Archive for category Pharmacological

[WEB PAGE] Dysport is Now Approved for Upper Limb Spasticity as Well

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The United States Food and Drug Administration (FDA) has expanded the use of Dysport (abobotulinumtoxinA) for injection to include the treatment of upper limb spasticity in children two years of age and older, excluding spasticity caused by cerebral palsy (CP), Ipsen Biopharmaceuticals, an affiliate of Ipsen, announces in a news release.

This approval makes Dysport the first botulinum toxin approved by the FDA for both pediatric spasticity indications, following the previous approval to treat children with lower limb spasticity aged two and older received in July 2016.

“For physicians, it is reassuring to have a botulinum toxin treatment in Dysport which demonstrated sustained symptom relief for spasticity, which can be physically challenging for children,” says Ann Tilton, MD, study investigator and Professor of Clinical Neurology at the Louisiana State University Health Sciences Center New Orleans, in the release.

“This FDA decision for Dysport means we now have an approved therapy to offer children and adolescents seeking improvements in mobility in both upper and lower limbs.”

The approval is based on a Phase 3 study with children aged two to 17 years old being treated for upper limb spasticity. Due to Orphan Drug Exclusivity, this approval excludes use in children with upper limb spasticity caused by CP. Dysport demonstrated statistically significant improvements from baseline at Week 6 with doses of 8 Units/kg and 16 Units/kg vs. 2 Units/kg, as measured by the Modified Ashworth Scale (MAS) in the elbow or wrist flexors.

Dysport demonstrated a reduction in spasticity symptoms through 12 weeks for most children for both upper and lower limbs. In the upper limb study, a majority of patients were retreated between 16-28 weeks; however, some patients had a longer duration of response (ie, 34 weeks or more). The most frequent adverse reactions observed were upper respiratory tract infection and pharyngitis, the release explains.

“This approval is a testament to Ipsen’s legacy in neurotoxin research and continued commitment to advancing patient care,” states Kimberly Baldwin, Vice President, Franchise Head, Neuroscience Business Unit, Ipsen. “We believe the data for both pediatric upper and lower limb spasticity underscore the role of Dysport as an important treatment option for patients seeking long-lasting spasticity symptom relief.”

For more information, visit Ipsen.

[Source(s): Ipsen, Business Wire]

 

via Dysport is Now Approved for Upper Limb Spasticity as Well – Rehab Managment

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[BLOG POST] Benefits Of Magnesium For Traumatic Brain Injury treatment

magnesium tabletMagnesium is a vital nutrient that the human body requires in order to function healthily. It’s important for a range of bodily processes, including regulating nerve functions, blood sugar levels, blood pressure, and making protein, bone, and DNA. It’s one of the 24 essential vitamins and minerals critical for a healthy body.

Magnesium cannot be produced by the body itself – in other words, it needs to be sourced elsewhere, such as from food or supplements. The levels of magnesium needed for each person varies on gender, age and size. However, when a Traumatic Brain Injury occurs, magnesium becomes a nutrient you should strive for with its many mental and physical health benefits.

Many ordinary people today use Magnesium supplements to help with their energy, flexibility, muscle strength, and even sleep or stress management. In particular, people who have a love for fitness or sports take regular Magnesium tablets to assist with recovery and performance.

 

So, what could it do for TBI?

Magnesium For TBI
Following a traumatic brain injury, the side effects of anxiety, stress, brain swelling, cramping and tightening of muscles, stiff muscles, and insomnia are quite possible.

That’s where magnesium comes in to save the day.

Increase Flexibility, Decrease Tone, Reduce
Considering magnesium can assist with flexibility and loosening tight muscles, increasing your magnesium intake after a traumatic brain injury can likely help alleviate your stiff, cramped muscles.

Low magnesium levels can also cause a large build-up of lactic acid, which results in workout pain and tightness.

Taking magnesium for this particular problem allows your muscles to relax correctly before and after exercise.

 

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Stress & Anxiety
Magnesium can also help to control stress hormones. Serotonin, in particular, depends on magnesium for production.

This is responsible for relaxing your nervous system and encouraging positive moods, thus stabilizing you mentally.

Low magnesium levels are linked with anxiety behaviours and heightened stress – all the more reason to ensure you are taking in adequate amounts after your injury.

Brain Swelling
Magnesium is an anti-inflammatory, and as such, it can help to reduce brain swelling from a traumatic brain injury.

It increases cardiac output and cerebral blood flow. When the body has appropriate levels of it circulating throughout the body, people can experience improved neurological and cognitive outcomes.

It has also shown to possibly reduce pain intensity and headache severity.

Insomnia
Serotonin also helps encourage a good night sleep. Low magnesium levels can affect the sleep-regulating hormone melatonin, too.

Insomnia is indeed a common symptom of magnesium deficiency seen in many people today. They experience restless sleep and constant waking during the night, which leads to unhealthy sleep.

By maintaining the correct magnesium levels, people can enjoy deep, undisturbed sleep. Along with the melatonin, magnesium plays a role in maintaining healthy levels of “GABA” which is a neurotransmitter that promotes optimal sleep quality.

How To Take Magnesium

Magnesium can be taken in the form of a tablet supplement, but there are many magnesium-rich foods that can be incorporated into your daily diet, as well.

Try this list of power foods to hit your daily magnesium intake.

Dark leafy green vegetables
Flax seeds and pumpkin seeds
Almonds
Seaweed
Brown rice
Avocado’s
Walnuts, cashews, pecans

 

Other Sources of Magnesium

Magnesium Cream: Magnesium cream delivers the nutrients full spectrum of benefits, soothes muscle tension and increases flexibility in the applied area.

Magnesium Oil: Magnesium oil is  a no mess, easy-to-absorb, form of magnesium that may be able to raise levels of this nutrient within the body when applied topically to the skin.

 

In Conclusion

Ensuring that you have optimal levels of magnesium is the first step towards a healthy recovery following TBI.

It will help your muscles improve in flexibility, reduce pain, balance hormone levels, encourage positive moods, and sleep more soundly.

via Benefits Of Magnesium For Traumatic Brain Injury – treatment

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[ARTICLE] Therapeutic Potential of Neurotrophins for Repair After Brain Injury: A Helping Hand From Biomaterials – Full Text

Stroke remains the leading cause of long-term disability with limited options available to aid in recovery. Significant effort has been made to try and minimize neuronal damage following stroke with use of neuroprotective agents, however, these treatments have yet to show clinical efficacy. Regenerative interventions have since become of huge interest as they provide the potential to restore damaged neural tissue without being limited by a narrow therapeutic window. Neurotrophins, such as brain-derived neurotrophic factor (BDNF), and their high affinity receptors are actively produced throughout the brain and are involved in regulating neuronal activity and normal day-to-day function. Furthermore, neurotrophins are known to play a significant role in both protection and recovery of function following neurodegenerative diseases such as stroke and traumatic brain injury (TBI). Unfortunately, exogenous administration of these neurotrophins is limited by a lack of blood-brain-barrier (BBB) permeability, poor half-life, and rapid degradation. Therefore, we have focused this review on approaches that provide a direct and sustained neurotrophic support using pharmacological therapies and mimetics, physical activity, and potential drug delivery systems, including discussion around advantages and limitations for use of each of these systems. Finally, we discuss future directions of biomaterial drug-delivery systems, including the incorporation of heparan sulfate (HS) in conjunction with neurotrophin-based interventions.

