Archive for category Pharmacological

[ARTICLE] Objective assessment of cortical activity changes in stroke patients before and after hand rehabilitation with and without botulinum toxin injection – Full Text


Background Upper limb spasticity is a disabling condition and may result in severe functional limitation. The peripheral action of botulinum toxin (BTX) injection on spasticity is well known, but there are debates around its possible central action.
Aim The aim of this study was to assess the clinical, functional, and cortical activation outcome of two antispastic treatments for stroke of the hand and wrist. Thirty patients with upper limb poststroke spasticity were recruited in this study.
Patients and methods They were randomly allocated to two groups: group A and group B. Both groups received rehabilitation program, whereas group B received additional BTX injection. All patients were assessed at baseline and 8 weeks after treatment using the Modified Ashworth Scale, the Action Research Arm Test and Nine-Hole Peg Test, and somatosensory-evoked potential study of the median nerve.
Results Group B showed a higher percentage of change in Modified Ashworth Scale of the wrist flexors and long flexors of fingers and in Action Research Arm Test compared with group A.
Conclusion BTX injection in spastic muscles of the wrist and hand, followed by a rehabilitation program led to greater clinical and functional improvement compared with implementing the rehabilitation program alone.


Upper limb spasticity can be disabling and can result in several functional limitations. Although some neural plasticity following stroke contributes to motor recovery, maladaptive plasticity can weaken motor function and limits the recovery. Spasticity represents an example of maladaptive plasticity [1].

Local injection of botulinum toxin-A (BTX) is the standard treatment for spasticity, particularly in poststroke patients. In addition to its peripheral action, evidence of its possible effects on central nervous systems has emerged [1].

Somatosensory-evoked potential (SEP) studies in patients with spasticity showed improvement in SEP following BTX injection, which may support the possible central action of BTX in the cerebral cortex [2],[3].[…]

Continue —> Objective assessment of cortical activity changes in stroke patients before and after hand rehabilitation with and without botulinum toxin injection Abu-Bakr OA, Nassar NM, Al-Ganzoury AM, Ahmed KA, Tawfik EA – Egypt Rheumatol Rehabil


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[WEB SITE] Can Ritalin Help Mitigate Brain Injury Symptoms?

Can Ritalin Help Mitigate Brain Injury Symptoms?


My 54-year-old husband sustained a TBI when he fell asleep at the wheel while driving and hit a tree. The doctors say that he damaged all four parts of his brain. It’s been more than one and a half years and he’s still totally dependent on me to take care of him. Do you think Ritalin would help stimulate his brain?


Methylphenidate (Ritalin) is one of the commonly used brain stimulants in people who have suffered traumatic brain injury. It increases chemicals in the brain that have a stimulating effect (norepinephrine and dopamine).

After traumatic brain injury, doctors commonly prescribe Ritalin for low arousal or initiation, poor attention and concentration, depression, and slow processing speed. There is research that shows that Ritalin may speed recovery early after moderate to severe TBI. There is also research showing that Ritalin increases mental processing speed after TBI, which can improve memory function in some people.

All medications have side effects and the risks need to be weighed against possible benefits. One of the good things about the standard formulation of Ritalin is that it is short acting so if side effects occur they wear off in a few hours. Some potential side effects include keeping you up at night (if taken too close to bedtime), decreased appetite, headache, irritability, and paranoia.

In your husband’s case, his doctor needs to look at why he is so dependent. If arousal, attention, and/or initiation are playing a significant role, a stimulant can be considered. Careful monitoring for effects and/or side effects is needed when starting this medication and it should only be done by a doctor who has experience in caring for people with traumatic brain injury. Ritalin and most stimulants are controlled substances and will require frequent visits to the doctor for prescriptions.

Source: Can Ritalin Help Mitigate Brain Injury Symptoms? | BrainLine

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[ARTICLE] A randomised controlled cross-over double-blind pilot study protocol on THC:CBD oromucosal spray efficacy as an add-on therapy for post-stroke spasticity – Full Text


Introduction Stroke is the most disabling neurological disorder and often causes spasticity. Transmucosal cannabinoids (tetrahydrocannabinol and cannabidiol (THC:CBD), Sativex) is currently available to treat spasticity-associated symptoms in patients with multiple sclerosis. Cannabinoids are being considered useful also in the treatment of pain, nausea and epilepsy, but may bear and increased risk for cardiovascular events. Spasticity is often assessed with subjective and clinical rating scales, which are unable to measure the increased excitability of the monosynaptic reflex, considered the hallmark of spasticity. The neurophysiological assessment of the stretch reflex provides a precise and objective method to measure spasticity. We propose a novel study to understand if Sativex could be useful in reducing spasticity in stroke survivors and investigating tolerability and safety by accurate cardiovascular monitoring.

