Antipsychotic augmentation vs. monotherapy in schizophrenia: systematic review,meta‐analysis and meta‐regression analysis

Antipsychotic polypharmacy in schizophrenia is much debated, since it is common and costly with unclear evidence for its efficacy and safety. We conducted a systematic literature search and a random effects meta‐analysis of randomized trials comparing augmentation with a second antipsychotic vs. continued antipsychotic monotherapy in schizophrenia. Co‐primary outcomes were total symptom reduction and study‐defined response. Antipsychotic augmentation was superior to monotherapy regarding total symptom reduction (16 studies, N=694, standardized mean difference, SMD=–0.53, 95% CI: ?0.87 to ?0.19, p=0.002). However, superiority was only apparent in open‐label and low‐quality trials (both p<0.001), but not in double‐blind and high‐quality ones (p=0.120 and 0.226, respectively). Study‐defined response was similar between antipsychotic augmentation and monotherapy (14 studies, N=938, risk ratio = 1.19, 95% CI: 0.99 to 1.42, p=0.061), being clearly non‐significant in double‐blind and high‐quality studies (both p=0.990). Findings were replicated in clozapine and non‐clozapine augmentation studies. No differences emerged regarding all‐cause/specific‐cause discontinuation, global clinical impression, as well as positive, general and depressive symptoms. Negative symptoms improved more with augmentation treatment (18 studies, N=931, SMD=–0.38, 95% CI: ?0.63 to ?0.13, p<0.003), but only in studies augmenting with aripiprazole (8 studies, N=532, SMD=–0.41, 95% CI: ?0.79 to ?0.03, p=0.036). Few adverse effect differences emerged: D2 antagonist augmentation was associated with less insomnia (p=0.028), but more prolactin elevation (p=0.015), while aripiprazole augmentation was associated with reduced prolactin levels (p<0.001) and body weight (p=0.030). These data suggest that the common practice of antipsychotic augmentation in schizophrenia lacks double‐blind/high‐quality evidence for efficacy, except for negative symptom reduction with aripiprazole augmentation.     

Electromagnetic effects on forearm disuse osteopenia: a randomized, double-blind, sham-controlled study

A randomized, double‐blind, sham‐controlled, feasibility and dosing study was undertaken to determine if a common pulsing electromagnetic field (PEMF) treatment could moderate the substantial osteopenia that occurs after forearm disuse. Ninety‐nine subjects were randomized into four groups after a distal radius fracture, or carpal surgery requiring immobilization in a cast. Active or identical sham PEMF transducers were worn on the distal forearm for 1, 2, or 4 h/day for 8 weeks starting after cast removal (“baseline”) when bone density continues to decline. Bone mineral density (BMD) and bone geometry were measured in the distal forearm by dual energy X‐ray absorptiometry (DXA) and peripheral quantitative computed tomography (pQCT) at entry (“baseline”) and 8, 16, and 24 weeks later. Significant average BMD losses after baseline were observed in the affected forearm at all time points (5–7% distally and 3–4% for the radius/ulna shaft). However, after adjusting for age, gender, and baseline BMD there was no evidence of a positive effect of active versus sham PEMF treatment on bone loss by DXA or pQCT for subjects completing all visits (n = 82, ～20 per group) and for an intent‐to‐treat analysis (n = 99). Regardless of PEMF exposure, serum bone‐specific alkaline phosphatase (BSAP) was normal at baseline and 8 weeks, while serum c‐terminal collagen teleopeptide (CTX‐1) was markedly elevated at baseline and less so at 8 weeks. Although there was substantial variability in disuse osteopenia, these results suggested that the particular PEMF waveform and durations applied did not affect the continuing substantial disuse bone loss in these subjects. Bioelectromagnetics 32:273–282, 2011. © 2010 Wiley‐Liss, Inc.     