Introduction

Stroke consistently remains a leading cause of death and disability worldwide (Mozaffarian et al., 2015). While stroke preferentially affects older people, stroke can affect anyone of any age, race, or gender (Feigin et al., 2014). In addition, ethnic disparities are known to exist, for instance, New Zealand Māori, and Pacific Island populations experience a stroke at a much younger age than Europeans (Feigin et al., 2006). With the global population continuing to age, the number of people suffering from a stroke and subsequently living with a lasting disability is also expected to rise. As a result, there is an urgent and unmet need to find treatment options to aid in improving recovery of lost functions.

The central nervous system CNS has a limited capacity to regenerate, which is one of the main causes for why stroke patients recover poorly. In addition, there is a lack of spontaneous recovery seen after stroke, leading to a large personal, and societal burden (Mozaffarian et al., 2015). This burden has led research into investigating neural mechanisms of regeneration and repair, in the hope to restore and improve lost functions following stroke. Depending on the neuronal area affected by the stroke (i.e., motor, speech, or language centers), rehabilitation, mental practice, and music therapies have all been shown to increase the capacity to recover after a stroke (Johansson, 2011). However, in patients who have had a large stroke, rehabilitation is less effective in facilitating an improvement in functional recovery (Johansson, 2011).

Significant work has shown that exogenous administration of GFs can help facilitate the repair of injured CNS tissue via their ability to regulate neuronal growth and survival (Connor and Dragunow, 1998Sofroniew et al., 2001Berretta et al., 2014). In particular, BDNF has been highlighted as being a key regulator of rehabilitation-induced recovery after stroke (Ploughman et al., 20072009). Moreover, activity-driven increases in BDNF have also been shown to promote motor recovery after stroke (Fritsch et al., 2010Clarkson et al., 2011).

The regenerative capabilities of neurotrophin-mediated interventions have already been observed in preclinical models of neurodegenerative diseases. Specifically, systemic administration of BDNF, NGF, and NT-3 have been reported to enhance neurite outgrowth, neurogenesis, and functional recovery in rodent models of stroke (Grill et al., 1997Jakeman et al., 1998Ramer et al., 2000Winkler et al., 2000Schäbitz et al., 20042007). However, the translation of such treatments into a clinical setting has been challenged by poor BBB permeability, off-target effects on the PNS, and short half-life (Chan et al., 2017). Approximately 98 percent of all compounds targeting the CNS have failed to cross the BBB (Pardridge, 2005), creating a need for alternative approaches. As a novel solution to this issue, various biomaterials have been engineered to provide an effective, and sustained drug-delivery system to the injured brain. These systems allow stem cells and/or small drug molecules including neurotrophins to bypass the BBB (Aizawa et al., 2008) and be delivered directly to the site of injury.

Heparan sulfate, as the GAG cleaved from its protein backbone, is thought to provide a novel approach for the delivery of neurotrophins to the injured CNS. HS plays a critical role in coordinating GFs and mediating their biological potential (Xu and Esko, 2014). This highly sulfated biopolymer is ideally suited as a component of a biomaterial therapeutic for brain injury. It is chemically stable, physiologically tolerated, has a demonstrated long-term benefit to wound repair by tunable protein-interactions and has been demonstrated to tolerate the level of γ-irradiation treatment required to sterilize sufficiently medical-device-like materials (Smith et al., 2018). In addition, HS has demonstrated a remarkable propensity to stabilize short-lived GF’s in what appears to be a selective fashion (Wang et al., 2014Wijesinghe et al., 2017).

The effects of BDNF and other GFs have previously been investigated in various stroke models and have shown strong regenerative potential (Berretta et al., 2014). In general, BDNF is believed to have a beneficial effect on stroke recovery via several mechanisms: protection against acute ischemic injury (Schäbitz et al., 2007), increased angiogenesis (Kermani and Hempstead, 2007), neurogenesis (Schäbitz et al., 2007), and neural repair (Mamounas et al., 2000) as well as enhanced synaptic plasticity (Waterhouse and Xu, 2009Clarkson et al., 2011). Whilst the use of BDNF and other GFs to promote neuroprotection and minimize the spread of damage during the acute phase of injury has been extensively studied (Pardridge, 2005Wu, 2005Cai et al., 2014), this work will not be reviewed here. This review instead summarizes past experimental evidence that highlights how neurotrophins have shown potential as a delayed treatment option for aiding in repair and regeneration of neural tissue for stroke and other neurodegenerative diseases. In addition, we discuss novel biomaterial delivery systems that have been utilized to enhance the delivery of neurotrophins to the CNS, as utilizing such delivery systems have resulted in a further improvement in functional recovery when treatment is delayed by days to weeks post injury.

Stroke Pathophysiology and Mechanisms of Endogenous Repair

Stroke occurs when blood flow to the brain is either obstructed by an occlusion (ischemic) or following rupturing (hemorrhagic) of a cerebral blood vessel. Lack of oxygen and glucose, and a build-up of toxic by-products, cause the areas of the brain deprived of blood flow to undergo a chain of pathological events (ischemic cascade), ultimately leading to cell death, and loss of function associated with that region of the brain (Dirnagl et al., 1999). As time passes, a lack of reperfusion to the penumbra (regions surrounding the core infarct) results in further expansion until the stroke is fully formed. Whilst neuroprotective agents have shown preclinical success at restoring reperfusion and minimizing cellular damage, they are only effective when administered within the first few hours following stroke onset and have failed to translate into clinical use, with the exception of thrombolytic compounds (Moretti et al., 2015). As a result, much needed stroke research unraveling the mechanisms associated with neuroregeneration and repair in the days to weeks following a stroke have highlighted a number of targetable treatment options, some of which have already resulted in the establishment of clinical trials.

Whilst the CNS shows limited capacity for regeneration and repair, under pathological conditions such as stroke, axonal sprouting, endogenous neurogenesis, and spontaneous functional recovery appear to be enhanced (Carmichael et al., 2001Benowitz and Carmichael, 2010). In addition, Stroemer et al. (1995) reported that both GAP-43 and synaptophysin, two proteins involved with neurite growth and synaptogenesis; are upregulated throughout the neocortex 2 weeks following a focal infarct in rats. Further, these researchers show a positive correlation between improved locomotor function and stroke-induced elevations in GAP-43 and synaptophysin. It has since been established that enhancing neuronal connections throughout the ischemic brain via pharmacological interventions correlates with an improvement in functional motor recovery after stroke (Lee et al., 2004Overman et al., 2012Clarkson et al., 2013Cook et al., 2017).

Neurogenesis occurs continuously in two areas of the healthy adult CNS: the SVZ of the lateral ventricle, and the subgranular zone (SGZ) of the hippocampal dentate gyrus. In these areas, self-renewing multipotent cells known as NSPCs differentiate into both neuronal, and glial cells (Taupin, 2006). Under physiological conditions these NSPCs migrate to the dentate gyrus or olfactory bulb to replenish the continuously dying granule cells or olfactory neurons, respectively. Following acute injury to the CNS, these resident neural progenitors may also be induced in an attempt to replace damaged neurons (Zhang et al., 2005Greenberg, 2007). Supporting this notion, many animal models of stroke have reported the upregulation of SVZ and SGZ neurogenesis, peaking around 7–10 days post-stroke (Iwai et al., 20022003Parent et al., 2002Carmichael et al., 2005). Furthermore, stroke-induced local changes to the microvasculature has been found to attract neuroblasts generated within the SVZ and facilitate their migration to the ischemic boundary zone (peri-infarct), an area lying lateral to the stroke (Carmichael et al., 2005Yamashita et al., 2006Thored et al., 2007).

