Combination of Long-Acting Injectable Antipsychotics in the Treatment of Psychiatric Disorders-A Systematic Review of the Literature and Case Series.

BACKGROUND: The treatment of refractory schizophrenia is complex, and compliance with oral treatment, including clozapine, can be challenging at times. The purpose of this case series and literature review article is to evaluate the efficacy of the combined use of 2 different long-acting injectable antipsychotics (LAIAs) on the number of psychiatric hospitalizations and emergency department visits. There are currently few data to support this treatment option, despite the frequent use of combinations of oral antipsychotics. METHODS: We extracted the data from 8 different patients who received combination LAIAs from 1 hospital setting. We evaluated the frequency of hospitalization and emergency department visits before and after treatment with a mirror-image study design. A systematic review of existing literature was included to find all previously reported cases of combination LAIAs. RESULTS: The frequency of hospitalizations was greatly reduced after the initiation of combination LAIA treatment in the majority of the cases at study site, as well as in the literature review. The number of ED visits was not as clearly affected. In the literature review, combinations of 2 LAIAs with different mechanisms of action were often documented. Symptom scores were also reduced in most reviewed cases. CONCLUSIONS: Combinations of LAIAs seem to be promising as a treatment option for refractory psychotic disorders. This combination could be a treatment option for patients with limited alternatives, such as clozapine resistant or not eligible. The higher risk of adverse effects and long-term risks are not well documented.

Neural function in DCC mutation carriers with and without mirror movements.

OBJECTIVE: Recently identified mutations of the axon guidance molecule receptor gene, DCC, present an opportunity to investigate, in living human brain, mechanisms affecting neural connectivity and the basis of mirror movements, involuntary contralateral responses that mirror voluntary unilateral actions. We hypothesized that haploinsufficient DCC+/- mutation carriers with mirror movements would exhibit decreased DCC mRNA expression, a functional ipsilateral corticospinal tract, greater "mirroring" motor representations, and reduced interhemispheric inhibition. DCC+/- mutation carriers without mirror movements might exhibit some of these features. METHODS: The participants (n = 52) included 13 DCC+/- mutation carriers with mirror movements, 7 DCC+/- mutation carriers without mirror movements, 13 relatives without the mutation or mirror movements, and 19 unrelated healthy volunteers. The multimodal approach comprised quantitative real time polymerase chain reaction, transcranial magnetic stimulation (TMS), functional magnetic resonance imaging (fMRI) under resting and task conditions, and measures of white matter integrity. RESULTS: Mirror movements were associated with reduced DCC mRNA expression, increased ipsilateral TMS-induced motor evoked potentials, increased fMRI responses in the mirroring M1 and cerebellum, and markedly reduced interhemispheric inhibition. The DCC+/- mutation, irrespective of mirror movements, was associated with reduced functional connectivity and white matter integrity. INTERPRETATION: Diverse connectivity abnormalities were identified in mutation carriers with and without mirror movements, but corticospinal effects and decreased peripheral DCC mRNA appeared driven by the mirror movement phenotype. ANN NEUROL 2019;85:433-442.

Modulation of physiological mirror activity with transcranial direct current stimulation over dorsal premotor cortex.

Humans have a natural tendency towards symmetrical movements, which rely on a distributed cortical network that allows for complex unimanual movements. Studies on healthy humans using rTMS have shown that disruption of this network, and particularly the dorsal premotor cortex (dPMC), can result in increased physiological mirror movements. The aim of the present set of experiments was to further investigate the role of dPMC in restricting motor output to the contralateral hand and determine whether physiological mirror movements could be decreased in healthy individuals. Physiological mirror movements were assessed before and after transcranial direct current stimulation (tDCS) over right and left dPMC in three conditions: bilateral, unilateral left and unilateral right stimulation. Mirror EMG activity was assessed immediately before, 0, 10 and 20 min after tDCS. Results show that physiological mirroring increased significantly in the hand ipsilateral to cathodal stimulation during bilateral stimulation of the dPMC, 10 and 20 min after stimulation compared to baseline. There was no significant modulation of physiological mirroring in the hand ipsilateral to anodal stimulation in the bilateral condition or following unilateral anodal or unilateral cathodal stimulation. The present data further implicate the dPMC in the control of unimanual hand movements and show that physiological mirroring can be increased but not decreased with dPMC tDCS.