Methods and analysis We will recruit 50 patients with spasticity following stroke to take THC:CBD in a double-blind placebo-controlled cross-over study. Spasticity will be assessed with a numeric rating scale for spasticity, the modified Ashworth scale and with the electromyographical recording of the stretch reflex. The cardiovascular risk will be assessed prior to inclusion. Blood pressure, heart rate, number of daily spasms, bladder function, sleep disruption and adverse events will be monitored throughout the study. A mixed-model analysis of variance will be used to compare the stretch reflex amplitude between the time points; semiquantitative measures will be compared using the Mann-Whitney test (THC:CBD vs placebo) and Wilcoxon test (baseline vs treatment).


Stroke is one of the most disabling neurological disease and frequently determines important chronic consequences such as spasticity. Prevalence of poststroke spasticity ranges from 4% to 42.6%, with the prevalence of disabling spasticity ranging from 2% to 13%.1 Treatment of poststroke spasticity is based on rehabilitation, local injection of botulinum toxin (BoNT) in the affected muscles for focal spasticity and/or use of classic oral drugs such as tizanidine, baclofen, thiocolchicoside and benzodiazepines, which are not always effective and have a good number of possible side effects.

The transmucosal administration of delta-9-tetrahydrocannabinol and cannabidiol (THC and CBD at 1:1 ratio oromucosal spray, Sativex) is able to reduce spasticity acting on endocannabinoid receptors CB1and CB2. This novel drug has been licensed after an extensive clinical trial programme2–4 in adult patients with multiple sclerosis who have shown no significant benefit from other antispasmodic drugs. More than 45 000 patient/years of exposure since its approval in more than 15 EU countries support their antispasticity effectiveness and safety profile in this indication.5 Besides improving spasticity, cannabinoids can be beneficial in reducing pain, chemotherapy-induced nausea and vomiting; moreover, they contribute to reducing seizures and to lowering eye pressure in glaucoma.6Cannabinoids can also exert psychological effects by lowering anxiety levels and inducing sedation or euphoria. Marijuana, which is the main source of cannabinoids, is declared illegal in many countries mostly because of the risk of abuse, dependence and withdrawal syndrome, related to the effect of its high amounts of THC. Several reports support an increased ischaemic stroke risk related to relevant abuse of smoked marijuana7–17 as well as synthetic cannabinoids.18–20 Ischaemic stroke following cannabis involves more frequently basal ganglia and cerebellum where CB1 and CB2 receptors show a higher expression.13

The ‘French Association of the Regional Abuse and Dependence Monitoring Centres Working Group on Cannabis Complications’ warns about the increased cardiovascular risk related to the use of herbal cannabis, mostly consisting of acute coronary syndromes and peripheral arteriopathies, potentially leading to life-threatening conditions.21 The detrimental consequences of cannabinoids could be attributed to the increase in heart rate22 as well as arterial spasms also in the context of a reversible cerebral vasoconstriction syndrome,23 but also vasculitis, postural hypotension and cardioembolism.24

On the other side, some studies support a beneficial effect on stroke evolution of cannabinoid receptors stimulation. In fact, cannabinoid-mediated activation of CB1 and CB2 receptors reduces inflammation and neuronal injury in acute ischaemic stroke.25 Activation of CB2 receptors shows protective effects after ischaemic injury26 and inhibits atherosclerotic plaque progression.27 28

To our knowledge, no correlations have been reported between haemorrhagic stroke and cannabinoids intake. In our opinion, the modification of blood pressure is the most important cannabinoid effect that should be taken into account in patients with a previous haemorrhagic stroke or predisposed to intracranial bleeding. Cannabinoids are indeed capable of inducing blood pressure fluctuations in a specific triphasic pattern (low-high-low) potentially harmful if the patient is with bleeding risk.29Ischaemic disease is not included among THC:CBD oromucosal spray contraindications. However, considering that, to our knowledge, no study has been performed with THC:CBD oromucosal spray on post-stroke spasticity, we believe that a particular caution should be used in stroke patients.