Interestingly, preclinical research indicates NSPCs offer the majority of their regenerative potential through bystander effects, specifically by providing a rich source of GFs to the injured tissue rather than contributing to structural reconstruction (Chen et al., 2000). Supporting this, preclinical work has shown that MSCs facilitate an improvement in functional recovery, even though they fail to differentiate into mature neurons or glia when grafted into the ischemic boundary zone of rats exposed to a MCAo (Chen et al., 2000). Moreover, at least a portion of the therapeutic potential of MSCs has been ascribed to their ability to enhance endogenous neurogenesis and protect newborn cells from deleterious environments (Yoo et al., 2008), both of which are mechanisms mediated by neurotrophin signaling pathways. Although explicit evidence directly linking enhanced neurogenesis and functional recovery is sparse, a direct causal relationship seems probable with almost all neuroregenerative agents that improve neurological function following stroke also potentiating neurogenesis (Zhang et al., 2001Wang et al., 2004Schäbitz et al., 2007Cook et al., 2017). Of note, HS has also been demonstrated to support the proliferation (without differentiation) of stem cells ex vivo (Dombrowski et al., 2009Wijesinghe et al., 2017).

In addition to changes in neurogenesis, angiogenesis and axonal sprouting, work over the past few years has highlighted a chronic imbalance in brain excitability following stroke (Clarkson, 2012). Specifically, stroke has been reported to weaken transcallosal inhibition from the ipsilesional hemisphere onto the intact, contralesional hemisphere (Murase et al., 2004Duque et al., 2005). This further exacerbates an increase in tonic GABAergic inhibition onto the stroked hemisphere, limiting its potential for cortical plasticity, and spontaneous recovery after stroke (Clarkson et al., 2010). Indeed, restoring neuronal excitability in the ipsilesional stroke hemisphere via increasing AMPA activity, and/or dampening tonic GABAergic inhibition has shown great promise to enhance recovery of lost function (Clarkson et al., 20102015Orfila et al., 2017). Whilst the above evidence collectively supports an intrinsic capability of the ischemic brain to regenerate and repair itself, it must be reiterated that these mechanisms alone are most often insufficient to cause a complete reversal of the functional impairment (Yamashita and Abe, 2012). Furthermore, age-related decreases in neurogenesis (Cooper-Kuhn et al., 2004Kernie and Parent, 2010) and angiogenesis (Sonntag et al., 1997) have been reported, making it even harder for endogenous repair mechanisms to overcome damage and promote recovery. Accordingly, regenerative interventions have begun to target the potentiation of these endogenous mechanisms to try and maximize functional recovery in animal models of stroke and other neurodegenerative conditions such as SCI and Alzheimer’s disease (Wang et al., 2004Piantino et al., 2006Schäbitz et al., 2007Weishaupt et al., 2014Choi et al., 2018). This has been demonstrated in the case of the endogenous stimulation of key GF’s by addition of HS on a biomaterial support to the wound site (Murali et al., 2013).

Neurotrophins for Repair and Regeneration

Neurotrophins are the predominant mediators of neuronal survival and regeneration throughout the CNS, making them of particular interest in neuroregenerative research. The neurotrophin family consists of several main GFs, including NGF, BDNF, and NT-3. All neurotrophins are initially synthesized as precursor proteins, known as pro-neurotrophins. These pro-neurotrophins can then be cleaved intracellularly by furin or proconvertases, or extracellularly by metalloproteases and plasmin, to form stable mature neurotrophins. Whilst mature neurotrophins selectively bind to their respective Trk to exert neurotrophic effects, pro-neurotrophins have been found to conduct somewhat opposing, pro-apoptotic effects through the p75NTR/sortilin receptor (see Figure 1: further information on neurotrophin signaling pathways can be found below; (Nykjaer et al., 2004Teng et al., 2005). This finding has left the scientific world moving away from the passive function of these pro-domains, and has brought a new level of complexity to the role and function of neurotrophin signaling in the CNS (Zanin et al., 2017).

Figure 1. Neurotrophin signaling through the p75NTR and Trk receptors. This diagram depicts the major intracellular signaling pathways associated through each neurotrophin receptor. Each Trk receptor isoform binds mature neurotrophins and acts through three predominant pathways. Activation of PLC-γ1 results in PKC-mediated promotion of synaptic plasticity. Activation of Ras initiates MAPK-mediated promotion of neuronal regeneration and growth. Activation of PI3-K results in activation of Akt and promotion of NF-κB-mediated cell survival. Each of these pathways are also known to regulate genetic transcription, further promoting pro-survival, and regenerative gene expression. The p75NTR receptor also regulates three main pathways. When a mature neurotrophin binds to an isolated p75NTR NF-κB-mediated cell survival is promoted. If the p75NTR is co-expressed with the sortilin receptor, pro-neurotrophins can bind, and cause activation of JNK-c-Jun mediated cell death and degeneration. A receptor complex consisting of Nogo, p75NTR, and Lingo1 can bind both pro- and mature-neurotrophins to alter neurite outgrowth in a RhoA-dependent manner. NGF, nerve growth factor; BDNF, brain-derived neurotrophic factor; NT-3, neurotrophin-3; Trk, tropomyosin receptor kinase; mNT, mature neurotrophin; ProNT, proneurotrophin; p75NTR, pan neurotrophin receptor 75; PLCy1, phospholipase C gamma one; PKC, protein kinase C; MAPK, mitogen-activated protein kinase; TFs, transcription factors; PI3-K, phosphoinositide 3-kinase; NF-kB, nuclear factor kappa-light-chain-enhancer of activated B cells; JNK, c-Jun N-terminal kinase

[…]

 

Continue —> Frontiers | Therapeutic Potential of Neurotrophins for Repair After Brain Injury: A Helping Hand From Biomaterials | Neuroscience

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[WEB SITE] Nootropics: Types, safety, and risks of smart drugs

Last reviewed 

Nootropics, or “smart drugs,” are a class of substances that can boost brain performance. They are sometimes called cognition enhancers or memory enhancing substances.

Prescription nootropics are medications that have stimulant effects. They can counteract the symptoms of medical conditions such as attention deficit hyperactivity disorder (ADHD), narcolepsy, or Alzheimer’s disease.

Nonprescription substances that can enhance brain performance or focus — such as caffeine and creatine — are also considered nootropics. They do not treat diseases but may have some effects on thinking, memory, or other mental functions.

This article looks at prescription and nonprescription smart drugs, including their uses, side effects, and safety warnings.

Prescription nootropics

a woman taking nootropics at her desk.

A person may take a nootropic to treat ADHD, narcolepsy, or dementia.