Relationship between transcranial magnetic stimulation measures of intracortical inhibition and spectroscopy measures of GABA and glutamate+glutamine.

Transcranial magnetic stimulation (TMS) can provide an index of intracortical excitability/inhibition balance. However, the neurochemical substrate of these measures remains unclear. Pharmacological studies suggest the involvement of GABAA and GABAB receptors in TMS protocols aimed at measuring intracortical inhibition, but this link remains inferential. Proton magnetic resonance spectroscopy ((1)H-MRS) permits measurement of GABA and glutamate + glutamine (Glx) concentrations in the human brain and might help in the direct empirical assessment of the relationship between TMS inhibitory measures and neurotransmitter concentrations. In the present study, MRS-derived relative concentrations of GABA and Glx measured in the left M1 of healthy participants were correlated with TMS measures of intracortical inhibition. Glx levels were found to correlate positively with TMS-induced silent period duration, whereas no correlation was found between GABA concentration and TMS measures. The present data demonstrate that specific TMS measures of intracortical inhibition are linked to shifts in cortical Glx, rather than GABA neurotransmitter levels. Glutamate might specifically interact with GABAB receptors, where higher MRS-derived Glx concentrations seem to be linked to higher levels of receptor activity.

Risperidone is not only a prodrug: psychosis induced by medication switch from risperidone to paliperidone - a case report.

Once administered, risperidone is converted into its pharmacologically active form, paliperidone. Thus, their pharmacological effects are expected to be equivalent. We encountered a psychosis induced by the switch from risperidone to paliperidone.This is the case of a schizoaffective patient stabilised on risperidone long-acting injection (LAI) who consented to switch to paliperidone LAI. On day 0, he received his first dose of paliperidone. On day 86, he presented to the emergency department with an acute psychotic episode. On day 92, he committed a violent act. The patient was restarted on risperidone LAI and stabilised.Risperidone is extensively metabolised to paliperidone via CYP450 2D6. Interindividual and ethnic genetic polymorphism cause variability in CYP450 2D6 phenotypes. In this possible case of low-functioning alleles, the patient had a higher risperidone to paliperidone ratio at steady state. Although risperidone is paliperidone's prodrug, this case highlights the interindividual pharmacotherapeutic response to these two antipsychotics.

Visual compatibility and particle counter evaluations of syringes of intramuscular psychotropic coadministered solutions.

BACKGROUND: Patients in the acute phase of agitation can require the administration of multiple drugs by intramuscular injection in order to temporarily stabilise their condition. Administration of multiple psychotropic medications in a single syringe can be beneficial to both the patient and healthcare professionals. However, there are very little data in the literature regarding psychotropic drug compatibility in syringes for acute agitation. OBJECTIVE: The aim of this study was to assess the visual compatibility of various combinations of 12 intramuscular psychotropic medications in syringes, and to validate compatibility with the use of a particle counter. The medications evaluated were benztropine mesylate, diazepam, dimenhydrinate, diphenhydramine hydrochloride, haloperidol lactate, hydroxyzine, lorazepam, loxapine, methotrimeprazine, midazolam, olanzapine and zuclopenthixol acetate. METHODS: Compounded solutions of medication combinations underwent visual inspection initially and after 0.25, 0.5, 1, 2 and 4 hours using a white background and a black background. In order to validate the compatibility results, the presence of particulate matter was determined by light obscuration. RESULTS: This study identified 35 combinations that were visually compatible and 35 that were visually incompatible. We chose eight highly clinically relevant combinations to test using the requirements of the United States Pharmacopoeia (USP) chapter 788 (Particulate Matter in Injections). Of those eight, six were physically compatible, including the triple combinations of lorazepam and haloperidol with either benztropine or diphenhydramine. CONCLUSION: These physical compatibility results will give healthcare professionals an idea of the possible compatible combinations of psychotropic drugs in syringes, and thus complete some of the missing data in the literature.

