Difference between treatment-resistant schizophrenia and clozapineresistant schizophrenia

We read the impressive review article“Clozapine resistant schizophrenia:Newer avenues of management”with great enthusiasm and appreciation.The author believes that preventing clozapine resistance from developing may be the most effective treatment strategy for patients with clozapine-resistant schizophrenia(CRS),and optimizing clozapine treatment is a key component.Disentangling the differences between treatment-resistant schizophrenia and CRS is important for studies addressing treatment strategies for these difficult-to-treat populations.

Ketamine enhances structural plasticity in human dopaminergic neurons:possible relevance for treatment-resistant depression

Depression refers to a series of mental health issues characterized by loss of interest and enjoyment in everyday life,low mood and selected emotional,cognitive,physical and behavioral symptoms.Depression is a common disorder,affecting 5–15%of the general population.When diagnosed as major depressive disorder（MDD）,patients are currentlytreated with pharmacological agents such as serotonin or noradren- aline uptake inhibitors （SSRI or SNRI） or tricyclics.

Altered thalamic subregion functional networks in patients with treatment-resistant schizophrenia

BACKGROUND The thalamus plays a key role in filtering information and has extensive interconnectivity with other brain regions.A large body of evidence points to impaired functional connectivity(FC)of the thalamocortical pathway in schizophrenia.However,the functional network of the thalamic subregions has not been investigated in patients with treatment-resistant schizophrenia(TRS).AIM To identify the neural mechanisms underlying TRS,we investigated FC of thalamic sub-regions with cortical networks and voxels,and the associations of this FC with clinical symptoms.We hypothesized that the FC of thalamic subregions with cortical networks and voxels would differ between TRS patients and HCs.METHODS In total,50 patients with TRS and 61 healthy controls(HCs)matched for age,sex,and education underwent resting-state functional magnetic resonance imaging(rs-fMRI)and clinical evaluation.Based on the rs-fMRI data,we conducted a FC analysis between thalamic subregions and cortical functional networks and voxels,and within thalamic subregions and cortical functional networks,in the patients with TRS.A functional parcellation atlas was used to segment the thalamus into nine subregions.Correlations between altered FC and TRS symptoms were explored.RESULTS We found differences in FC within thalamic subregions and cortical functional networks between patients with TRS and HCs.In addition,increased FC was observed between thalamic subregions and the sensorimotor cortex,frontal medial cortex,and lingual gyrus.These abnormalities were associated with the pathophysiology of TRS.CONCLUSION Our findings suggest that disrupted FC within thalamic subregions and cortical functional networks,and within the thalamocortical pathway,has potential as a marker for TRS.Our findings also improve our understanding of the relationship between the thalamocortical pathway and TRS symptoms.

Genetic variables of the glutamatergic system associated with treatment-resistant depression:A review of the literature

Depression is a common,recurrent mental disorder and one of the leading causes of disability and global burden of disease worldwide.Up to 15%-40%of cases do not respond to diverse pharmacological treatments and,thus,can be defined as treatment-resistant depression(TRD).The development of biomarkers predictive of drug response could guide us towards personalized and earlier treatment.Growing evidence points to the involvement of the glutamatergic system in the pathogenesis of TRD.Specifically,the N-methyl-D-aspartic acid receptor(NMDAR)andα-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor(AMPAR),which are targeted by ketamine and esketamine,are proposed as promising pathways.A literature search was performed to identify studies on the genetics of the glutamatergic system in depression,focused on variables related to NMDARs and AMPARs.Our review highlights GRIN2B,which encodes the NR2B subunit of NMDAR,as a candidate gene in the pathogenesis of TRD.In addition,several studies have associated genes encoding AMPAR subunits with symptomatic severity and suicidal ideation.These genes encoding glutamatergic receptors could,therefore,be candidate genes for understanding the etiopathogenesis of TRD,as well as for understanding the pharmacodynamic mechanisms and response to ketamine and esketamine treatment.