Prescription nootropics include:

  • modafinil (Provigil), a stimulant that addresses the sudden drowsiness of narcolepsy
  • Adderall, which contains amphetamines to treat ADHD
  • methylphenidate (Ritalin), a stimulant that can manage symptoms of narcolepsy and ADHD
  • memantine (Axura), which treats symptoms of Alzheimer’s disease

While these can be effective in treating specific medical conditions, a person should not take them without a prescription.

Like any prescription medications, they carry risks of side effects and interactions, and a person should only take them under a doctor’s care.

Common side effects of prescription nootropics include:

Some evidence suggests that people who use prescription nootropics to improve brain function have a higher risk of impulsive behaviors, such as risky sexual practices.

Healthcare providers should work closely with people taking prescription nootropics to manage any side effects and monitor their condition.

Over-the-counter nootropics

The term “nootropic” can also refer to natural or synthetic supplements that boost mental performance. The following sections discuss nootropics that do not require a prescription.

Caffeine

Many people consume beverages that contain caffeine, such as coffee or tea, because of their stimulant effects. Studies suggest that caffeine is safe for most people in moderate amounts.

Having a regular cup of coffee or tea may be a good way to boost mental focus. However, extreme amounts of caffeine may not be safe.

The Food and Drug Administration (FDA) recommend that people consume no more than 400 milligrams (mg) of caffeine a day. This is the amount in 4–5 cups of coffee.

Caffeine pills and powders can contain extremely high amounts of the stimulant. Taking them can lead to a caffeine overdose and even death, in rare cases.

Women who are pregnant or may become pregnant may need to limit or avoid caffeine intake. Studies have found that consuming 4 or more servings of caffeine a day is linked to a higher risk of pregnancy loss.

L-theanine

L-theanine is an amino acid that occurs in black and green teas. People can also take l-theanine supplements.

A 2016 review reported that l-theanine may increase alpha waves in the brain. Alpha waves may contribute to a relaxed yet alert mental state.

L-theanine may work well when paired with caffeine. Some evidence suggests that this combination helps boost cognitive performance and alertness. Anyone looking to consume l-theanine in tea should keep the FDA’s caffeine guidelines in mind.

There are no dosage guidelines for l-theanine, but many supplements recommend taking 100–400 mg per day.

Omega-3 fatty acids

person at desk holding omega 3 supplements in palm

Studies have shown that omega-3 fatty acids are important to fight against brain aging.

These polyunsaturated fats are found in fatty fish and fish oil supplements. This type of fat is important for brain health, and a person must get it from their diet.

Omega-3s help build membranes around the body’s cells, including the neurons. These fats are important for repairing and renewing brain cells.

A 2015 review found that omega-3 fatty acids protect against brain aging. Other research has concluded that omega-3s are important for brain and nervous system function.

However, a large analysis found “no benefit for cognitive function with omega‐3 [polyunsaturated fatty acids] supplementation among cognitively healthy older people.” The authors recommend further long term studies.

A person can get omega-3 supplements in various forms, including fish oil, krill oil, and algal oil.

These supplements carry a low risk of side effects when a person takes them as directed, but they may interact with medications that affect blood clotting. Ask a doctor before taking them.

Racetams

Racetams are synthetic compounds that can affect neurotransmitters in the brain. Some nootropic racetams include:

  • piracetam
  • pramiracetam
  • phenylpiracetam
  • aniracetam

A study conducted in rats suggests that piracetam may have neuroprotective effects.

One review states that “Some of the studies suggested there may be some benefit from piracetam, but, overall, the evidence is not consistent or positive enough to support its use for dementia or cognitive impairment.” Confirming this will require more research.

There is no set dosage for racetams, so a person should follow instructions and consult a healthcare provider. Overall, studies have no found adverse effects of taking racetams as directed.

Ginkgo biloba

Ginkgo biloba is a tree native to China, Japan, and Korea. Its leaves are available as an herbal supplement.

2016 study found that gingko biloba is “potentially beneficial” for improving brain function, but confirming this will require more research.

Ginkgo biloba may help with dementia symptoms, according to one review, which reported the effects occurring in people who took more than 200 mg per day for at least 5 months.

However, the review’s authors note that more research is needed. Also, with prescription nootropics available, ginkgo biloba may not be the most safe or effective option.

Panax ginseng

Panax ginseng is a perennial shrub that grows in China and parts of Siberia. People use its roots for medicinal purposes.

People should not confuse Panax ginseng with other types of ginseng, such as Siberian or American varieties. These are different plants with different uses.

2018 review reports that Panax ginseng may help prevent certain brain diseases, including Alzheimer’s disease, Parkinson’s disease, and Huntington’s disease. It also may help with brain recovery after a stroke.

Panax ginseng interacts with many medications, so consult a doctor before taking it. A typical dosage for mental function is 100–600 mg once or twice a day.

Rhodiola

Some evidence suggests that Rhodiola rosea L., also known as rhodiola or roseroot, can help with cognitive ability.

One review reported that rhodiola may have neuroprotective effects and may help treat neurodegenerative diseases.

Another review found that rhodiola helped regulate neurotransmitters in the brain, having a positive effect on mood.

Rhodiola capsules have varying strengths. Usually, a person takes a capsule once or twice daily.

Creatine

Creatine is an amino acid, which is a building block of protein. This supplement is popular among athletes because it may help improve exercise performance. It may also have some effects on mental ability.

A 2018 review found that taking creatine appears to help with short term memory and reasoning. Whether it helps the brain in other ways is unclear.

The International Society of Sports Nutrition report that creatine supplementation of up to 30 grams per day is safe for healthy people to take for 5 years.

Another 2018 review notes that there has been limited research into whether this supplement is safe and effective for adolescent athletes.

Do nootropics work?

Some small studies show that some nootropic supplements can affect the brain. But there is a lack of evidence from large, controlled studies to show that some of these supplements consistently work and are completely safe.

Because of the lack of research, experts cannot say with certainty that over-the-counter nootropics improve thinking or brain function — or that everyone can safely use them.

For example, one report on cognitive enhancers found that there is not enough evidence to indicate that they are safe and effective for healthy people. The researchers also point to ethical concerns.

However, there is evidence that omega-3 fatty acids can benefit the brain and overall health. In addition, caffeine can improve mental focus in the short term.

Notes on the safety of nootropics

doctor and patient in office discussing adrenal cancer

A person should talk to a doctor about any interactions supplements may have with existing medications.

Also, some supplements may not contain what their labels say. A study of rhodiola products, for example, found that some contain contaminants or other ingredients not listed on the label.

For this reason, it is important to only purchase supplements from reputable companies that undergo independent testing.

BUYING NOOTROPICSA prescription is necessary for some nootropics, such as Provigil and Adderall. Over-the-counter nootropics are available in some supermarkets and drug stores, or people can choose between brands online:

Not all of these supplements are recommended by healthcare providers and some may interact with medications. Always speak to a doctor before trying a supplement.

Summary

Many doctors agree that the best way to boost brain function is to get adequate sleep, exercise regularly, eat a healthy diet, and manage stress.

For people who want to boost their cognitive function, nootropic supplements may help, in some cases. Anyone interested in trying a nootropic should consult a healthcare professional about the best options.