The decision of which method of measure is considered as end point is a major issue in studies involving spasticity. The definition of spasticity provided by Lance is one of the most precise and reliable, focusing on the stretch reflex as the neurophysiological equivalent of spasticity.30 Probably because of technical complexity and required expertise, neurophysiological approaches are rarely adopted. Clinical rating scales such as the modified Ashworth scale (MAS)31 or subjective scores such as the numeric rating scale (NRS) for spasticity are being widely used.32 33 Recent evidence supports the idea that MAS and NRS are indeed useful to quickly rate spasticity in a clinical setting, however NRS provide a very variable and imprecise assessment of many symptoms related to spasticity, but where spasticity itself is probably only a common factor.34 The adoption of stretch reflex as the most appropriate neurophysiological measure of spasticity increases the specificity and reduces the variability of the end point and is particularly suitable for clinical trials.

Our proposal is therefore to assess the efficacy of THC:CBD oromucosal spray in patients with spasticity following stroke as add-on to first-line antispasticity medications with an experimental pilot randomised placebo-controlled cross-over clinical trial using the stretch reflex as primary outcome measure. Prior to inclusion in the study, we propose strict selection criteria in order to reduce the risk of relevant side effects. […]

Continue —>  A randomised controlled cross-over double-blind pilot study protocol on THC:CBD oromucosal spray efficacy as an add-on therapy for post-stroke spasticity | BMJ Open


Graphical representation of the study protocol, particularly depicting the cross-over design and the time points. THC/CBD, tetrahydrocannabinol/cannabidiol.

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[Abstract] Citicoline in severe traumatic brain injury: indications for improved outcome – CNS

Goal-oriented management of traumatic brain injury (TBI) can save the lives
and/or improve the long-term outcome of millions of affected patients worldwide.
Additionally, enhancing quality of life will save enormous socio-economic costs; however, promising TBI treatment strategies with neuroprotective agents, such as citicoline (CDP-choline), lacked evidence or produced contradictory results in clinical trials. During a prehospital TBI project to optimize early TBI care within 14 Austrian trauma centers, data on 778 TBI patients were prospectively collected. As preceding evaluations suggested a beneficial outcome in TBI patients treated at the Wiener Neustadt Hospital (WNH), we aimed to investigate the potential role of citicoline administration, solely applied in WNH, in those patients. In a retrospective subgroup analysis we compared 67 patients from WNH with citicoline administration and 67 matched patients from other Austrian centers without citicoline use. Patients with Glasgow Coma Scale score <13 on site and/or Abbreviated Injury Scale of the region “head” >2 were included. Our analysis revealed significantly reduced rates of intensive care unit (ICU) mortality (5% vs. 24%, p < 0.01), in-hospital mortality (9% vs. 24%, p = 0.035) and 6‑month mortality (13% vs. 28%, p = 0.031), as well as of unfavorable outcome (34% vs. 57%, p = 0.015) and observed vs. expected ratio for mortality (0.42 vs. 0.84) in the WNH (citicoline receivers) group. Despite the limitations of a retrospective subgroup analysis our findings suggest a possible correlation between early and consequent citicoline administration and beneficial outcomes.
Therefore, we aim to set up an initiative for a prospective, multicenter
randomized controlled trial with citicoline in sTBI (severe TBI) patients.

Source: Traumatic Brain Injury Resource Guide – Research Reports – Citicoline in severe traumatic brain injury: indications for improved outcome

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[ARTICLE] Botulinum toxin type-A overdose for the treatment of spastic muscles in two patients with brain injuries – Full Text


Spasticity is commonly encountered clinically, and always affects patients’ motor ability and capacity for self-care which necessitates intervention. At present, numerous methods have been proposed with varying effects. Many reports show that the most effective method is to inject botulinum toxin, type A (BTX-A) into the spasming muscles, but the doses are different. The guidline of BTX-A injection in Chinese adults is restricted to 600 IU each time within 3 months. In this article, we treated two brain injury patients with severe regional spasticity with overdose of China-making BTX-A whose trademark is HengLi. The treatment improved spasticity and with little adverse effects. We therefore conclude that overdoses of BTX-A could also be safe and more efficient used in some patients who are showing severe spasticity of limb muscles, but it should be vary with each individual and a large sample size trial is needed for a further confirmation.