Pulsed electromagnetic fields stimulation affects BMD and local factor production of rats with disuse osteoporosis

Pulsed electromagnetic fields (PEMF) have been used widely to treat nonunion fractures and related problems in bone healing, as a biological and physical method. With the use of Helmholtz coils and PEMF stimulators to generate uniform time‐varying electromagnetic fields, the effects of extremely low frequency electromagnetic fields on bone mineral density (BMD) and local factor production in disuse osteoporosis (DOP) rats were investigated. Eighty 4‐month‐old female Sprague Dawley (SD) rats were randomly divided into intact (INT) group, DOP group, calcitonin‐treated (CT) group, and PEMF stimulation group. The right hindlimbs of all the rats were immobilized by tibia‐tail fixation except for those rats in the INT group. Rats in the CT group were injected with calcitonin (2 IU/kg, i.p., once a day) and rats in the PEMF group were irradiated with PEMF immediately postoperative. The BMD, serum transforming growth factor‐beta 1 (TGF‐β1), and interleukin‐6 (IL‐6) concentration of the proximal femur were measured 1, 2, 4, and 8 weeks after treatment. Compared with the CT and DOP groups, the BMD and serum TGF‐β1 concentration in the PEMF group increased significantly after 8 weeks. The IL‐6 concentration in the DOP group was elevated significantly after operation. The PEMF group showed significantly lower IL‐6 level than the DOP group. The results found demonstrate that PEMF stimulation can efficiently suppress bone mass loss. We, therefore, conclude that PEMF may affect bone remodeling process through promoting TGF‐β1 secretion and inhibiting IL‐6 expression. Bioelectromagnetics 31:113–119, 2010. © 2009 Wiley‐Liss, Inc.     

A theoretical study of bone remodelling under PEMF at cellular level

Pulsed electromagnetic field (PEMF) devices have been used clinically to slow down osteoporosis and accelerate the healing of bone fractures for many years. However, the underlying mechanism by which bone remodelling under PEMF is regulated remains poorly understood. In this paper, a mathematical model of bone cell population of bone remodelling under PEMF at cellular level is developed to address this issue for the first time. On the basis of this model and control theory, parametric study of control mechanisms is carried out and a number of possible control mechanisms are identified. These findings will help further the understanding of bone remodelling under PEMF and advance therapies and pharmacological developments in clinical trials.     

A theoretical study of bone remodelling under PEMF at cellular level

Pulsed electromagnetic field (PEMF) devices have been used clinically to slow down osteoporosis and accelerate the healing of bone fractures for many years. However, the underlying mechanism by which bone remodelling under PEMF is regulated remains poorly understood. In this paper, a mathematical model of bone cell population of bone remodelling under PEMF at cellular level is developed to address this issue for the first time. On the basis of this model and control theory, parametric study of control mechanisms is carried out and a number of possible control mechanisms are identified. These findings will help further the understanding of bone remodelling under PEMF and advance therapies and pharmacological developments in clinical trials.     

Effects of PEMF on microcirculation and angiogenesis in a model of acute hindlimb ischemia in diabetic rats

Hindlimb ischemia is a major complication of diabetic patients due to poor neovascularization. Therapy with pulsed electromagnetic fields (PEMF) can promote angiogenesis in ischemic lesions. However, the efficacy and therapeutic mechanisms of PEMF in diabetes‐related hindlimb ischemia are unclear. Sprague–Dawley rats were injected with streptozocin to induce diabetes, and 10 weeks later diabetic rats were subjected to surgical induction of acute hindlimb ischemia. The rats were randomized and treated with PEMF, and the blood perfusion of individual rats was determined longitudinally by laser Doppler perfusion imaging (LDPI). The neovascular density was examined using immunofluorescent analysis of CD31 expression and alkaline phosphatase (AP) staining. The levels of VEGF, VEGFR, FGF‐2, and FGFR1 expression, and ERK 1/2 and P38 phosphorylation in the muscles were characterized using enzyme‐linked immunosorbent assay (ELISA) and Western blot assays. The values of LDPI in the PEMF‐treated rats at 14 and 28 days post surgery were significantly greater than those in the controls, accompanied by significantly elevated levels of anti‐CD31 and AP staining. The relative levels of FGF‐2 and FGFR1, but not VEGF and VEGFR expression, and ERK1/2, but not P38 phosphorylation, in the muscles of the PEMF‐treated rats were significantly higher than those in the controls. Our data indicated that PEMF enhanced acute hindlimb ischemia‐related perfusion and angiogenesis, associated with up‐regulating FGF‐2 expression and activating the ERK1/2 pathway in diabetic rats. Therefore, PEMF may be valuable for the treatment of diabetic patients with ischemic injury. Bioelectromagnetics 34:180–188, 2013. © 2012 Wiley Periodicals, Inc.     

