Characteristics of Patients With Intractable Obsessive-Compulsive Disorder With High/Low Responsiveness to Gamma Knife Surgery.

OBJECTIVE: Obsessive-compulsive disorder (OCD) is a psychiatric condition that causes significant distress and social costs and often follows a chronic course with frequent relapses. Approximately 20% of patients do not respond to medication or cognitive behavioral therapy; gamma knife surgery (GKS) has been proposed as a treatment option for these patients. However, research on GKS for OCD patients is rare. METHODS: In this study, 10 patients with treatment-resistant OCD underwent GKS, and the treatment response and side effects were assessed. The improvement in patients' obsessive-compulsive symptoms was evaluated using the Yale-Brown Obsessive Compulsive Scale (YBOCS) scores following GKS. Additionally, the characteristics distinguishing the groups with favorable responses to GKS from those with less favorable responses were examined. RESULTS: GKS was well tolerated, and patients demonstrated a statistically significant reduction in YBOCS scores before and after GKS (p=0.016). Patients that responded to GKS exhibited distinct characteristics from those who did not respond. Patients who responded poorly tended to present an earlier age of onset, a longer duration of illness, more frequent hospitalizations, poorer social functioning, and a greater incidence of suicide attempts/thoughts. CONCLUSION: This study not only demonstrated that GKS is a safe and effective treatment method for intractable OCD but also revealed characteristics distinguishing patients who respond well to GKS from those who do not. These results may aid in the selection of patients for future application of GKS.

A naturalistic cohort study of first-episode schizophrenia spectrum disorder: A description of the early phase of illness in the PSYSCAN cohort.

BACKGROUND: We examined the course of illness over a 12-month period in a large, international multi-center cohort of people with a first-episode schizophrenia spectrum disorder (FES) in a naturalistic, prospective study (PSYSCAN). METHOD: Patients with a first episode of schizophrenia, schizoaffective disorder (depressive type) or schizophreniform disorder were recruited at 16 institutions in Europe, Israel and Australia. Participants (N = 304) received clinical treatment as usual throughout the study. RESULTS: The mean age of the cohort was 24.3 years (SD = 5.6), and 67 % were male. At baseline, participants presented with a range of intensities of psychotic symptoms, 80 % were taking antipsychotic medication, 68 % were receiving psychological treatment, with 46.5 % in symptomatic remission. The mean duration of untreated psychosis was 6.2 months (SD = 17.0). After one year, 67 % were in symptomatic remission and 61 % were in functional remission, but 31 % had been readmitted to hospital at some time after baseline. In the cohort as a whole, depressive symptoms remained stable over the follow-up period. In patients with a current depressive episode at baseline, depressive symptoms slightly improved. Alcohol, tobacco and cannabis were the most commonly used substances, with daily users of cannabis ranging between 9 and 11 % throughout the follow-up period. CONCLUSIONS: This study provides valuable insight into the early course of a broad range of clinical and functional aspects of illness in FES patients in routine clinical practice.

Impact of long-acting injectable aripiprazole on the concomitant medication and antipsychotic polypharmacy: a retrospective, observational study of 127 patients with psychosis.

Antipsychotic polypharmacy (APP) has become prevalent over the years, but several concerns have been raised over APP. Accumulating evidence suggests that aripiprazole long-acting injectable (LAI) may reduce the rate of APP, but the association remains speculative. This retrospective observational study included 127 patients with psychosis and observed them for 1.8 ±â€…1.3 years, up to 4 years. Prescription data of antipsychotics (APs), mood stabilisers, benzodiazepines, and anti-extrapyramidal side effect medications were obtained at baseline and the last observation. Daily chlorpromazine equivalent (CPZ) dose of APs decreased from 124.40 ±â€…235.35 mg to 77.95 ±â€…210.36 mg (P = 0.027). The daily dose of anticholinergics and beta-blockers also significantly decreased after introducing aripiprazole LAI. Among the patients having APP, the number of concurrent APs along with daily CPZ dose of APs decreased after initiation of aripiprazole LAI from 1.28 ±â€…0.62 to 0.85 ±â€…0.73 (P < 0.001) and 298.33 ±â€…308.70 mg to 155.43 ±â€…280.53 mg (P = 0.004), respectively. Treatment with aripiprazole LAI for up to 4 years in patients with psychosis was associated with a reduced number of prescribed APs in patients having an APP and a reduced dose of APs and concurrent psychotropic medications.