 

via Nootropics: Types, safety, and risks of smart drugs

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[ARTICLE] Pharmacological management of long-term aggression secondary to traumatic brain injuries – Full Text

Abstract

Aggression is common after traumatic brain injuries (TBI) in acute and chronic settings. However, there is limited guidance regarding its assessment and effective management. Whilst a number of pharmacological options are available for long term treatment, the evidence base is not of an adequate strength to support a unified practice. This article will explore the currently available guidelines and recommendations for treating chronic aggression after TBIs and evaluate the evidence for its pharmacological management.


Introduction

Aggression is a long term neurobehavioural sequelae of TBIs with incidences quoted from 11.5-33.7%.1 In TBI patients, aggressive behaviour tends to be impulsive rather than premeditated and can manifest as episodic dyscontrol syndrome, disinhibition or exacerbated premorbid antisocial traits.2 The underlying mechanisms of aggression are complex allowing numerous and diverse interventions targeting various pathways.

In acute settings, Lombard and Zafonte (2005) describe non-pharmacological measures to manage aggression including environmental alterations and ensuring minimal or non-contact restraints. Screening for systemic causes, optimising pain control and patients’ sleep-wake cycle are also advocated. In the event of failed non-pharmacological treatment, Lombard and Zafonte (2005) recommend that medication choice should be tailored to individuals; with side effect profiles taken into consideration.3

For chronic aggression, psychological therapies are used as a first line with pharmacological interventions trialled in later stages.4 Psychological therapy options include cognitive behavioural therapy (CBT), behavioural management utilising operant learning theory and contingency management. However, a review by Alderman (2013) concluded that further evidence using scientific methods is needed to analyse these approaches.5  Comparatively, there is a diverse body of literature addressing long term pharmacological treatment although quality among studies are varied. This article will focus on the aetiology for chronic post TBI aggression, current management guidelines and the evidence for long term pharmacological interventions.[…]

via Pharmacological management of long-term aggression secondary to traumatic brain injuries | ACNR | Online Neurology Journal

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[ARTICLE] Paired Associative Stimulation as a Tool to Assess Plasticity Enhancers in Chronic Stroke – Full Text

Background and Purpose: The potential for adaptive plasticity in the post-stroke brain is difficult to estimate, as is the demonstration of central nervous system (CNS) target engagement of drugs that show promise in facilitating stroke recovery. We set out to determine if paired associative stimulation (PAS) can be used (a) as an assay of CNS plasticity in patients with chronic stroke, and (b) to demonstrate CNS engagement by memantine, a drug which has potential plasticity-modulating effects for use in motor recovery following stroke.

Methods: We examined the effect of PAS in fourteen participants with chronic hemiparetic stroke at five time-points in a within-subjects repeated measures design study: baseline off-drug, and following a week of orally administered memantine at doses of 5, 10, 15, and 20 mg, comprising a total of seventy sessions. Each week, MEP amplitude pre and post-PAS was assessed in the contralesional hemisphere as a marker of enhanced or diminished plasticity. Strength and dexterity were recorded each week to monitor motor-specific clinical status across the study period.

Results: We found that MEP amplitude was significantly larger after PAS in baseline sessions off-drug, and responsiveness to PAS in these sessions was associated with increased clinical severity. There was no observed increase in MEP amplitude after PAS with memantine at any dose. Motor threshold (MT), strength, and dexterity remained unchanged during the study.

Conclusion: Paired associative stimulation successfully induced corticospinal excitability enhancement in chronic stroke subjects at the group level. However, this response did not occur in all participants, and was associated with increased clinical severity. This could be an important way to stratify patients for future PAS-drug studies. PAS was suppressed by memantine at all doses, regardless of responsiveness to PAS off-drug, indicating CNS engagement.

Introduction

The capacity of the brain to make structural, physiological, and genetic adaptations following stroke, otherwise known as plasticity, is likely to be critical for improving sensorimotor impairments and functional activities. Promotion of adaptive plasticity in the central nervous system (CNS) leading to sustained functional improvement is of paramount importance, given the personal suffering and cost associated with post-stroke disability (Ma et al., 2014). In addition to rehabilitation therapies to retrain degraded motor skills, animal and human studies have tried to augment recovery with neuropharmacologic interventions. Unfortunately, few if any have had a notable effect in patients or have come into routine use (Martinsson et al., 2007Chollet et al., 2011Cramer, 2015Simpson et al., 2015). Methods to screen drugs based on their presumed mechanism of action on plasticity in human motor systems could speed translation to patients. However, there is currently no accepted method in stroke patients for evaluating the potential effectiveness or individual responsiveness to putative “plasticity enhancing” drugs in an efficient, low-cost, cross-sectional manner, in order to establish target engagement in humans and to avoid the extensive time and cost of protracted clinical trials.

Paired associative stimulation (PAS) is a safe, painless, and non-invasive technique known to result in short-term modulation of corticospinal excitability in the adult human motor system, lasting ∼90 min (Stefan et al., 2000Wolters et al., 2003). Post-PAS excitability enhancement has been considered an LTP-like response thought to relate to transient changes in synaptic efficacy in the glutamatergic system at the N-methyl-D-aspartate (NMDA) receptor, since both human NMDA receptor deficiency (Volz et al., 2016) and pharmacological manipulation with dextromethorphan (Stefan et al., 2002) can block the effect. While PAS has been explored as a potential therapeutic intervention in patients with residual motor deficits after stroke (Jayaram and Stinear, 2008Castel-Lacanal et al., 2009), it has not previously been investigated for its potential use as an assay of motor system plasticity in this context. Prior studies have suggested that motor practice and PAS share the same neuronal substrates, modulating LTP and LTD-like plasticity in the human motor system (Ziemann et al., 2004Jung and Ziemann, 2009); therefore, as an established non-invasive human neuromodulation method (Suppa et al., 2017), we reasoned that PAS would be a suitable assay in the present study to examine the effect of a drug on motor system plasticity.

Here, we examine the effect of memantine, a drug used for treatment of Alzheimer’s disease, on the PAS response in patients with chronic stroke. Memantine is described pharmacologically as a low affinity, voltage dependent, non-competitive, NMDA antagonist (Rogawski and Wenk, 2003). At high concentrations, like other NMDA-R antagonists, it can inhibit synaptic plasticity. At lower, clinically relevant concentrations, memantine can, under some circumstances, promote synaptic plasticity by selectively inhibiting extra-synaptic glutamate receptor activity while sparing normal synaptic transmission, and hence may have clinical utility for rehabilitation (Xia et al., 2010). Interest in specifically using the drug for its interaction with stroke pathophysiology stems from animal models of both prevention (Trotman et al., 2015), in which pre-conditioning reduced infarct size, as well as for functional recovery, in which chronic oral administration starting >2 h post-stroke resulted in improved function through a non-neuroprotective mechanism (López-Valdés et al., 2014). In humans, memantine taken over multiple days has been used to demonstrate that the NMDA receptor is implicated in specific transcranial magnetic paired-pulse measures (Schwenkreis et al., 1999), and short-term training-induced motor map reorganization (Schwenkreis et al., 2005). In studies of neuromodulation, memantine blocked the facilitatory effect of intermittent theta-burst stimulation (iTBS) (Huang et al., 2007). Similarly, LTP-like plasticity induced by associative pairing of painful laser stimuli and TMS over primary motor cortex (M1) can also be blocked by memantine (Suppa et al., 2013). The effects of memantine on the PAS response have not yet been demonstrated, including examination of potential dose-response effects, which would be important for the potential clinical application of memantine for stroke recovery.