Prevalence and Characteristics of Treatment-Resistant Hypertension among Hypertensive Japanese Outpatients

Aims: To retrospectively investigate the prevalence and characteristics of treatment-resistant hypertension (R-HT) among consecutive hypertensive outpatients, since patients with R-HT are candidates for catheter-based renal sympathetic denervation (RD). Methods: Consecutive hypertensive outpatients (n = 999) were recruited in our hospital. R-HT patients who were candidates for RD had clinic systolic blood pressure > 160 mmHg despite taking three or more antihypertensive drugs including at least one diuretics at higher than standard doses. Results: Our survey indicated that only 26 patients (2.6%) were potential candidates for renal denervation. Candidates for RD showed a significantly higher age (P < 0.005), brain natriuretic peptide level (P = 0.0001), urinary albumin/creatinine excretion ratio in spot urine (P < 0.005), pulse wave velocity (P < 0.01), left ventricular end-diastolic diameter (P < 0.005), and interventricular septal thickness (P < 0.005) than the other 973 patients. Candidates for denervation had a significantly lower hemoglobin (P = 0.0001), serum albumin (P < 0.001), eGFR (P < 0.0005), plasma renin activity (P = 0.0001), and plasma aldosterone level (P < 0.005) than other patients, while their urinary sodium/creatinine ratio was higher, indicating that patients with R-HT appeared to have a high salt intake. Conclusion: Our retrospective clinical survey indicated that only 0.5% of Japanese hypertensive outpatients (5/999 patients) were candidates for RD. Therefore, establishment of hypertension cohort network will be essential to recruit R-HT patients for RD.

Case Reports: Treatment-Resistant Schizophrenia with Severe Type 2 Diabetes Mellitus Treated with Clozapine

Objective: Clozapine is regarded as the most effective drug for treatment of schizophrenia but has complex adverse effects associated with hyperglycemia and diabetes mellitus. Method: We report that clozapine was very effective to treat positive, negative, and cognitive symptoms and well tolerated to a treatment-resistant schizophrenia patient with severe type 2 diabetes mellitus (DM) under cautious blood-sugar monitoring. Results: Clozapine itself and discontinuation of other psychotropic and anticholinergic agents after switching may improve cognitive function and adherence to the treatment regimens for schizophrenia and DM. Conclusion: Clozapine can be administered to treatment-resistant schizophrenia patients even with severe DM with caution.

A follow-up study on features of sensory gating P50 in treatment-resistant depression patients

Background Depressive disorder is a well-known chronic, recurrent and disabling mental disease with high direct and indirect costs to society in both western and eastern cultures. Approximately 40% of depressed patients show only partial or no response to initial or even multiple antidepressant medications and are usually called treatment-resistant depression （TRD） patients. The present work was to measure the features of sensory gating （SG） P50 in TRD patients with the intent of understanding the characteristics of this disease. Methods In 50 TRD patients, 39 non-treatment-resistant depression （NTRD） patients and 51 healthy controls （HC）, auditory evoked potential P50 was measured using the conditioning/testing paradigm presented with auditory double clicks stimuli, and 36 TRD patients had repeated measurements after an 8-week venlafaxine treatment course. Results All the depressive disorder patients, including the TRD and NTRD groups, showed an increased testing stimulus wave （$2-P50） amplitude compared to controls （P 〈0.01 and P 〈0.05）, but there was no significant difference between the TRD and NTRD groups （P 〉0.05）. There were significant differences in the ratio of testing stimulus （S2） and conditioning stimulus （S1） （S2/S1） and in the value of 100 × （1-S2/S1） among the three groups. Compared to the baseline, TRD patients had no significant changes of features and different expression of P50 after acute treatment （P 〉0.05）. Meanwhile, a statistically significant positive correlation of S2/S1 with the scores of the 17-item Hamilton Rating Scale for Depression （HAMD-17） （P 〈0.01）, and a significantly negative correlation of S1-S2, 100 × （1-S2/S1） with the scores of HAMD-17 （P 〈0.01） were observed in the TRD patients＇ baseline measurement, but there was no correlation after venlafaxine treatment （P 〉0.05）. Conclusions Both the TRD and NTRD patients had obvious SG deficits, with a more severe deficit in TRD patients. Although, with a correlated relationship to the severity of depressive symptoms, SG P50 deficit might be suggested as a trait marker for TRD, and a combination of S2/S1 ratio, S1-S2 and 100 × （1-S2/S1）, was recommended for electrophysiological measurement in TRD patients.