Prescribing and deprescribing trends in schizophrenia: An overview of inpatients in Belgium and in the Canadian province of Québec.

Although switching to antipsychotic monotherapy improves patient outcomes in schizophrenia, antipsychotic deprescribing is rarely performed, and its use varies between countries, as do psychotropic prescribing patterns. This study aimed to determine factors associated with antipsychotic deprescribing at discharge after a psychiatric hospitalization and to compare psychotropic prescribing patterns between Belgium and Québec, Canada. Data on adult inpatients with schizophrenia were collected retrospectively in seven hospitals. At discharge, the number of antipsychotics had decreased in 22.2% of the 63 Canadian patients and 9.9% of the 516 Belgian patients. A number of factors increased the likelihood of antipsychotic deprescribing: a hospitalization in the Canadian hospital (aOR = 4.13, 95% CI 1.48-11.5), living in a residential facility (aOR = 2.51, 95% CI 1.05-4.39), ≥2 previous antipsychotic trials (aOR = 15.38, 95% CI 3.62-65.36), having an antipsychotic side effect (aOR = 1.86, 95% CI 1.01-3.44) and being in a general hospital (aOR = 2.28, 95% CI 1.09-4.75). Patients on a long-acting injectable antipsychotic (aOR = 0.51, 95% CI 0.26-0.98), with prior clozapine use (aOR = 0.36, 95% CI 0.13-0.95), greater antipsychotic exposure (aOR = 0.35, 95% CI 0.2-0.61) and more hypno-sedatives (aOR = 0.65, 95% CI 0.43-0.98), were less likely to be deprescribed. Specific deprescribing interventions could target patients who are less likely to be deprescribed.

The PROMISING Project: A Pilot Study to Improve Geriatric Care Through a Pharmacist-Led Psychotropic Stewardship Program.

BACKGROUND AND OBJECTIVE: Psychotropic medications are frequently prescribed during acute care, even in older patients. They represent a risk for inappropriate long-term use and increase the overall risk of morbidity and mortality in this population. Our project aimed to evaluate the feasibility of a psychotropic medication stewardship program led by pharmacists. METHODS: We conducted a prospective, observational pilot study in patients aged 75 years and older, admitted to a surgical unit with at least one active prescription of a psychotropic medication (antipsychotic, benzodiazepine or non-benzodiazepine receptor agonist). Each psychotropic medication was assessed for potential deprescription, and if eligible, a recommendation from the stewardship pharmacist was made to the medical team. RESULTS: Among 183 patients, 93.4% were eligible for a potential deprescription. A total of 298 prescriptions were evaluated by the stewardship pharmacists, of which 57.7% were antipsychotics, 22.8% were benzodiazepines and 19.5% were non-benzodiazepine receptor agonists. Most of the assessed prescriptions were started during current hospitalization (62.7%). The median time required for the intervention per patient was 17 min 30 s. The stewardship pharmacists made 192 suggestions for 258 eligible prescriptions, with 69.8% being deprescription recommendations. Of all the deprescription suggestions, 75.4% were accepted by the medical team and 84.8% of those accepted persisted at discharge. CONCLUSION: The implementation of a pharmacist-led psychotropic medication stewardship program on surgical units in our hospital is feasible and is a promising approach to improve geriatric care.

Interhemispheric control of unilateral movement.

To perform strictly unilateral movements, the brain relies on a large cortical and subcortical network. This network enables healthy adults to perform complex unimanual motor tasks without the activation of contralateral muscles. However, mirror movements (involuntary movements in ipsilateral muscles that can accompany intended movement) can be seen in healthy individuals if a task is complex or fatiguing, in childhood, and with increasing age. Lateralization of movement depends on complex interhemispheric communication between cortical (i.e., dorsal premotor cortex, supplementary motor area) and subcortical (i.e., basal ganglia) areas, probably coursing through the corpus callosum (CC). Here, we will focus on transcallosal interhemispheric inhibition (IHI), which facilitates complex unilateral movements and appears to play an important role in handedness, pathological conditions such as Parkinson's disease, and stroke recovery.