In our study, we set out to determine whether PAS might be a useful tool to probe the potential for plasticity after stroke in persons with chronic hemiparesis and apply PAS as an assay to look at drug effects on motor system plasticity using memantine. We hypothesized that (a) PAS would enhance corticospinal excitability in the contralesional hemisphere of stroke patients, and that (b) since PAS-induced plasticity is thought to involve a short-term change in glutamatergic synaptic efficacy, memantine would have a dose-dependent effect on PAS response. We predicted that at low doses, memantine would enhance PAS-induced plasticity through selective blockade of extrasynaptic NMDA receptors, whereas higher doses would inhibit PAS-induced plasticity.[…]

 

Continue —> Frontiers | Paired Associative Stimulation as a Tool to Assess Plasticity Enhancers in Chronic Stroke | Neuroscience

Figure 1. Axial MR/CT images for individual patients illustrating the stroke lesion. Images are displayed in radiological convention. Images are labeled by participant number.

 

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[WEB SITE] Marijuana could be effective against traumatic brain injury

Although the lives of patients dealing with a traumatic brain injury have improved manifold in recent years, they find themselves vulnerable to a host of side-effects that come with the modern-day medicine such as opioid painkillers, antidepressants, mood stabilizers and anti-seizure medicines.

The good news, however, is that we can now make use of legal cannabis to treat a traumatic brain injury, without the fear of death and other side-effects (recall, marijuana consumption has never resulted in a single death thus far).

A study published in 2014 found that testing positive for THC while sustaining a traumatic brain injury was associated with decreased mortality – from 11.5% to down to just 2.4%. In this post, we’ll take a look at the available research and scientific evidence that may help us determine if (and how) marijuana could help improve the condition of a person battling TBI.

Symptoms of a traumatic brain injury

TBIs occur because of a severe blow to the head, typically during an athletic event or a road accident. The common symptoms include:

  • Mood swings
  • Headaches
  • Seizures
  • Difficulties while speaking
  • Loss of motor control
  • Loss of memory

How cannabis could prove to be a breakthrough

1) Relieving Symptoms

Cannabis-derived medicines are known to drastically reduce the intensity and frequency of some types of seizures, while at the same time also displaying potent anti-anxiety and antidepressant effects, and that too without any serious side-effects.

Interestingly, a 2017 survey of 271 medical marijuana patients found that nearly 63% of participants preferred cannabis over prescription medications for the management of pain and anxiety.

2) Protection against a TBI

In order to understand this point well, you first need to have a clear understanding of the term ‘endocannabinoids’. Just like a cannabis plant produces phytocannabinoids (CBD, THC), the human body naturally produces similar molecules named endocannabinoids, which are used by the nervous and immune system to communicate.

A number of pre-clinical studies like this have shown that endocannabinoids have neuroprotective properties, which helps the brain and nervous system to recover after a blow.

It has been seen in animal models that CBD works by boosting levels of the body’s own endocannabinoids; while THC — the compound responsible for the “high” — works by taking the place of natural endocannabinoids itself in the body.

Growth of new brain cells

A study from the University of Saskatchewan (2005) found that when rodents were administered with synthetic THC, the cannabinoid apparently boosted the growth of new brain cells in a region known as the hippocampus.

The hippocampus region is responsible for memory, learning and the autonomic nervous system; research has shown that patients battling anxiety and depression often have this portion of their brain adversely affected.

Hence, the growth of new cells, courtesy of cannabis, may help in tackling the situation.

Reduced Brain inflammation

It is a well-known fact that CBD has anti-inflammatory properties. Preclinical research has found that CBD treatment immediately after a loss of oxygen can significantly reduce brain damage.

This 2011 study found that CBD treatment administered to newborn pigs after an injury effectively reduced brain edema, seizures and improved overall motor skills and behavior within just 72 hours after the injury.

Conclusion

The power of cannabinoids should never be underestimated. It’s only a matter of time before cannabis replaces most of the opioid medicines in use for traumatic brain injury treatment.

 

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[Abstract + References] Pharmacological and Therapeutic Properties of Cannabidiol for Epilepsy

Abstract

Cannabidiol (CBD) is a major active component of the Cannabis plant, which, unlike tetrahydrocannabinol (THC), is devoid of euphoria-inducing properties. During the last 10 years, there has been increasing interest in the use of CBD-enriched products for the treatment of epilepsy. In 2018, an oil-based highly purified liquid formulation of CBD (Epidiolex) derived from Cannabis sativa was approved by the US Food and Drug Administration for the treatment of seizures associated with Dravet syndrome (DS) and Lennox-Gastaut syndrome (LGS). The mechanisms underlying the antiseizure effects of CBD are unclear but may involve, among others, antagonism of G protein-coupled receptor 55 (GPR55), desensitization of transient receptor potential of vanilloid type 1 (TRPV1) channels, and inhibition of adenosine reuptake. CBD has complex and variable pharmacokinetics, with a prominent first-pass effect and a low oral bioavailability that increases fourfold when CBD is taken with a high-fat/high-calorie meal. In four randomized, double-blind, parallel-group, adjunctive-therapy trials, CBD given at doses of 10 and 20 mg/kg/day administered in two divided administrations was found to be superior to placebo in reducing the frequency of drop seizures in patients with LGS and convulsive seizures in patients with DS. Preliminary results from a recently completed controlled trial indicate that efficacy also extends to the treatment of seizures associated with the tuberous sclerosis complex. The most common adverse events that differentiated CBD from placebo in controlled trials included somnolence/sedation, decreased appetite, increases in transaminases, and diarrhea, behavioral changes, skin rashes, fatigue, and sleep disturbances. About one-half of the patients included in the DS and LGS trials were receiving concomitant therapy with clobazam, and in these patients a CBD-induced increase in serum levels of the active metabolite norclobazam may have contributed to improved seizure outcomes and to precipitation of some adverse effects, particularly somnolence.

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[Abstract] Pharmacological interventions and rehabilitation approach for enhancing brain self-repair and stroke recovery

Abstract

Neuroplasticity is a natural process occurring in the brain for entire life. Stroke is the leading cause of long term disability and huge medical and financial problem throughout the world. Research conducted over the past decade focused mainly on neuroprotection in the acute phase of stroke while very little studies targets chronic stage. Recovery after stroke depends on the ability of our brain to reestablish structural and functional organization of neurovascular networks. Combining adjuvant therapies and drugs may enhance the repair processes and restore impaired brain functions. Currently, there are some drugs and rehabilitative strategies that can facilitate brain repair and improve clinical effect even years after stroke onset. Moreover, some of compounds such as citicoline, fluoxetine, niacin, levodopa etc. are already in clinical use or are being trial in clinical issues. Many studies testing also cell therapies, in our review we will focused on studies where cells have been implemented at the early stage of stroke. Next, we discuss pharmaceutical interventions. In this section selected methods of cognitive, behavioral and physical rehabilitation as well as adjuvant interventions for neuroprotection including non invasive brain stimulation and extremely low frequency electromagnetic field. The modern rehabilitation represents new model of physical interventions with limited therapeutic window up to six months after stroke. However, last studies suggest, that time window for stroke recovery is much longer than previous thought. This review attempts to present the progress in neuroprotective strategies, both pharmacological and non-pharmacological that can stimulate the endogenous neuroplasticity in post stroke patients.