Spasticity often occurs after brain injury and always affects the motor ability and other function of the patient, thereby necessitating intervention in some cases. At present, the most effective method is injection of BTX-A in the spasming muscles. However, there is no unified guideline for the injection doses [1], the highest dosage for a single injection is less than 600 IU in Chinese guideline. So the most usage dose of BTX-A which injected to the spastic muscles of patient, was always 100-500 IU per time of per patient in our clinical work days, and sometimes it seems to take insufficient effects during a period of 2 weeks, the effect of BTA-A even last for more than 3 months.

So in patients with extensive or severe muscle spasm we decided to increase the dose of BTX-A. Although the halflethal dose of BTX-A is 40 IU/kg of body weight, which implies that a dose of BTX-A over 600 IU is safe, even a larger dose might be safe enough, but it is not confirmed yet, only few trials of small sample has been published, and the doses are less than that we used [2]. Thus, we tried administering higher BTX-A doses in two patients who had developed a severe regional spasticity after brain injury. To our knowledge, none of this kind of reports has been published yet.

Case Presentation

This study was conducted in accordance with the declaration of Helsinki, and it was conducted with approval from the Ethics Committee of the affiliated hospital of Qingdao University. Written informed consents were obtained from the participants. All procedures were performed with the consent of the patients and their family members.

Case 1

A 57-year-old man was admitted because of sudden glossolalia with choking and coughing while drinking, who was also unable to walk and swallow, had an over 10 years history of high blood pressure, but irregular use of antihypertensive agents. He was carried to our hospital for further rehabilitation after a preliminary treatment in a local hospital. Physical examination (PE) at admittance: BP 148/86 mmHg. The systolic pressure was a little higher, and his heart rate, rhythm and both the lungs were heard normal.

Nervous system examination (NSE): Although consciously, but the patient was anepia, depressed, and a little uncooperative on checking. His right nasolabial groove was relatively shallower, and poor tongue controlling. 0-1 grade muscle strength on his right side, and 3-4 grade on the left, increased muscle tone, and hyperactive tendon reflex, Modified Ashworth Scales (MAS) of both sides are range from 1+ to 2 grade. Right Babinski’s sign was positive (+), but the left was doubtful positive (±). Thus the patient was diagnosed as brain stem infarction. He was treated by kinesitherapy (occupational and physical training), and swallowing disorder treatment. After 2 weeks of rehabilitation, his sitting balance reached grade 2; He could stand up from bed with one person’s assistance, but could not take a step. He experienced difficulty in lifting his feet and obvious spasticity of his right limbs. His MAS for left elbow flexion muscle, right hamstring, and right triceps surae was grade 2, whereas his left triceps surae was grade 1+. After taking Tizanidine (an oral antispasmodic drug) for about one month, with the dose gradually increasing from 6 mg/d to 12 mg/d. However, there was appeared some unexpected symptoms, such as dizziness and/or sleepiness [3].

Thus we decided to administer a local injection of megadose of BTX-A in the severe spasming limb muscles. The right upper flexor muscles and the right lower limb were injected with 250 IU and 450 IU, respectively. We chose 5 muscles as the targets for injection:

  1. The adduction muscle
  2. Hamstring muscles

  3. Triceps surae

  4. Posterior tibial muscle

  5. And/or flexor digitorum longus

We used surface electrodes to detect the most contracted and sensitive parts of the muscles, marked on the surface then inserted needle electrodes deeply into the muscle to search for the appropriate motor points. Drug preparation: 100 U BTX-A was diluted with 2 ml normal saline to a final concentration of 50 U/ml. 4-6 injection points for a large muscle and 1-2 for small muscles were selected; each point injected 0.5-1 ml (25-50 U) BTX-A. After 4-10 days, the tone of the injected muscles was decreased, and gradually the patient could also stand and take steps in a stable condition. Two weeks to 3 months after injection both the patient’s Modified Ashworth Scale (MAS) and independent functional walking ability improved significantly, except a short period of mild weakness of muscle strength, there is no adverse effect occurred.

Cases 2

A 48-year old male was admitted to ICU 2 months after multiple traumatic injuries during a traffic accident. PE: Clearminded and spoke fluently, but high-level intelligence was impaired, especially the memory and orientation ability, and both of his eyes had limited abduction, hypopsia of counting fingers at a 60 cm distance. The muscle forces for both the upper limbs were grade 4 (MMT), moving with slight fibrillation. The proximal muscle force of the left leg was grade 2, whereas the distal level was 0. The right lower limb proximal muscle force was grade 1 and the distal was grade 0, with increased muscle tone of MAS grade, for the bilateral quadriceps were level 3, and the bilateral adductors were level 2-3. Magnetic resonance imaging (MRI) showed changes after the traumatic brain injury, including hydrocephalus. Thus the final diagnosis of the patient was “Brain injury, Multiple fractured ribs, Left femur fracture, and Acute suppurative myelitis”.