Assessing cardiometabolic parameter monitoring in inpatients taking a second-generation antipsychotic: The CAMI-SGA study - a cross-sectional study.

OBJECTIVES: This study aims to determine the proportion of initial cardiometabolic assessment and its predicting factors in adults with schizophrenia, bipolar disorder or other related diagnoses for whom a second-generation antipsychotic was prescribed in the hospital setting. DESIGN: Cross-sectional study. SETTING: The psychiatry unit of a Canadian tertiary care teaching hospital in Montreal, Canada. PARTICIPANTS: 402 patients with aforementioned disorders who initiated, restarted or switched to one of the following antipsychotics: clozapine, olanzapine, risperidone, paliperidone or quetiapine, between 2013 and 2016. PRIMARY OUTCOME MEASURES: We assessed the proportion of cardiometabolic parameters monitored. SECONDARY OUTCOME MEASURES: We identified predictors that influence the monitoring of cardiometabolic parameters and we assessed the proportion of adequate interventions following the screening of uncontrolled blood pressure and fasting glucose or glycated haemoglobin (HbA1c) results. RESULTS: Only 37.3% of patients received monitoring for at least three cardiometabolic parameters. Blood pressure was assessed in 99.8% of patients; lipid profile in 24.4%; fasting glucose or HbA1c in 33.3% and weight or body mass index in 97.8% of patients while waist circumference was assessed in 4.5% of patients. For patients with abnormal blood pressure and glycaemic values, 42.3% and 41.2% subsequent interventions were done, respectively. The study highlighted the psychiatric diagnosis (substance induced disorder OR 0.06 95% CI 0.00 to 0.44), the presence of a court-ordered treatment (OR 0.79 95% CI 0.35 to 1.79) and the treating psychiatrist (up to OR 34.0 95% CI 16.2 to 140.7) as predictors of cardiometabolic monitoring. CONCLUSIONS: This study reports suboptimal baseline cardiometabolic monitoring of patients taking an antipsychotic in a Canadian hospital. Optimising collaboration within a multidisciplinary team may increase cardiometabolic monitoring.

Opioid Use and Pain Control in the Elderly After Elective or Urgent Orthopaedic Surgery: A Retrospective Cohort Study.

BACKGROUND: As an increasing number of elderly are undergoing orthopaedic procedures, it is important to understand and evaluate postoperative pain management in this population, especially in regard to opioid use. Data in the literature pertaining to the very elderly remains scarce. OBJECTIVES: This study was conducted to evaluate whether older patients require lower opioid doses than their younger counterparts after undergoing an elective or urgent orthopaedic procedure, and to assess the cumulative incidence of adverse events and length of stay for each age group. METHODS: A retrospective cohort study was performed to compare the mean opioid use and pain control between two groups of elderly patients (65-79 years and ≥ 80 years of age). The study included 250 patients who underwent either an elective arthroplasty or urgent orthopaedic surgery following a fracture. Data were collected during the 7 days following surgery. RESULTS: No significant difference was found in mean and maximal pain scores between the two groups. Opioid use (expressed in intravenous morphine equivalents) was higher in the younger group. The difference reached statistical significance on the first postoperative day (subjects 65-79 years of age taking 21.3 mg, vs. 10.9 mg for the group over 80 years of age; mean difference 10.3 mg, 95% confidence interval 1.3-19.4). This was also observed in patients undergoing elective surgery on postoperative days 1, 5, 6 and 7. No difference in opioid use was observed between age groups in patients undergoing urgent surgery. Acute cognitive status deterioration, delirium, oxygen desaturation and constipation were observed more frequently in the older group, while mean length of stay was higher in the older group undergoing urgent surgery (8 vs. 17 days, p < 0.001). CONCLUSIONS: Our findings further support age-related differences in opioid requirements during the postoperative context after elective orthopaedic surgery, while no difference was found between age groups after urgent surgery.

The effects of bi-hemispheric M1-M1 transcranial direct current stimulation on primary motor cortex neurophysiology and metabolite concentration.