Treating comorbid anxiety and depression: Psychosocial and pharmacological approaches

Comorbid anxiety with depression predicts poor outcomes with a higher percentage of treatment resistance than either disorder occurring alone. Overlap of anxiety and depression complicates diagnosis and renders treatment challenging. A vital step in treatment of such comorbidity is careful and comprehensive diagnostic assessment. We attempt to explain various psychosocial and pharmacological approaches for treatment of comorbid anxiety and depression. For the psychosocial component, we focus only on generalized anxiety disorder based on the following theoretical models:(1) "the avoidance model";(2) "the intolerance of uncertainty model";(3) "the meta-cognitive model";(4) "the emotion dysregulation model"; and(5) "the acceptance based model". For depression, the following theoretical models are explicated:(1) "the cognitive model";(2) "the behavioral activation model"; and(3) "the interpersonal model". Integration of these approaches is suggested. The treatment of comorbid anxiety and depression necessitates specific psychopharmacological adjustments as compared to treating either condition alone. Serotonin reuptake inhibitors are considered first-line treatment in uncomplicated depression comorbid with a spectrum of anxiety disorders. Short-acting benzodiazepines(BZDs) are an important "bridging strategy" to address an acute anxiety component. In patients with comorbid substance abuse, avoidance of BZDs is recommended and we advise using an atypical antipsychotic in lieu of BZDs. For mixed anxiety and depression comorbid with bipolar disorder, we recommend augmentation of an antidepressant with either lamotrigine or an atypical agent. Combination and augmentation therapies in the treatment of comorbid conditions vis-à-vis monotherapy may be necessary for positive outcomes. Combination therapy with tricyclic antidepressants, gabapentin and selective serotonin/norepinephrine reuptake inhibitors(e.g., duloxetine) are specifically useful for comorbid chronic pain syndromes. Aripiprazole, quetiapine, risperidone and other novel atypical agents may be effective as augmentations. For treatment-resistant patients, we recommend a "stacking approach" not dissimilar from treatment of hypertension In conclusion, we delineate a comprehensive approach comprising integration of various psychosocial approaches and incremental pharmacological interventions entailing bridging strategies, augmentation therapies and ultimately stacking approaches towards effectively treating comorbid anxiety and depression.

Altered serous levels of monoamine neurotransmitter metabolites in patients with refractory and non-refractory depression

The study examined plasma metabolite changes of monoamine neurotransmitters in patients with treatment-resistant depression （TRD） and non-TRD before and after therapy. All 30 TRD and 30 non-TRD patients met the diagnostic criteria for a depressive episode in accordance with the International Classification of Diseases, Tenth Revision. Before treatment, and at 4, 6, and 8 weeks after treatment, the plasma metabolite products of monoamine neurotransmitters in TRD group, including 5-hydroxyindoleacetic acid, 3-methoxy-4-hydroxyphenyl ethylene glycol and homovanillic acid, were significantly lower than those in the non-TRD group. After two types of anti-depressive therapy with 5-serotonin and norepinephrine reuptake inhibitor, combined with psychotherapy, the Hamilton Depression Rating Scale scores were significantly reduced in both groups of patients, and the serous levels of 5-hydroxyindoleacetic acid and 3-methoxy-4-hydroxyphenyl ethylene glycol were significantly increased. In contrast, the homovanillic acid level exhibited no significant change. The levels of plasma metabolite products of peripheral monoamine neurotransmitters in depressive patients may predict the degree of depression and the therapeutic effects of treatment.

Low-dose clozapine-related seizure: A case report and literature review

BACKGROUND Treatment-resistant schizophrenia is a severe form of schizophrenia characterized by poor response to at least two antipsychotic drugs and is typically treated with clozapine.However,clozapine lowers the epileptic threshold,leading to seizures,which are severe side effects of antipsychotics that result in multiple complications.Clozapine-related seizures are generally considered to be dose-dependent and especially rare in the low-dose(150-300 mg/d)clozapine treated population.Due to clinical rarity,little is known about its clinical characteristics and treatment.CASE SUMMARY A 62-year-old Chinese man with a 40-year history of treatment-resistant schizophrenia presented to the Emergency Department with symptoms of myoclonus,consciousness disturbance and vomiting after taking 125 mg clozapine.Upon admission,the patient had a suddenly generalized tonic-clonic seizure lasting for about half a minute with persistent disturbance of consciousness,fever,cough and bloody sputum,which was considered to be low-dose clozapine-related seizure.After antiepileptic and multiple anti-infection treatments,the patient was discharged without epileptic or psychotic symptoms.CONCLUSION Our aim is to highlight the early prevention and optimal treatment of clozapine related seizure through case analysis and literature review.