After routine rehabilitation therapy for 3 months, the patient’s sitting balance was restored to level 2. He could stand up and sit down with assistance. He could stand but could not move with walking aid. The bilateral iliopsoas muscle forces were 2-3 level. He could walk 3-5 meters on flat ground with the use of bandages and support from two persons. His hips showed obvious bilateral adduction leading to an atypical scissors gait, which made knee flexion and sitting difficult. He was given a little dose of Tizanidine firstly, however, Tizanidine administration was rapidly terminated because of its adverse effects, such as lethargy, low blood pressure [3]. BTX-A injection was then administered to his bilateral adductor muscles and quadriceps femoris at a final dose of 350 U each. The dilution and injection methods were the same as those described in Case 1. After 3-7 days of injection, we evaluated the patients’ lower limb muscles spasm degree [4]. The MAS was improved significantly, and the grade of functional walking ability improved at 2 and 4 weeks respectively after the injection, lasting more than 3 months.


BTX-A has been used to treat muscle tension disease for more than 50 years, and it has been widely applied by now [510]. At present, BTX-A can be made in several countries including China. The commercial name of Chinese BTX-A is HengLi, each vial contents 100 U. BTX blocks the physiological function of cholinergic nerve conduction, especially at the muscle-nerve joints, thus causing voluntary muscle relaxation. BTX-A is one of the most toxic substances in the world. However, after nearly 50 years of clinical application, the safety of BTX-A has been fully demonstrated [11]. A halflethal dose of mankind is 40 IU/kg, but with a maximum permissible dose of 600 U being the Chinese domestic expert consensus in 2010. As a result, repeated injections may cause immune complex diseases, so repeated BTX-A injection within 3 months is prohibited, but repeated injections have been reported in a short term within 1 week. Repeated injection in a short term is not well understood, and therefore, we do not advocate this approach.

We report two cases with muscle spasms after brain injury, who were treated by injecting BTX-A. Both the injection doses exceed the maximum dose of the Expert Consensus but were far from the median lethal dose. In both cases, no adverse reactions occurred, and the treatment helped achieving better clinical effects than the alternatives, similar to that reported in previous studies [1214]. Overdosage of BTX-A can be more efficacy and safe enough, therefore, in our further clinical study, according to the individual need and economic characteristics of the patient, we should reasonably and individually adjust the doses of BTX-A to achieve the best therapeutic effect and more beneficial to the patients’ self-care ability.


Source: Botulinum toxin type-A overdose for the treatment of spastic muscles in two patients with brain injuries

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[WEB SITE] Efficacy of methylphenidate for the treatment of mental sequelae after traumatic brain injury

BACKGROUND: This study aimed to evaluate the effect of methylphenidate for treating mental sequelae after traumatic brain injury (TBI).
METHODS: Thirty-six patients with TBI were randomly divided into the intervention group and placebo group. The participants in the intervention group received methylphenidate, while subjects in the placebo group were administered a placebo.
This study was conducted from January 2014 to December 2016. The outcome measurements included Mental Fatigue Scale, Choice Reaction Time, Compensatory Tracking Task, Mental Arithmetic Test, Digit Symbol Substitution Test, Mini-Mental State Examination (MMSE), Beck Depression Inventory (BDI), and Hamilton Rating Scale for Depression. In addition, safety was also recorded and assessed.
RESULTS: A total of 33 subjects completed the study. Methylphenidate showed greater efficacy than placebo, with decreased scores on the Mental Fatigue Scale, Choice Reaction Time, and Compensatory Tracking Task in the intervention group compared to the placebo group (P < .01, respectively). Furthermore, increased scores on the Mental Arithmetic Test, Digit Symbol Substitution Test, and MMSE in the intervention group, compared to those in the placebo group (P < .01 respectively), were observed. In addition, a significant difference in the scores on the BDI (P = .04) and Hamilton Rating Scale for Depression (P = .005) was observed between the 2 groups. The safety at the end of the 30 week-treatment was similar between the 2 groups (P > .05).
CONCLUSION: The results of this study demonstrated that methylphenidate could effectively improve mental fatigue and cognitive functions in patients with TBI.