PURPOSE: The aim of the present study was to assess, in healthy individuals, the impact of M1-M1 tDCS on primary motor cortex excitability using transcranial magnetic stimulation and sensorimotor metabolite concentration using 1H-MRS. METHODS: For both experiments, each participant received the three following interventions (20 min tDCS, 1 mA): left-anodal/right-cathodal, left-cathodal/right-anodal, sham. The effects of tDCS were assessed via motor evoked potentials (experiment 1) and metabolite concentrations (experiment 2) immediately after and 12 minutes following the end of stimulation and compared to baseline measurement. RESULTS: No effect of M1-M1 tDCS on corticospinal excitability was found. Similarly, M1-M1 tDCS did not significantly modulate metabolite concentrations. High inter-subject variability was noted. Response rate analysis showed a tendency towards inhibition following left-anodal/right-cathodal tDCS in 50% of participants and increased GABA levels in 45% of participants. CONCLUSION: In line with recent studies showing important inter-subject variability following M1-supraorbital tDCS, the present data show that M1-M1 stimulation is also associated with large response variability. The absence of significant effects suggests that current measures may lack sensitivity to assess changes in M1 neurophysiology and metabolism associated with M1-M1 tDCS.

Cortical thickness in adults with agenesis of the corpus callosum.

Agenesis of the corpus callosum (AgCC) is a congenital malformation that can occur in isolation or in association with other neurological conditions. Although the behavioral manifestations associated with AgCC have been widely studied, the effects of complete absence of the corpus callosum (CC) on cerebral cortex anatomy are still not completely understood. In this study, cortical thickness in adults with complete AgCC was compared to a group of healthy controls. Results showed highly variable patterns of cortical thickness in AgCC individuals, with few areas showing significant and consistent alterations including primary visual cortex, primary somatosensory cortex and primary motor cortex. These results suggest relatively limited effects of AgCC on cortical morphology, which are mostly restricted to primary sensory and motor areas.

The use of magnetic resonance spectroscopy as a tool for the measurement of bi-hemispheric transcranial electric stimulation effects on primary motor cortex metabolism.

Transcranial direct current stimulation (tDCS) is a neuromodulation technique that has been increasingly used over the past decade in the treatment of neurological and psychiatric disorders such as stroke and depression. Yet, the mechanisms underlying its ability to modulate brain excitability to improve clinical symptoms remains poorly understood. To help improve this understanding, proton magnetic resonance spectroscopy ((1)H-MRS) can be used as it allows the in vivo quantification of brain metabolites such as γ-aminobutyric acid (GABA) and glutamate in a region-specific manner. In fact, a recent study demonstrated that (1)H-MRS is indeed a powerful means to better understand the effects of tDCS on neurotransmitter concentration. This article aims to describe the complete protocol for combining tDCS (NeuroConn MR compatible stimulator) with (1)H-MRS at 3 T using a MEGA-PRESS sequence. We will describe the impact of a protocol that has shown great promise for the treatment of motor dysfunctions after stroke, which consists of bilateral stimulation of primary motor cortices. Methodological factors to consider and possible modifications to the protocol are also discussed.

Multimodal assessment of primary motor cortex integrity following sport concussion in asymptomatic athletes.

OBJECTIVE: Recent studies have shown, in asymptomatic concussed athletes, metabolic disruption in the primary motor cortex (M1) and abnormal intracortical inhibition lasting for more than six months. The present study aims to assess if these neurochemical and neurophysiological alterations are persistent and linked to M1 cortical thickness. METHODS: Sixteen active football players who sustained their last concussion, on average, three years prior to testing and 14 active football players who never sustained a concussion were recruited for a single session of proton magnetic resonance spectroscopy ((1)H-MRS) and transcranial magnetic stimulation (TMS). Measures of M1 and whole brain cortical thickness were acquired, and (1)H-MRS data were acquired from left M1 using a MEGA-PRESS sequence. Cortical silent period (CSP) and long-interval intracortical inhibition (LICI) were measured with TMS applied over left M1. RESULTS: No significant group differences were observed for metabolic concentrations, TMS measures, and cortical thickness. However, whereas GABA and glutamate levels were positively correlated in control athletes, this relationship was absent in concussed athletes. CONCLUSION: These data suggest the general absence of neurophysiologic, neurometabolic and neuroanatomical disruptions in M1 three years following the last concussive event. However, correlational analyses suggest the presence of a slight metabolic imbalance between GABA and glutamate concentrations in the primary motor cortex of concussed athletes. SIGNIFICANCE: The present study highlights the importance of multimodal assesments of the impacts of sport concussions.

