced refractory widespread pain continuously despite analgesics. Brain magnetic resonance imaging revealed moderate or severe atrophic changes in the temporal lobes and hippocampus. Three-dimensional stereotactic surface projection (3D-SSP) analysis of brain single photon emission computed tomography (SPECT), indicated severe hypoperfusion on the right side of the medial temporal lobe, both sides of the anterior corpus callosum, anterior cingulate gyrus, and primary sensory area. Genetic analysis uncovered no pathogenic mutations. CONCLUSIONS: Neurodegenerative disorders are rarely complicated by FMS, which is associated with relatively severe pain. Central sensitization may be a possible risk factor of widespread pain in elderly patients with NCD.

The E3 ligase synoviolin controls body weight and mitochondrial biogenesis through negative regulation of PGC-1ß.

Obesity is a major global public health problem, and understanding its pathogenesis is critical for identifying a cure. In this study, a gene knockout strategy was used in post-neonatal mice to delete synoviolin (Syvn)1/Hrd1/Der3, an ER-resident E3 ubiquitin ligase with known roles in homeostasis maintenance. Syvn1 deficiency resulted in weight loss and lower accumulation of white adipose tissue in otherwise wild-type animals as well as in genetically obese (ob/ob and db/db) and adipose tissue-specific knockout mice as compared to control animals. SYVN1 interacted with and ubiquitinated the thermogenic coactivator peroxisome proliferator-activated receptor coactivator (PGC)-1ß, and Syvn1 mutants showed upregulation of PGC-1ß target genes and increase in mitochondrion number, respiration, and basal energy expenditure in adipose tissue relative to control animals. Moreover, the selective SYVN1 inhibitor LS-102 abolished the negative regulation of PGC-1ß by SYVN1 and prevented weight gain in mice. Thus, SYVN1 is a novel post-translational regulator of PGC-1ß and a potential therapeutic target in obesity treatment.

Fibromyalgia.

Fibromyalgia is a common illness characterized by chronic widespread pain, sleep problems (including unrefreshing sleep), physical exhaustion and cognitive difficulties. The definition, pathogenesis and treatment are controversial, and some even contest the existence of this disorder. In 1990, the American College of Rheumatology (ACR) defined classification criteria that required multiple tender points (areas of tenderness occurring in muscles and muscle-tendon junctions) and chronic widespread pain. In 2010, the ACR preliminary diagnostic criteria excluded tender points, allowed less extensive pain and placed reliance on patient-reported somatic symptoms and cognitive difficulties. Fibromyalgia occurs in all populations worldwide, and symptom prevalence ranges between 2% and 4% in the general population. The prevalence of people who are actually diagnosed with fibromyalgia ('administrative prevalence') is much lower. A model of fibromyalgia pathogenesis has been suggested in which biological and psychosocial variables interact to influence the predisposition, triggering and aggravation of a chronic disease, but the details are unclear. Diagnosis requires the history of a typical cluster of symptoms and the exclusion of a somatic disease that sufficiently explains the symptoms by medical examination. Current evidence-based guidelines emphasize the value of multimodal treatments, which encompass both non-pharmacological and selected pharmacological treatments tailored to individual symptoms, including pain, fatigue, sleep problems and mood problems. For an illustrated summary of this Primer, visit: http://go.nature.com/LIBdDX.

Antipsychotic switching versus augmentation among early non-responders to risperidone or olanzapine in acute-phase schizophrenia.

PURPOSE: We examined whether augmentation with olanzapine would be superior to switching to olanzapine among early non-responders (ENRs) to risperidone, and whether augmentation with risperidone would be superior to switching to risperidone among ENRs to olanzapine. We performed a rater-blinded, randomized clinical trial at psychiatric emergency sites. Eligible patients were newly admitted patients with acute schizophrenia. ENRs to the initial antipsychotic (Clinical Global Impressions-Improvement Scale: ≥ 4 at 2 weeks) were allocated to receive either augmentation with or switching to the other antipsychotic (RIS+OLZ vs. RIS-OLZ; OLZ+RIS vs. OLZ-RIS) RESULTS: Sixty patients who completed 2 weeks of risperidone treatment were divided into 33 early responders (RIS-ER) and 27 ENRs (RIS+OLZ, n=14; RIS-OLZ, n=13). Although time to treatment discontinuation for any cause was significantly shorter in RIS+OLZ group (54.1 days [95% confidence interval, 41.3-67.0]) than in RIS-ER group (68.7 [61.2-76.2]; P=0.050), it was not significantly shorter in RIS-OLZ group (58.5 [43.1-73.9]) than in RIS-ER group (P=0.19). Sixty patients who completed 2 weeks of olanzapine treatment were divided into 36 early responders (OLZ-ER) and 24 ENRs (OLZ+RIS, n=11; OLZ-RIS, n=13). Although time to treatment discontinuation for any cause was significantly shorter in OLZ-RIS group (56.1days [40.7-71.5]) than in OLZ-ER group (74.9 [68.5-81.3]; P=0.008), it was not significantly shorter in OLZ+RIS group (64.6 [49.6-79.6]) than in OLZ-ER group (P=0.20). CONCLUSION: Despite the lack of pharmacokinetic investigation of dose adequacy in this study, it is possible that switching to olanzapine among ENRs to risperidone might have a small advantage over augmentation with olanzapine, while augmentation with risperidone might have a small advantage over switching to risperidone among ENRs to olanzapine. Further research is required before it would be appropriate to modify routine practice in the direction of these findings.