Source: Traumatic Brain Injury Resource Guide – Research Reports – Efficacy of methylphenidate for the treatment of mental sequelae after traumatic brain injury

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[WEB SITE] This FDA Approved Drug Could Permanently Repair Brain Damage in Victims

In Brief
  • Using a drug already approved for clinical trials, researchers were able to reduce brain damage and boost the growth of new brain cells in mice suffering from strokes.
  • The research offers new hope to those dealing with the aftermath of strokes, which are the fifth leading cause of death in the United States.

Old Drug, New Treatment

Researchers from the University of Manchester have developed a new treatment that could limit the damage caused by strokes and also promote repair in the affected area of the brain. What’s more, the drug they’re using has already been clinically approved.

The researchers’ study is published in Brain, Behavior and Immunityand it recounts how they developed their treatment using mice bred to develop ischemic strokes, the most prevalent type of stroke and one that occurs when an artery that supplies oxygen-rich blood to the brain is blocked. Soon after the mice experienced a stroke, the researchers treated them with interleukin-1 receptor antagonist (IL-1Ra), an anti-inflammatory drug that is already licensed for use in treating rheumatoid arthritis.

They noticed a reduction in the amount of brain damage typically observed after a stroke and also noted that the drug boosted neurogenesis (the birth of new cells) in the areas that did experience brain damage in the days following the treatment. The mice even regained the motor skills they lost due to the stroke.

Hope for a Cure

Stroke is the fifth leading cause of death in the United States and about 800,000 people suffer from one each year, according to the Centers for Disease Control and Prevention (CDC). They occur when the flow of blood to the brain is interrupted, usually due to a blood clot or a buildup of fat that broke off from the arteries and traveled to the brain. The condition is extremely dangerous because brain cells can die within a few minutes of the stroke, causing permanent damage or even death.

We still don’t have a treatment to adequately prevent or reverse the damage to the brain caused by strokes, but the Manchester researchers believe that their development could change that. Though they are still in early stages of clinical trials, they hope to eventually move on to larger trials and eventually human testing. Together with other research, this new study offers hope to the thousands of people whose lives are impacted by strokes worldwide.

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[WEB PAGE] Faster-acting antidepressants may soon be a reality

Understanding where antidepressants act is the key to improving their function.


Using cutting-edge techniques, researchers have investigated the mechanism by which common antidepressants work, finally pinning down the specific receptors responsible for their action. The findings might pave the way to designing improved, faster-acting antidepressants.

Depression is characterized by persistent low mood and feelings of hopelessness, and it is one of the most common mental disorders in the United States. In 2014, there were an estimated 15.7 million U.S. adults who experienced at least one major depressive episode, representing around 6.7 percent of the country’s adults.

Treatments for depression generally include talking therapies in conjunction with medication. The class of drugs most commonly prescribed is selective serotonin reuptake inhibitors (SSRIs), and these include brands such as Prozac and Zoloft.

SSRIs can help some people with depression, but they are not perfect; not everyone responds well to them, and side effects including nausea, insomnia, agitation, and erectile dysfunction can be unpleasant.

Also, SSRIs can take some time to kick in; although some people might feel some benefit within hours or even minutes, most people do not feel the full antidepressant effect until they have been taking the drugs for weeks or even months.

How do SSRIs work?

In the brain, messages are sent between neurons by releasing neurotransmitters into a gap between the cells, or the synapse. Serotonin is one such neurotransmitter. It is released from the first neuron and binds to receptors on the second neuron.

Normally, once serotonin has been released into the synapse and relayed its message, the majority is reabsorbed into the first nerve cell for reuse at a later date. SSRIs prevent serotonin from being reabsorbed. In this way, they ensure that serotonin hangs around in the synapse for a longer time, exerting more of an effect.

Although SSRIs have been known to medical science since the 1950s, their exact mechanism is not understood. This is because there are at least 1,000 types of neuron that can be influenced by a surge in serotonin, and some of these neurons may be excited, while others might be inhibited.

The mixed response is because there are 14 subtypes of serotonin receptor throughout the body and any single nerve could have a cocktail of receptor types. Teasing out which receptor subtype is playing the most significant role has proven challenging.