Anodal transcranial direct current stimulation modulates GABAB-related intracortical inhibition in the M1 of healthy individuals.

It is known that transcranial direct current stimulation (tDCS) can induce polarity-specific shifts in brain excitability of the primary motor cortex (M1) with anodal tDCS enhancing and cathodal tDCS reducing cortical excitability. However, less is known about its impact on specific intracortical inhibitory mechanisms, such as γ-aminobutyric acid B (GABAB)-mediated inhibition. Consequently, the aim of the present study was to assess the impact of anodal and cathodal tDCS on M1 intracortical inhibition in healthy individuals. Long-interval intracortical inhibition (LICI) and cortical silent period (CSP) duration, both presumably mediated by GABAB receptors, were assessed using transcranial magnetic stimulation immediately before and after a 20 min session of tDCS over the left M1. Anodal tDCS significantly enhanced motor evoked potential size and reduced CSP duration, whereas it had no effect on LICI. Cathodal stimulation did not significantly modulate motor evoked potential size, CSP duration or LICI. This study provides evidence that anodal tDCS, presumably by synaptic plasticity mechanisms, has a direct effect on GABAB-meditated inhibition assessed by the CSP, but not by LICI. Our results further suggest that CSP and LICI probe distinct intracortical inhibitory mechanisms as they are differentially modulated by anodal tDCS. Finally, these data may have clinical value in patients in whom a pathological increase in CSP duration is present, such as schizophrenia.

Occlusion of LTP-like plasticity in human primary motor cortex by action observation.

Passive observation of motor actions induces cortical activity in the primary motor cortex (M1) of the onlooker, which could potentially contribute to motor learning. While recent studies report modulation of motor performance following action observation, the neurophysiological mechanism supporting these behavioral changes remains to be specifically defined. Here, we assessed whether the observation of a repetitive thumb movement--similarly to active motor practice--would inhibit subsequent long-term potentiation-like (LTP) plasticity induced by paired-associative stimulation (PAS). Before undergoing PAS, participants were asked to either 1) perform abductions of the right thumb as fast as possible; 2) passively observe someone else perform thumb abductions; or 3) passively observe a moving dot mimicking thumb movements. Motor evoked potentials (MEP) were used to assess cortical excitability before and after motor practice (or observation) and at two time points following PAS. Results show that, similarly to participants in the motor practice group, individuals observing repeated motor actions showed marked inhibition of PAS-induced LTP, while the "moving dot" group displayed the expected increase in MEP amplitude, despite differences in baseline excitability. Interestingly, LTP occlusion in the action-observation group was present even if no increase in cortical excitability or movement speed was observed following observation. These results suggest that mere observation of repeated hand actions is sufficient to induce LTP, despite the absence of motor learning.

Neurophysiological investigation of congenital mirror movements in a patient with agenesis of the corpus callosum.

We describe a patient with complete agenesis of the corpus callosum and congenital mirror movements in which primary motor cortex (M1) excitability of both hemispheres was assessed with transcranial magnetic stimulation. Voluntary contraction of the index finger was associated with bilateral electromyographic activity in the first dorsal interosseus muscle. Motor-evoked potentials of identical latencies were produced bilaterally after unilateral M1 stimulation. Measures of intracortical inhibition and facilitation were within normal limits bilaterally although a shorter contralateral silent period was found for both hemispheres. Taken together, the current data suggest a pattern of M1 excitability very similar to that found in patients with congenital mirror movements and no other motor abnormality.