 

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[ARTICLE] Pharmacological management of long-term aggression secondary to traumatic brain injuries

Abstract
Aggression is common after traumatic brain injuries (TBI) in acute and chronic settings. However, there is limited guidance regarding its assessment and effective management. Whilst a number of pharmacological options are available for long term treatment, the evidence base is not of an adequate strength to support a unified practice. This article will explore the currently available guidelines and recommendations for treating chronic aggression after TBIs and evaluate the evidence for its pharmacological management.


Introduction

Aggression is a long term neurobehavioural sequelae of TBIs with incidences quoted from 11.5-33.7%.1 In TBI patients, aggressive behaviour tends to be impulsive rather than premeditated and can manifest as episodic dyscontrol syndrome, disinhibition or exacerbated premorbid antisocial traits.2 The underlying mechanisms of aggression are complex allowing numerous and diverse interventions targeting various pathways.

In acute settings, Lombard and Zafonte (2005) describe non-pharmacological measures to manage aggression including environmental alterations and ensuring minimal or non-contact restraints. Screening for systemic causes, optimising pain control and patients’ sleep-wake cycle are also advocated. In the event of failed non-pharmacological treatment, Lombard and Zafonte (2005) recommend that medication choice should be tailored to individuals; with side effect profiles taken into consideration.3

For chronic aggression, psychological therapies are used as a first line with pharmacological interventions trialled in later stages.4 Psychological therapy options include cognitive behavioural therapy (CBT), behavioural management utilising operant learning theory and contingency management. However, a review by Alderman (2013) concluded that further evidence using scientific methods is needed to analyse these approaches.5  Comparatively, there is a diverse body of literature addressing long term pharmacological treatment although quality among studies are varied. This article will focus on the aetiology for chronic post TBI aggression, current management guidelines and the evidence for long term pharmacological interventions.

Aetiology

Post TBI aggression has been associated with lesions affecting the prefrontal cortex – particularly the orbitofrontal and ventromedial areas – causing a loss of behavioural regulation. Disruption to inhibitory pathways between the prefrontal cortex and limbic system also results in limbic kindling and inappropriate emotional responses to negative stimuli thus facilitating aggressive behaviour.2 Associated neurotransmitter abnormalities include low cortical serotonin and impaired gamma amino-butyric acid (GABA)/ glutamate levels.6 Altered catecholamine and cholinergic levels are associated with cognitive impairment2 thus distorting information processing and predisposing patients to aggression.6 In TBI patients, underlying anxiety, affective disorders, seizures and frontal lobe dysfunction also increase susceptibility.10

Differentials for aggression

When identifying a cause for chronic aggressive behaviour, a patient’s previous experiences, comorbid psychiatric conditions and alcohol and/or substance abuse must be established with a collateral history.2,7  McAllister (2008) highlights the importance of determining pre-injury behaviour in order to exclude the possibility of symptoms being an exaggeration of pre-injury personality traits.8 Additionally, psychosocial factors must be deduced to identify possible triggers.2,7

Clinicians must be aware that aggression can be a presenting feature of other psychiatric disorders. Depression has a prevalence of 18.5% to 61% in post-TBI patients  and is linked with aggression due to their shared association with frontal lobe lesions and serotonin level imbalance.9 Other differentials include manic disorders (which can involve a more marked aggressive component if secondary to TBIs), anxiety disorders and alcohol and/or substance abuse. Personality and behavioural disorders such as affective lability, behavioural disinhibition and acquired antisocial behaviour should also be considered.8

Management guidelines

The National Institute for Health and Care Excellence (NICE) refers to the Scottish Intercollegiate Guidelines Network (SIGN) for rehabilitating patients with acquired brain injuries (ABIs). Psychological treatments advocated by SIGN include CBT, contingency management procedures, music therapy and comprehensive neurobehavioural rehabilitation (CNR).10 Family involvement appears to be associated with better outcomes2 and is also recommended.10

Of the studies quoted by SIGN, CNR was found to cause a positive effect in ABI patients in one systematic review although inconsistent results were obtained for the other three methods. Regarding pharmacological treatment, SIGN advises propranolol and pindolol as first line options.10

Pharmacological treatment

The aberrant neurotransmitter changes in the cortex and limbic areas as a result of TBIs2 provide targets for pharmacological therapy (as summarised in Table 1). Theoretically, cortical behavioural regulation can be enhanced by serotonergic agents and antagonists of dopaminergic and noradrenergic neurotransmission. Limbic hyperactivity can be dampened by the use of gamma aminobutyric acid (GABA) agonists, glutamatergic antagonists and anticholinergics.6

Impaired behavioural regulation

Antidepressants

Selective serotonin reuptake inhibitors (SSRIs) are indicated for their increase in dopamine and serotonin availability and the treatment of depression contributing to aggressive behaviour. In a trial conducted by Kant et al (1998), sertraline reduced aggression within one week of treatment although TBI severities were variable within the population.11 These results are mirrored in other trials presenting sertraline as a viable treatment option.12 Citalopram used in conjunction with carbamazepine successfully treated behavioural symptoms in a clinical trial of 22 patients conducted by Perino et al (2001)13 although the separate effects of both drugs are impossible to differentiate. A case study by Sloan et al (1992) found that fluoxetine improved emotional lability in one patient within a week.13

Tricyclic antidepressants have been shown to be useful for managing both post-traumatic and chronic aggression. Amitriptyline has reduced aggression with good tolerability despite its strong anticholinergic side effects in several studies and is suggested as the best option for treating behavioural disorders secondary to frontal lobe injuries without impairing cognition.13

Antipsychotics

There is a wide body of literature advocating antipsychotics for managing aggression due to their sedative effects.13 Nevertheless, the cognitive and extrapyramidal side effects of typical antipsychotics limit their value for chronic use. Comparatively, atypical antipsychotics have a milder side effect profile and are preferred although their cognitive impact in TBI patients is unclear.2 Furthermore, unlike older generations, atypical antipsychotics antagonise 5HT2 receptors and are therefore implicated in reduced aggression.9

Of the typical antipsychotics, chlorpromazine reduced explosiveness in one case study conducted by Sandel et al (1993). Various case studies also report haloperidol improving chronic agitation in TBI patients although significant side effects were encountered.13 Of the atypical antipsychotics the level of evidence is low. Quetiapine reduced aggression and irritability in seven patients in a trial conducted by Kim and Bijlani (2006).11 Olanzapine significantly reduced aggression within six months in a case study conducted by Umansky and Geller (2000). Clozapine was associated with varying levels of improvement in six case studies conducted by Michals et al (1993) however seizures were experienced in two patients.13

Overall, there is no reliable evidence advocating antipsychotic use for managing chronic post-TBI aggression. If antipsychotics are commenced for this purpose, it is suggested that their use is restricted to patients with psychosis.13

Beta blockers

Beta blockers are useful for cases where aggression is caused by underlying anxiety13 due to its inhibition of noradrenergic levels.9 A Cochrane review of four RCTs found that pindolol and propranolol reduced aggression within two to six weeks of starting treatment in ABI patients however no recommendations were made due to heterogeneity between samples, a small number of trials and small sample sizes.  The authors acknowledge that the trials involved high doses and so recommend caution when prescribing beta blockers for aggression.4

Methylphenidate

Methylphenidate is a psychostimulant indicated for its enhancement of dopamine and noradrenaline in the frontal lobe improving arousal and alertness.13 Mooney (1993) found in a single RCT that methylphenidate significantly improved anger scores in TBI patients.4 However other studies have yielded mixed results12,13 and no firm conclusion can be made.