Therapeutic Effects of 15 Hz Pulsed Electromagnetic Field on Diabetic Peripheral Neuropathy in Streptozotocin-Treated Rats

Although numerous clinical studies have reported that pulsed electromagnetic fields (PEMF) have a neuroprotective role in patients with diabetic peripheral neuropathy (DPN), the application of PEMF for clinic is still controversial. The present study was designed to investigate whether PEMF has therapeutic potential in relieving peripheral neuropathic symptoms in streptozotocin (STZ)-induced diabetic rats. Adult male Sprague–Dawley rats were randomly divided into three weight-matched groups (eight in each group): the non-diabetic control group (Control), diabetes mellitus with 15 Hz PEMF exposure group (DM+PEMF) which were subjected to daily 8-h PEMF exposure for 7 weeks and diabetes mellitus with sham PEMF exposure group (DM). Signs and symptoms of DPN in STZ-treated rats were investigated by using behavioral assays. Meanwhile, ultrastructural examination and immunohistochemical study for vascular endothelial growth factor (VEGF) of sciatic nerve were also performed. During a 7-week experimental observation, we found that PEMF stimulation did not alter hyperglycemia and weight loss in STZ-treated rats with DPN. However, PEMF stimulation attenuated the development of the abnormalities observed in STZ-treated rats with DPN, which were demonstrated by increased hind paw withdrawal threshold to mechanical and thermal stimuli, slighter demyelination and axon enlargement and less VEGF immunostaining of sciatic nerve compared to those of the DM group. The current study demonstrates that treatment with PEMF might prevent the development of abnormalities observed in animal models for DPN. It is suggested that PEMF might have direct corrective effects on injured nerves and would be a potentially promising non-invasive therapeutic tool for the treatment of DPN.     

The assessment and management of insomnia: an update

Insomnia poses significant challenges to public health. It is a common condition associated with marked impairment in function and quality of life, psychiatric and physical morbidity, and accidents. As such, it is important that effective treatment is provided in clinical practice. To this end, this paper reviews critical aspects of the assessment of insomnia and the available treatment options. These options include both non‐medication treatments, most notably cognitive behavioral therapy for insomnia, and a variety of pharmacologic therapies such as benzodiazepines, “z‐drugs”, melatonin receptor agonists, selective histamine H1 antagonists, orexin antagonists, antidepressants, antipsychotics, anticonvulsants, and non‐selective antihistamines. A review of the available research indicates that rigorous double‐blind, randomized, controlled trials are lacking for some of the most commonly administered insomnia therapies. However, there are an array of interventions which have been demonstrated to have therapeutic effects in insomnia in trials with the above features, and whose risk/benefit profiles have been well characterized. These interventions can form the basis for systematic, evidence‐based treatment of insomnia in clinical practice. We review this evidence base and highlight areas where more studies are needed, with the aim of providing a resource for improving the clinical management of the many patients with insomnia.     

Intermittent pulsed electromagnetic field stimulation activates the mTOR pathway and stimulates the proliferation of osteoblast‐like cells

Pulsed electromagnetic fields (PEMFs) have been shown to be a noninvasive physical stimulant for bone fracture healing. However, PEMF stimulation requires a relatively long period of time and its mechanism of action has not yet been fully clarified. Recently, the mammalian target of rapamycin (mTOR) pathway has been shown to be involved in bone formation. This study aimed to investigate the effects of PEMFs on osteoblastic MC3T3‐E1 cells by examining various cellular responses including changes in the mTOR pathway. Continuous PEMF stimulation induced a transient phosphorylation of the mTOR pathway, whereas intermittent PEMF stimulation (1 cycle of 10 min stimulation followed by 20 min of stimulation pause) revitalized the reduced phosphorylation. Moreover, PEMF stimulation stimulated cell proliferation (bromodeoxyuridine incorporation) rather than differentiation (alkaline phosphatase activity), with a more notable effect in the intermittently stimulated cells. These results suggest that intermittent PEMF stimulation may be effective in promoting bone fracture healing by accelerating cell proliferation, and in shortening stimulation time. Bioelectromagnetics. 2019;40:412–421. © 2019 Bioelectromagnetics Society.     