Alterations in blood proteins in the prodromal stage of bipolar II disorders.

Although early intervention may help prevent the progression of bipolar disorder, there are some controversies over early pharmacological intervention. In this study, we recruited 40 subjects in the prodromal stage of BD-II (BP), according to bipolar at-risk state criteria. We compared the expression of their plasma proteins with that of 48 BD-II and 75 healthy control (HC) to identify markers that could be detected in a high-risk state. The multiple reaction monitoring method was used to measure target peptide levels with high accuracy. A total of 26 significant peptides were identified through analysis of variance with multiple comparisons, of which 19 were differentially expressed in the BP group when compared to the BD-II and HC groups. Two proteins were overexpressed in the BP group; and were related to pro-inflammation and impaired neurotransmission. The other under-expressed peptides in the BP group were related to blood coagulation, immune reactions, lipid metabolism, and the synaptic plasticity. In this study, significant markers observed in the BP group have been reported in patients with psychiatric disorders. Overall, the results suggest that the pathophysiological changes included in BD-II had already occurred with BP, thus justifying early pharmacological treatment to prevent disease progression.

The Role of Estrogen Receptors and Their Signaling across Psychiatric Disorders.

Increasing evidence suggests estrogen and estrogen signaling pathway disturbances across psychiatric disorders. Estrogens are not only crucial in sexual maturation and reproduction but are also highly involved in a wide range of brain functions, such as cognition, memory, neurodevelopment, and neuroplasticity. To add more, the recent findings of its neuroprotective and anti-inflammatory effects have grown interested in investigating its potential therapeutic use to psychiatric disorders. In this review, we analyze the emerging literature on estrogen receptors and psychiatric disorders in cellular, preclinical, and clinical studies. Specifically, we discuss the contribution of estrogen receptor and estrogen signaling to cognition and neuroprotection via mediating multiple neural systems, such as dopaminergic, serotonergic, and glutamatergic systems. Then, we assess their disruptions and their potential implications for pathophysiologies in psychiatric disorders. Further, in this review, current treatment strategies involving estrogen and estrogen signaling are evaluated to suggest a future direction in identifying novel treatment strategies in psychiatric disorders.

Glucagon-Like Peptide-1 Receptor Agonist Differentially Affects Brain Activation in Response to Visual Food Cues in Lean and Obese Individuals with Type 2 Diabetes Mellitus.

BACKGROUND: To investigate the effects of a glucagon-like peptide-1 receptor agonist on functional brain activation in lean and obese individuals with type 2 diabetes mellitus (T2DM) in response to visual food cues. METHODS: In a randomized, single-blinded, crossover study, 15 lean and 14 obese individuals with T2DM were administered lixisenatide or normal saline subcutaneously with a 1-week washout period. We evaluated brain activation in response to pictures of high-calorie food, low-calorie food, and nonfood using functional magnetic resonance imaging and measured appetite and caloric intake in participants who were given access to an ad libitum buffet. RESULTS: Obese individuals with T2DM showed significantly greater activation of the hypothalamus, pineal gland, parietal cortex (high-calorie food vs. low-calorie food, P<0.05), orbitofrontal cortex (high-calorie food vs. nonfood, P<0.05), and visual cortex (food vs. nonfood, P<0.05) than lean individuals with T2DM. Lixisenatide injection significantly reduced the functional activation of the fusiform gyrus and lateral ventricle in obese individuals with T2DM compared with that in lean individuals with T2DM (nonfood vs. high-calorie food, P<0.05). In addition, in individuals who decreased their caloric intake after lixisenatide injection, there were significant interaction effects between group and treatment in the posterior cingulate, medial frontal cortex (high-calorie food vs. low-calorie food, P<0.05), hypothalamus, orbitofrontal cortex, and temporal lobe (food vs. nonfood, P<0.05). CONCLUSION: Brain responses to visual food cues were different in lean and obese individuals with T2DM. In addition, acute administration of lixisenatide differentially affected functional brain activation in these individuals, especially in those who decreased their caloric intake after lixisenatide injection.

Adjunctive use of anti-inflammatory drugs for schizophrenia: A meta-analytic investigation of randomized controlled trials.