Amantadine

Amantadine increases dopamine availability and acts on glutamatergic pathways. An advantage of its use is its non-sedating qualities however there is contradicting evidence for its efficacy.13 An RCT conducted by Schneider (1999) found no significant improvement4 however the trial was limited by a small sample size and large heterogeneity. Interestingly, studies of a lower level of evidence demonstrate favourable results.13 Due to this variability, its efficacy is still in question.

Buspirone

Buspirone – a serotonergic agonist licensed for treating anxiety13 – has also reduced aggression in several case studies2,12,14 warranting further research. Its side effects are amenable for use in TBIs although one disadvantage is its delayed onset.13

Hyperactive limbic drive

Anticonvulsants

The mood stabilising effects of anticonvulsants are mediated through their enhancement of GABA transmission.2 Carbamazepine has been demonstrated in studies to be effective for managing acute and chronic post- TBI aggression.12,13 Its side effects include impaired balance, sedation13 and cognitive impairment particularly in brain injured patients2 due to their heightened sensitivity. In a trial conducted by Mattes (2005), Oxcarbazepine reduced impulsive aggression however the number of TBI participants in the sample was unclear. Nine of the 48 participants also dropped out due to adverse effects11 suggesting more research is needed into its tolerability in TBI patients. Valproate has also been demonstrated to effectively manage behavioural and affective disorders13 with a milder cognitive impact compared to carbamazepine.2 Regarding other anticonvulsants, the evidence is of a lower standard. Pachet et al (2003) found that lamotrigine reduced aggression with good tolerability in one case study.11 Topiramate has been demonstrated to effectively treat manic symptoms but due to its side effects of psychosis and cognitive impairment,2 may be inappropriate for TBI patients. Case reports reference lithium to reduce post – TBI agitation however it may be unsuitable as a first line option due to its neurotoxicity.13

Benzodiazepines

Benzodiazepines are indicated for their anticonvulsive, anti-anxiety and sedative qualities facilitated by stimulation of the GABA receptor.13 There is limited literature on their chronic use in TBI patients due to their side effects of agitation, cognitive impairment and tolerance2 thus they are recommended to be more appropriate for cases of acute agitation or anxiety.11

Conclusion

There are many challenges in assessing and managing chronic aggression due to its complex aetiology. Previous literature presents a selection of pharmacological options however, their effect on TBI patients has not been confirmed resulting in limited guidance. The heterogeneity between samples also renders it impossible to predict treatment outcomes in the TBI population warranting the need for low doses, slow titration and frequent monitoring.13 A six-week trial period is advised by Fleminger et al (2006) to ascertain effects of treatment before trialling a new medication.4 Patient and family education regarding realistic treatment outcomes and side effects of treatments is also necessary to ensure treatment compliance.2 In future, a clarification of the underlying neurochemical changes is needed to identify further treatment targets. Additional larger scale RCTs are also needed to guide decision making and predict treatment outcomes. Table 2 offers a practical guide on medication choice in relation to aggressive behaviour in ABI.

References

  1. Tateno A, Jorge RE, Robinson RG. Clinical correlates of aggressive behaviour after traumatic brain injury. J Neuropsychiatry Clin Neurosci. 2003;15(2):155-60.
  2. Kim E. Agitation, aggression and disinhibition syndromes after traumatic brain injury. NeuroRehabilitation 2002;17:297-310.
  3. Lombard LA, Zafonte RD. Agitation after traumatic brain injury: considerations and treatment options. Am J Phys Med Rehabil. 2005;84(10):797-812.
  4. Fleminger S, Greenwood RJ, Oliver DL. Pharmacological management for agitation and aggression in people with acquired brain injury. Cochrane Database Syst Rev. 2006;18(4):CD003299.
  5. Alderman N, Knight C, Brooks J. Rehabilitation Approaches to the Management of Aggressive Behaviour Disorders after Acquired Brain Injury. Brain Impairment. 2013;14(1):5-20.
  6. Siever LJ. Neurobiology of Aggression and Violence. Am J Psychiatry. 2008;165(4):429-42.
  7. McAllister TW. Neurobehavioral sequelae of traumatic brain injury: evaluation and management. World Psychiatry. 2008;7(1):3-10.
  8. Schwarzbold M, Diaz A, Martins ET, Rufino A, Amante LN, Thais ME et al. Psychiatric disorders and traumatic brain injury. Neuropsychiatr Dis Treat. 2008;4(4):797-816.
  9. Coccaro EF, Siever LJ. Pathophysiology and treatment of aggression. In: Davis KL, Charney D, Coyle JT, Nemeroff C, editors. Neuropsychopharmacology: The Fifth Generation of Progress. 5th ed. Pennsylvania: Lipincott, Williams & Wilkins; 2002:1709-23.
  10. Scottish Intercollegiate Guidelines Network. Brain injury rehabilitation in adults. Edinburgh: SIGN; 2013. 68 p. Report no.:130.
  11. Luauté J, Plantier D, Wiart L, Tell L, the SOFMER group. Care management of the agitation or aggressiveness crisis in patients with TBI. Systematic review of the literature and practice recommendations. Ann Phys Rehabil Med 2016;59(1):58-67.
  12. Warden DL, Gordon B, McAllister TW, Silver JM, Barth JT, Bruns J, et al. Guidelines for the Pharmacological Treatment of Neurobehavioral Sequelae of Traumatic Brain Injury. J Neurotrauma 2006;23(10):1468-501.
  13. Levy M, Berson A, Cook T, Bollegala N, Seto E, Tursanski S, et al. Treatment of agitation following traumatic brain injury: A review of the literature. NeuroRehabilitation 2005;20(4):279-306.
  14. Chew E, Zafonte RD. Pharmacological management of neurobehavioral disorders following traumatic brain injury – a state-of-the-art review. J Rehabil Res Dev 2009;46(6):851-79.

Anum Bhatti is currently in her final year of training for her MBchB at Keele University. She is interested in pursuing psychiatry as a career choice.

 

Dr George El-Nimr, MBChB, MSc (Neuropsych), MRCPsych, MSc (Psych), MMedEd, is a Consultant Neuropsychiatrist and Academic Secretary of the Faculty of Neuropsychiatry at the Royal College of Psychiatrists.

 

Correspondence to: Dr El-Nimr, Consultant Neuropsychiatrist, Neuropsychiatry Services, Bennett Centre, Richmond Terrace, Shelton, Stoke-on-Trent ST1 4ND. Tel: 01782 441614
Conflict of interest statement: None declared
Provenance and peer review: Submitted and externally reviewed
Date first submitted: 18/4/18
Date submitted after peer review: 21/9/18
Acceptance date: 15/5/19
To cite: Bhatti A, El-Nimr G. 
ACNR 2019;18(4);15-17
Published online: 1/8/19

via Pharmacological management of long-term aggression secondary to traumatic brain injuries | ACNR | Online Neurology Journal

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