The role of the dentate gyrus

A group of scientists from Rockefeller University in New York City, NY, recently set out to take a closer look at the action of SSRIs on a particular type of nerve cell. The team was headed up by Lucian Medrihan and Yotam Sagi, both research associates in the Laboratory of Molecular and Cellular Neuroscience, and Paul Greengard, Nobel laureate.

Their findings were recently published in the journal Neuron.

Many different types of synapses throughout the brain use serotonin as their neurotransmitter. An issue of major importance has been to identify where in the myriad of neurons the antidepressants initiate their pharmacological action.”

Paul Greengard

The team concentrated on a group of cells in the dentate gyrus (DG). According to the authors, they chose the DG because previous work has established that “SSRI treatment promotes a variety of synaptic, cellular, and network adaptations in the DG.”

Specifically, the team investigated cholecystokinin (CCK)-expressing neurons within the DG. These neurons were of interest because they are heavily influenced by neurotransmitter systems that are associated with mood disorders, such as depression.

Finding the right receptor

Using a technique called translating ribosome affinity purification, the team were able to identify the serotonin receptors on CCK cells. Sage explains, “We were able to show that one type of receptor, called 5-HT2A, is important for SSRIs’ long-term effect, while the other, 5-HT1B, mediates the initiation of their effect.

The next step in the study involved efforts to mimic SSRIs’ effects by manipulating CCK neurons in mice. They used chemogenetics to switch nerve cells on or off and implanted tiny electrodes inside the mouse brains.

The findings were clear. When the CCK neurons were inhibited, the pathways important for the mediation of SSRI responses lit up. In other words, the scientists had recreated a Prozac-like effect without using the drug.

To back up these findings, the team used behavioral experiments in a pool and observed swimming patterns. Again, silencing the CCK neurons created behavior that was similar to that displayed by the mice that had been given SSRIs: they swam for longer with increased vigor.

According to the researchers, understanding the importance of the DG and the specific cells important for treating depression will help to design faster-acting, more effective antidepressants with fewer side effects.

The work was carried out using techniques that would have been impossible just 5 years ago, and the studies that follow are likely to improve our understanding even further.

Source: Faster-acting antidepressants may soon be a reality

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[ARTICLE] Dose-Dependent Effects of Abobotulinumtoxina (Dysport) on Spasticity and Active Movements in Adults With Upper Limb Spasticity: Secondary Analysis of a Phase 3 Study – Full Text



AbobotulinumtoxinA has beneficial effects on spasticity and active movements in hemiparetic adults with upper limb spasticity (ULS). However, evidence-based information on optimal dosing for clinical use is limited.


To describe joint-specific dose effects of abobotulinumtoxinA in adults with ULS.


Secondary analysis of a phase 3 study (NCT01313299).


Multicenter, international, double-blind, placebo-controlled clinical trial.


A total of 243 adults with ULS >6 months after stroke or traumatic brain injury, aged 52.8 (13.5) years and 64.3% male, randomized 1:1:1 to receive a single-injection cycle of placebo or abobotulinumtoxinA 500 U or 1000 U (total dose).


The overall effect of injected doses were assessed in the primary analysis, which showed improvement of angles of catch in finger, wrist, and elbow flexors and of active range of motion against these muscle groups. This secondary analysis was performed at each of the possible doses received by finger, wrist, and elbow flexors to establish possible dose effects.

Main Outcome Measures

Angle of arrest (XV1) and angle of catch (XV3) were assessed with the Tardieu scale, and active range of motion (XA).


At each muscle group level (finger, wrist, and elbow flexors) improvements in all outcome measures assessed (XV1, XV3, XA) were observed. In each muscle group, increases in abobotulinumtoxinA dose were associated with greater improvements in XV3 and XA, suggesting a dose-dependent effect.


Previous clinical trials have established the clinical efficacy of abobotulinumtoxinA by total dose only. The wide range of abobotulinumtoxinA doses per muscle groups used in this study allowed observation of dose-dependent improvements in spasticity and active movement. This information provides a basis for future abobotulinumtoxinA dosing recommendations for health care professionals based on treatment objectives and quantitative assessment of spasticity and active range of motion at individual joints.


Upper limb spasticity (ULS) is a common symptom after stroke and traumatic brain injury (TBI) and is associated with impaired self-care and additional burden of care [1-5]. Among several treatment strategies, guidelines recommend intramuscular botulinum toxin injections as a first-line treatment for adults with ULS [6-11].