OBJECTIVE: Recent evidence suggests that adjuvant anti-inflammatory agents could improve the symptoms of patients with schizophrenia. However, the effects of the adjuvant anti-inflammatory agents on cognitive function, general functioning and side effects have not yet been systematically investigated. The present meta-analysis aimed to explore the effects of anti-inflammatory agents in patients with schizophrenia comprehensively. METHOD: We performed a literature search in online databases, including PubMed, EMBASE and the Cochrane Database of Systematic Reviews. Randomized, placebo-controlled double-blind studies that investigated clinical outcomes including psychopathology, neurocognition, general functioning and extrapyramidal side effects were included. The examined anti-inflammatory agents included aspirin, celecoxib, omega-3 fatty acids, estrogen, selective estrogen receptor modulator, pregnenolone, N-acetylcysteine, minocycline, davunetide and erythropoietin. RESULTS: Sixty-two double-blind randomized clinical trials studying 2914 patients with schizophrenia met the inclusion criteria for quantitative analysis. Significant overall effects were found for anti-inflammatory agents for reducing total, positive and negative symptom scores in the Positive and Negative Syndrome Scale. Cognitive improvements were significant with minocycline and pregnenolone augmentation therapy. General functioning was significantly enhanced by overall anti-inflammatory agents. There were no significant differences in side effects compared with placebo. Baseline total Positive and Negative Syndrome Scale score and illness duration were identified as moderating factors in the effects of anti-inflammatory augmentation on psychiatric symptom improvements. CONCLUSION: The comparative evaluation of efficacy and safety supported the use of anti-inflammatory adjuvant therapy over the use of antipsychotics alone. However, future studies could focus on patients with homogeneous clinical profile to figure out more detailed effects of anti-inflammatory therapy.

Small molecule-based lineage switch of human adipose-derived stem cells into neural stem cells and functional GABAergic neurons.

Cellular reprogramming using small molecules (SMs) without genetic modification provides a promising strategy for generating target cells for cell-based therapy. Human adipose-derived stem cells (hADSCs) are a desirable cell source for clinical application due to their self-renewal capacity, easy obtainability and the lack of safety concerns, such as tumor formation. However, methods to convert hADSCs into neural cells, such as neural stem cells (NSCs), are inefficient, and few if any studies have achieved efficient reprogramming of hADSCs into functional neurons. Here, we developed highly efficient induction protocols to generate NSC-like cells (iNSCs), neuron-like cells (iNs) and GABAergic neuron-like cells (iGNs) from hADSCs via SM-mediated inhibition of SMAD signaling without genetic manipulation. All induced cells adopted morphological, molecular and functional features of their bona fide counterparts. Electrophysiological data demonstrated that iNs and iGNs exhibited electrophysiological properties of neurons and formed neural networks in vitro. Microarray analysis further confirmed that iNSCs and iGNs underwent lineage switch toward a neural fate. Together, these studies provide rapid, reproducible and robust protocols for efficient generation of functional iNSCs, iNs and iGNs from hADSCs, which have utility for modeling disease pathophysiology and providing cell-therapy sources of neurological disorders.

The cost-effectiveness of deep brain stimulation for patients with treatment-resistant obsessive-compulsive disorder.

BACKGROUND: Obsessive-compulsive disorder (OCD) is a chronic neuropsychiatric disorder with a 2% to 3% lifetime prevalence; in addition, 10% of OCD patients are resistant to conventional therapy. Deep brain stimulation (DBS) has been an effective treatment for treatment resistant OCD patients (TROCD). We aimed to determine the cost-effectiveness of DBS for TROCD. METHODS: We used a Markov model to estimate the cost-effectiveness of DBS compared to conventional treatment for TROCD with a 10-year time horizon. Published data were used to estimate the rates of treatment response and complications. Costs were calculated from the perspective of the third-party payer. Data on quality of life were obtained from a literature review and a survey of OCD patients. We applied the model separately to Korea and the United Kingdom (UK) to enhance the validity. RESULTS: Base-case analysis showed an incremental cost-effectiveness ratio of US$37,865 per quality-adjusted life-year in Korea and US$34,462 per quality-adjusted life-year in the UK. According to the World Health Organization's criteria, DBS for TROCD was "cost-effective" in Korea (<3x GDP per capita) and "highly cost-effective" in the UK (

Comparison of the effectiveness of virtual cue exposure therapy and cognitive behavioral therapy for nicotine dependence.