Optimum Parameters of Specific 7.5 Hz Single Pulsed Electromagnetic Field Stimulation on Osteoblast Growth

This study examines the response of different time constant 7.5 Hz pulsed electromagnetic field (PEMF) stimulation on rat osteoblasts and tries to determine the shortest exposure time to the selected time constant PEMF that is necessary to increase cell viability in vitro. We use an in vitro rat osteoblast model to investigate, for different periods of time (1, 2, or 3 days), rat osteoblasts to 7.5 Hz PEMF of different time constants (694, 432, and 268 µsec) or exposure time (20 min, 1, 3, 9, and 24 hr) and have evaluated the field's effects on the cell viability by colorimetric tetrazolium (MTT) assay and PGE₂ concentrations by enzyme‐linked immunosorbent assay (ELISA). It was shown that time constant was not the dominant parameter affecting osteoblast growth, and a short time exposure of PEMF 20 min/day could increase cell viability and PGE₂ secretion significantly.     

Pulsed Electromagnetic Field Versus Whole Body Vibration on Cartilage and Subchondral Trabecular Bone in Mice With Knee Osteoarthritis

Pulsed electromagnetic field (PEMF) and whole body vibration (WBV) interventions are expected to be important strategies for management of osteoarthritis (OA). The aim of the study was to investigate the comparative effectiveness of PEMF versus WBV on cartilage and subchondral trabecular bone in mice with knee OA (KOA) induced by surgical destabilization of the medial meniscus (DMM). Forty 12-week-old male C57/BL mice were randomly divided into four groups (n = 10): Control, OA, PEMF, and WBV. OA was induced (OA, PEMF, and WBV groups) by surgical DMM of right knee joint. Mice in PEMF group received 1 h/day PEMF exposure with 75 Hz, 1.6 mT for 4 weeks, and the WBV group was exposed to WBV for 20 min/day with 5 Hz, 4 mm, 0.3 g peak acceleration for 4 weeks. Micro-computed tomography (micro-CT), histology, and immunohistochemistry analyses were performed to evaluate the changes in cartilage and microstructure of trabecular bone. The bone volume fraction (BV/TV), trabecular thickness (Tb.Th), and trabecular number (Tb.N) increased, and bone surface/bone volume (BS/BV) decreased by micro-CT analysis in PEMF and WBV groups. The Osteoarthritis Research Society International (OARSI) scores in PEMF and WBV groups were significantly lower than in the OA group. Immunohistochemical results showed that PEMF and WBV promoted expressions of Aggrecan, and inhibited expressions of IL-1β, ADAMTS4, and MMP13. Superior results are seen in PEMF group compared with WBV group. Both PEMF and WBV were effective, could delay cartilage degeneration and preserve subchondral trabecular bone microarchitecture, and PEMF was found to be superior to WBV. Bioelectromagnetics. 2020;41:298–307 © 2020 Bioelectromagnetics Society     

Effect of short duration electromagnetic field exposures on rat mass.

Daily preexposure and postexposure mass measurements of 65 rats (young males and females, old males) a proprietary pulsed wound healing field, pulsed electromagnetic field, (PEMF), or their control fields for 4 h/day for 21 days. Statistical analysis of mass changes over time showed that young rats exposed to PEMF lost more mass and recovered it more slowly compared to controls (2-4% more loss) than did older PEMF exposed rats or any 60 Hz exposed rats. We conclude that daily preexposure and postexposure mass measurements are needed to adequately assess the effects of electromagnetic fields on body mass.     

No effects of pulsed electromagnetic fields on expression of cell adhesion molecules (integrin, CD44) and matrix metalloproteinase-2/9 in osteosarcoma cell lines

Pulsed electromagnetic fields (PEMF) could enhance the cytocidal effects of chemotherapeutic drugs on malignant tumor cell lines, but metastasis effects of PEMF on tumor cells have not been investigated. We investigated the effects of PEMF exposure on the expression levels of some metastasis-related molecules, including integrin α subunits (α1, α2, α3, α4, α5, α6, αv), integrin β subunits (β1, β2, β3, β4), CD44, and matrix metalloproteinase-2/9 (MMP-2/9) in four human osteosarcoma cell lines (HOS, MG-63, SAOS-2, NY) and two mouse osteosarcoma cell lines (DOS, LM8) by using FACScan analysis, gelatin zymography, and Western blot analysis. Our results indicate that PEMF exposure has no effect on the expression of some molecules that are associated with tumor cell invasion and metastasis, and therefore suggest that PEMF exposure may be safely applied to chemotherapy for osteosarcoma.     