Psychogenic anorexia and non-alcoholic Wernicke's encephalopathy: Complete clinicoradiological recovery with thiamine

Rationale:Prolonged undernutrition may arise out of depression and lead to Wernicke's encephalopathy if timely diagnosis and intervention are missed.Wernicke's encephalopathy is potentially treatable,and appropriate treatment may revert clinical depression and cognitive dysfunction to some extent.Patient's concern:A 69-year-old female who had been taking escitalopram for one year developed tremor,ophthalmoplegia,ataxia,progressive cognitive decline,and convulsions.Diagnosis:Non-alcoholic Wernicke's encephalopathy and hypomagnesemia due to psychogenic anorexia.Interventions:High dose intravenous thiamine and magnesium were supplemented.Outcomes:The patient showed remarkable improvement in neurological complications and even in depressive features.Lessons:Wernicke's encephalopathy should not be ignored in the treatment of depression.

Therapeutic Efficacy of Neurostimulation for Depression:Techniques, Current Modalities, and Future Challenges

Depression is the most prevalent debilitating mental illness; it is characterized as a disorder of mood, cognitive function, and neurovegetative function. About one in ten individuals experience depression at some stage of their lives. Antidepressant drugs are used to reduce the symptoms but relapse occurs in ~ 20% of patients. However, alternate therapies like brain stimulation techniques have shown promising results in this regard. This review covers the brain stimulation techniques electroconvulsive therapy, transcranial direct current stimulation, repetitive transcranial magnetic stimulation, vagus nerve stimulation, and deep brain stimulation, which are used as alternatives to antide- pressant drugs, and elucidates their research and clinical outcomes.

Antidepressant Effects of Electroconvulsive Therapy Unrelated to the Brain＇s Functional Network Connectivity alterations at an Individual Level

Background： Electroconvulsive therapy （ECT） can alleviate the symptoms of treatment-resistant depression （TRD）. Functional network connectivity （FNC） is a newly developed method to investigate the brain＇s functional connectivity patterns. The first aim of this study was to investigate FNC alterations between TRD patients and healthy controls. The second aim was to explore the relationship between the ECT treatment response and pre-ECT treatment FNC alterations in individual TRD patients. Methods： This study included 82 TRD patients and 41 controls. Patients were screened at baseline and after 2 weeks of treatment with a combination of ECT and antidepressants. Group information guided-independent component analysis （G1G-ICA） was used to compute subject-specific functional networks （FNs）. Grassmann maniibld and step-wise forward component selection using support vector machines were adopted to perform the FNC measure and extract the functional networks＇ connectivity patterns （FCP）. Pearson＇s correlation analysis was used to calculate the correlations between the FCP and ECT response. Results： A total of 82 TRD patients in the ECT group were successfully treated. On an average, 8.50 ~ 2.00 ECT sessions were conducted. After ECT treatment, only 42 TRD patients had an improved response to ECT （the Hamilton scores reduction rate was more than 50%）, response rate 51%. 8 FNs （anterior and posterior default mode network, bilateral frontoparietal network, audio network, visual network, dorsal attention network, and sensorimotor network） were obtained using GIG-ICA. We did not found that FCPs were significantly different between TRD patients and healthy controls. Moreover, the baseline FCP was unrelated to the ECT treatment response. Conclusions： The FNC was not significantly different between the TRD patients and healthy controls, and the baseline FCP was unrelated to the ECT treatment response. These findings will necessitate that we modify the experimental scheme to explore the mechanisms underlying ECT＇s effects on depression and explore the specific predictors of the effects of ECT based on the pre-ECT treatment magnetic resonance imaging.

Updated Review on the Clinical Use of Repetitive Transcranial Magnetic Stimulation in Psychiatric Disorders

With the ability to modulate cortical activity,repetitive transcranial magnetic stimulation（r TMS） is becoming increasingly important in clinical applications for psychiatric disorders. Previous studies have demonstrated its promising efficacy in depression and schizophrenia, and emerging evidence has also been found in patients with anxiety disorder, obsessive–compulsive disorder, and substance or food craving. However, the overall literature features some conflicting results, varied quality of studies,and a lack of consensus on optimal r TMS parameters.Besides, the efficacy of r TMS in patients with medicationresistant symptoms has drawn most attention from clinicians. Here we review multi-site studies and double-blind randomized controlled trials（RCTs） in single sites, as well as meta-analyses of RCTs in the last three years, in order to update evidence on efficacy and the optimal protocol of r TMS in psychiatric disorders, especially for medicationresistant symptoms.