Previous studies have reported promising results regarding the effect of repeated virtual cue exposure therapy on nicotine dependence. This study aimed to compare the effectiveness of virtual cue exposure therapy (CET) and cognitive behavioral therapy (CBT) for nicotine dependence. Thirty subjects with nicotine dependence participated in 4 weeks of treatment with either virtual CET (n=15) or CBT (n=15). All patients were male, and none received nicotine replacement treatment during the study period. The main setting of the CET used in this study was a virtual bar. The primary foci of the CBT offered were (a) smoking cessation education, (b) withdrawal symptoms, (c) coping with high-risk situations, (d) cognitive reconstruction, and (e) stress management. Daily smoking count, level of expiratory carbon monoxide (CO), level of nicotine dependence, withdrawal symptoms, and subjective craving were examined on three occasions: week 0 (baseline), week 4 (end of treatment), and week 12 (follow-up assessment). After treatment, the daily smoking count, the expiratory CO, and nicotine dependence levels had significantly decreased. These effects continued during the entire study period. Similar changes were observed in both virtual CET and CBT groups. We found no interaction between type of therapy and time of measurement. Although the current findings are preliminary, the present study provided evidence that virtual CET is effective for the treatment of nicotine dependence at a level comparable to CBT.

Neuromagnetic auditory response and its relation to cortical thickness in ultra-high-risk for psychosis.

BACKGROUND: Higher cognitive dysfunction, lower perceptual disturbance and its relation to the structures that implicate such processes have been considered as key features in patients with schizophrenia. However, little is known about the relationship between perceptual processing and structural deficits in ultra-high-risk for psychosis. METHODS: We investigated the dipole moment of M100 auditory evoked response using a magnetoencephalography in 18 patients with schizophrenia, 16 ultra-high-risk for psychosis and 16 healthy controls, and their relation to cortical thinning on Heschl's gyrus and planum temporale. RESULTS: The auditory evoked M100 dipole moment was decreased in the ultra-high-risk subjects and in the patients with schizophrenia. Ultra-high-risk subjects showed impaired right M100 dipole magnitude, similar to patients with schizophrenia. Robust correlations between the cortical thickness of left Heschl's gyrus and the left M100 dipole moment were found in patients with schizophrenia. Moreover, correlations were also evident between right Heschl's gyrus and right M100 in subjects at ultra-high-risk for psychosis. CONCLUSIONS: The primary feature of auditory perception in ultra-high-risk subjects and schizophrenia patients is an encoding deficit that manifests as a reduced M100 dipole moment. The relationship between abnormal M100, thinning of cortical generators and their symptomatology were shown to exist prior to the onset of overt psychosis and progressively worsen over time. Therefore, they may be a potential indicator of the development of schizophrenia.

Probable case of neuroleptic malignant syndrome following administration of antituberculotic drugs in a chlorpromazine-treated patient.

Neuroleptic malignant syndrome (NMS), a potentially fatal adverse reaction to neuroleptics, is known to occur more often in the initial stage of antipsychotic treatment. We describe a patient with chronic schizophrenia who, in a few days after the addition of antituberculotic drugs to his antipsychotic regimen, developed probable NMS without pyrexia. We reasoned that rifampin, a strong hepatic enzyme inducer, decreased the plasma chlorpromazine concentration of the patient, with the result of cholinergic hyperactivity and finally, the symptoms of NMS. Therefore, physicians should be aware of drug interactions and the likelihood of NMS, and consider antipsychotic dose adjustment when prescribing drugs that may influence pharmacokinetic properties of antipsychotics in a patient with schizophrenia receiving long-term antipsychotic treatment.

Deficit of theory of mind in individuals at ultra-high-risk for schizophrenia.

BACKGROUND: Although a deficit in social cognition is regarded as an early indicator of schizophrenia, few studies have investigated social cognition in ultra-high-risk (UHR) individuals. METHODS: Our investigation involved subjects at UHR for psychosis (N=33) and an age- and IQ-matched healthy control (HC) group (N=36). Two types of theory of mind (ToM) tasks and a neuropsychological test battery were measured. RESULTS: Compared to the HC group, the UHR group performed significantly worse for ToM tasks, with the effect size at an intermediate level (0.64-0.68). Furthermore, the UHR group showed impaired performance in the executive and working memory tests, but not verbal memory tests. These deficits for ToM tests observed in the UHR group were significantly correlated with set-shifting tasks. CONCLUSIONS: Deficits in social cognition may be modest at the prodromal stage of schizophrenia and may be attributed to prefrontal dysfunction. To prevent or delay transition to psychosis, there is a need for specific preventive strategies targeting social functioning for the UHR group.