Botulinum toxin type A (BoNT-A) injections may target upper extremity muscle groups from the shoulder, to decrease adductor and internal rotation tone, to the elbow, wrist, fingers, and thumb, to decrease flexor tone [12,13]. Specific muscle selection is based on the pattern of muscle overactivity, functional deficits, and patient goals [6]. These goals include increased passive and active range of motion, improved function (feeding and dressing), easier care (palmar and axillary hygiene), and reduction of pain [13].

Evidence-based information on optimal dosing for clinical use is relatively sparse. Dosing is not interchangeable between different BoNT-A products; therefore, improving our understanding of product-specific dosing will minimize confusion among injectors and improve the quality of patient care [13].

Among BoNT-A formulations, abobotulinumtoxinA (Dysport; Galderma Laboratories, LP, Fort Worth, TX) has been shown to decrease muscle tone (as measured by the Modified Ashworth Scale [MAS]) [13-17] and pain [18] and to facilitate goal attainment [19] in adults with ULS. A recent systematic review [13] of 12 randomized controlled trials (RCTs) in ULS concluded that abobotulinumtoxinA (total dose range, 500-1500 U) was generally well-tolerated, with “strong evidence” to support reduced muscle tone.

This paper presents the results of a secondary analysis from a recently published large international clinical trial, demonstrating improved active range of motion after abobotulinumtoxinA treatment in adults with hemiparesis and ULS >6 months after stroke or TBI [20]. This phase 3, randomized, double-blind, placebo-controlled study demonstrated that a total dose of either 500 U or 1000 U abobotulinumtoxinA injected in the upper extremity also resulted in decreased muscle tone and improvements in global physician-assessed clinical benefit compared with placebo.

Apart from a systematic measurement of active range of motion (XA) against finger, wrist, and elbow flexors, another unique aspect of the trial was the assessment of spasticity at the finger, wrist, and elbow flexor groups with the Tardieu scale (TS) [21,22]. The TS is a standardized evaluation used to assess the angle of arrest at slow speed (ie, passive range of motion, XV1) and the angle of catch at fast speed (XV3). The trial demonstrated improvements for finger, wrist, and elbow joints at week 4 in XV3 at both abobotulinumtoxinA doses and in XA at 1000 U; for the 500-U dose, improvements in XA were seen in the finger flexors. Both doses were associated with a favorable safety profile [20]. This analysis aims to provide a detailed description of improvements in spasticity and the active range of motion for individual muscle groups by dose and to provide information on muscle-specific dosing, which can be used in future recommendations for injectors.

Continue —> Dose-Dependent Effects of Abobotulinumtoxina (Dysport) on Spasticity and Active Movements in Adults With Upper Limb Spasticity: Secondary Analysis of a Phase 3 Study – ScienceDirect


Figure 1. Change from baseline of Tardieu scale parameters and of active range of motion week 4 postinjection in (A) extrinsic finger flexors, (B) wrist flexors, and (C) elbow flexors. Dose groups were as follows (lowest to highest dose): 500 U/non-PTMG, 500 U/PTMG, 1000 U/non-PTMG, and 1000 U/PTMG. Standard deviations and mean change from baseline values are detailed in Table 3. PTMG = primary targeted muscle group; XV1 = passive range of motion; XV3 = angle of catch at fast speed; XA = active range of motion.

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Objective: The main aim of this study was to determine
the utilization patterns and effectiveness of onabotulinumtoxinA (Botox®) for treatment of spasticity in clinical practice.

Design: An international, multicentre, prospective, observational study at selected sites in North America, Europe, and Asia.

Patients: Adult patients with newly diagnosed or established focal spasticity, including those who had previously received treatment with onabotulinumtoxinA.

Methods: Patients were treated with onabotulinumtoxinA, approximately every 12 weeks, according to their physician’s usual clinical practice over a period of up to 96 weeks, with a final follow-up interview at 108 weeks. Patient, physician and caregiver data were collected.

Results: Baseline characteristics are reported. Of the 745 patients enrolled by 75 healthcare providers from 54 sites, 474 patients had previously received onabotulinumtoxinA treatment for spasticity. Lower limb spasticity was more common than upper limb spasticity, with stroke the most common underlying aetiology. The Short-Form 12 (SF-12) health survey scores showed that patients’ spasticity had a greater perceived impact on physical rather than mental aspects.

Conclusion: The data collected in this study will guide the development of administration strategies to optimize the effectiveness of onabotulinumtoxinA in the management of spasticity of various underlying

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