Osteoblasts stimulated with pulsed electromagnetic fields increase HUVEC proliferation via a VEGF‐A independent mechanism

The clinically beneficial effect of low frequency pulsed electromagnetic fields (ELF‐PEMF) on bone healing has been described, but the exact mechanism of action remains unclear. A recent study suggests that there is a direct autocrine mitogenic effect of ELF‐PEMF on angiogenesis. The hypothesis of this study is that ELF‐PEMF also has an indirect effect on angiogenesis by manipulation of vascular endothelial growth factor (VEGF)‐A‐based paracrine intercellular communication with neighboring osteoblasts. Conditioned media experiments measured fetal rat calvarial cell (FRC) and human umbilical vein endothelial cell (HUVEC) proliferation using tritiated thymidine uptake. We demonstrate that ELF‐PEMF (15 Hz, 1.8 mT, for 8 h) has an indirect effect on the proliferation rate of both endothelial cells and osteoblasts in vitro by altering paracrine mediators. Conditioned media from osteoblast cells stimulated with ELF‐PEMF increased endothelial proliferation 54‐fold, whereas media from endothelial cells stimulated with ELF‐PEMF did not affect osteoblast proliferation. We examined the role of the pro‐angiogenic mediator VEGF‐A in the mitogenic effect of ELF‐PEMF‐stimulated osteoblast media on endothelial cells. The production of VEGF‐A by FRC as measured by ELISA was not changed by exposure to PEMF, and blocking experiments demonstrated that the ELF‐PEMF‐induced osteoblast‐derived endothelial mitogen observed in these studies was not VEGF‐A, but some other soluble angiogenic mediator. Bioelectromagnetics 30:189–197, 2009. © 2008 Wiley‐Liss, Inc.     

Treatment of the restless legs syndrome with carbamazepine: a double blind study.

One hundred and seventy four patients suffering from the restless legs syndrome were examined in a double blind, between patient, placebo controlled study in general practice for five weeks to investigate the effects of carbamazepine and placebo on the syndrome. The syndrome was more common among middle aged women with relatively low systolic blood pressure. The median haemoglobin concentration was about average for the population, but the severity of the symptoms seemed to increase with decreasing concentrations of haemoglobin. Both placebo and carbamazepine showed a significant therapeutic effect (p less than 0.01). Carbamazepine was significantly more effective than placebo (p less than or equal to 0.03). The significant therapeutic effect of placebo in restless legs showed that only double blind controlled trials can confirm the efficacy of suggested treatments.     

Pediatric psychopharmacology: too much or too little?

This paper provides a selective overview of the past, present and future of pediatric psychopharmacology. The acceptance of medication use in child psychiatry was based on the results of double‐blind, placebo‐controlled trials documenting the efficacy of drug treatments for attention‐deficit/hyperactivity disorder, enuresis, depression, anxiety disorders, obsessive‐compulsive disorder and psychoses. This period of success was followed by a series of challenges, including a growing awareness of the long‐term adverse effects of medications and of the inadequacy of long‐term drug surveillance. There is great concern today that children are being overtreated with medication, especially in the US. Further advances in pediatric psychopharmacology may come from examination of large medical data sets including both pharmacological and psychiatric information, which could lead to drug repurposing, as well as from preclinical translational studies such as those using human induced pluripotent stem cells.     

On the pharmacological properties of Delta9-tetrahydrocannabinol (THC)

Cannabis is one of the first plants used as medicine, and the notion that it has potentially valuable therapeutic properties is a matter of current debate. The isolation of its main constituent, Delta9-tetrahydrocannabinol (THC), and the discovery of the endocannabinoid system (cannabinoid receptors CB1 and CB2 and their endogenous ligands) made possible studies concerning the pharmacological activity of cannabinoids. This paper reviews some of the most-important findings in the field of THC pharmacology. Clinical trials, anecdotal reports, and experiments employing animal models strongly support the idea that THC and its derivatives exhibit a wide variety of therapeutic applications. However, the psychotropic effects observed in laboratory animals and the adverse reactions reported during human trials, as well as the risk of tolerance development and potential dependence, limit the application of THC in therapy. Nowadays, researchers focus on other therapeutic strategies by which the endocannabinoid system might be modulated to clinical advantage (inhibitor or activator of endocannabinoid biosynthesis, cellular uptake, or metabolism). However, emerging evidence highlights the beneficial effects of the whole cannabis extract over those observed with single components, indicating cannabis-based medicines as new perspective to revisit the pharmacology of this plant.     

Pulsed Electromagnetic Fields Improve Bone Microstructure and Strength in Ovariectomized Rats through a Wnt/Lrp5/β-Catenin Signaling-Associated Mechanism

Growing evidence has demonstrated that pulsed electromagnetic field (PEMF), as an alternative noninvasive method, could promote remarkable in vivo and in vitro osteogenesis. However, the exact mechanism of PEMF on osteopenia/osteoporosis is still poorly understood, which further limits the extensive clinical application of PEMF. In the present study, the efficiency of PEMF on osteoporotic bone microarchitecture and bone quality together with its associated signaling pathway mechanisms was systematically investigated in ovariectomized (OVX) rats. Thirty rats were equally assigned to the Control, OVX and OVX+PEMF groups. The OVX+PEMF group was subjected to daily 8-hour PEMF exposure with 15 Hz, 2.4 mT (peak value). After 10 weeks, the OVX+PEMF group exhibited significantly improved bone mass and bone architecture, evidenced by increased BMD, Tb.N, Tb.Th and BV/TV, and suppressed Tb.Sp and SMI levels in the MicroCT analysis. Three-point bending test suggests that PEMF attenuated the biomechanical strength deterioration of the OVX rat femora, evidenced by increased maximum load and elastic modulus. RT-PCR analysis demonstrated that PEMF exposure significantly promoted the overall gene expressions of Wnt1, LRP5 and β-catenin in the canonical Wnt signaling, but did not exhibit obvious impact on either RANKL or RANK gene expressions. Together, our present findings highlight that PEMF attenuated OVX-induced deterioration of bone microarchitecture and strength in rats by promoting the activation of Wnt/LRP5/β-catenin signaling rather than by inhibiting RANKL-RANK signaling. This study enriches our basic knowledge to the osteogenetic activity of PEMF, and may lead to more efficient and scientific clinical application of PEMF in inhibiting osteopenia/osteoporosis.     

Extremely low frequency pulsed electromagnetic field designed for antinociception does not affect microvascular responsiveness to the vasodilator acetylcholine

A 225 µT, extremely low frequency, pulsed electromagnetic field (PEMF) that was designed for the induction of antinociception, was tested for its effectiveness to influence blood flow within the skeletal microvasculature of a male Sprague–Dawley rat model (n = 103). Acetylcholine (0.1, 1.0, or 10 mM) was used to perturb normal blood flow and to delineate differential effects of the PEMF, based on degree of vessel dilation. After both 30 and 60 min of PEMF exposure, we report no effects on peak perfusion response to acetylcholine (with only 0.2% of the group difference attributed to exposure). Spectral analysis of blood flow data was generated to obtain information related to myogenic activity (0.15–0.40 Hz), respiratory rate (0.4–2.0 Hz), and heart rate (2.0–7.0 Hz), including the peak frequency within each of the three frequency regions identified above, peak power, full width at half maximum (FWHM), and mean within band. No significant effects due to exposure were observed on myogenic activity of examined blood vessels, or on heart rate parameters. Anesthesia‐induced respiratory depression was, however, significantly reduced following PEMF exposure compared to shams (although exposure only accounted for 9.4% of the group difference). This set of data suggest that there are no significant acute physiological effects of 225 µT PEMF after 30 and 60 min of exposure on peak blood flow, heart rate, and myogenic activity, but perhaps a small attenuation effect on anesthetic‐induced respiratory depression. Bioelectromagnetics 31:64–76, 2010. © 2009 Wiley‐Liss, Inc.