Archive for category Pharmacological

[ARTICLE] Epileptic Disorders – Epilepsy and cannabidiol: a guide to treatment – Full Text

The therapeutic potential of cannabis-related products has been suggested for many years (Perucca, 2017), and interest in the subject in recent decades has fluctuated in parallel with perceptions of cannabis and changes in legislation. With the realisation that (-)-trans-Δ-9-tetrahydrocannabinol (THC) is a component with prominent psychoactive properties, attention shifted to the potential therapeutic value of cannabidiol (CBD). In recent decades, interest in the therapeutic value of CBD-containing products, as anti-inflammatory, anti-emetic, anti-psychotic, and anti-epileptic treatments, has emerged for a wide range of conditions. However, the supporting data is principally based on anecdotal or in vitro experiments with supraphysiological concentrations. In addition, other compounds that may be present in artisanal CBD preparations may have independent physiological effects, leading to inevitable confusion regarding the effectiveness and safety of the preparations.

It is only within the last two years that Class I evidence has become available for a pure form of CBD, based on placebo-controlled RCTs. In the light of this recent evidence, this review aims to provide information on the current status of what is known about CBD as a therapeutic option for epilepsy, which will likely be of value to neurologists and epileptologists. This paper contributes to the following competencies of the ILAE curriculum (Blümcke et al., 2019): “Demonstrate up-to-date knowledge about the range of pharmacological treatments for epilepsy ; Recommend appropriate therapy based on epilepsy presentation ; Demonstrate up-to-date knowledge about special aspects of pharmacological treatment ”.

LEGISLATION

Laws regarding the use of raw herbal cannabis, cannabis extracts and cannabinoid-based medicines differ between countries (Abuhasira et al., 2018; Specchio et al., 2020). Recreational use of cannabis has been legalised in Canada and Uruguay, as well as 11 states and the District of Columbia in the US. More restricted recreational use has been adopted in Georgia, South Africa, Spain, and The Netherlands. The use of herbal cannabis for medicinal purposes is now authorised in a number of countries, including Argentina, Australia, Canada, Chile, Colombia, Croatia, Ecuador, Cyprus, Germany, Greece, Israel, Italy, Jamaica, Lithuania, Luxembourg, North Macedonia, Norway, the Netherlands, New Zealand, Peru, Poland, Switzerland, and Thailand, as well as a number of states in the US.

Cannabis and cannabis extracts have not been approved by the FDA or the European Medicines Agency (EMA), although cannabinoid-based products have been approved by the FDA as well as by 23 European countries and Canada. In some cases, authorisation is specific to certain indications, while in others the choice of indication may be dictated by the physician (Abuhasira et al., 2018).

In the European Union, CBD, in contrast to THC, is not a controlled substance and according to EU law, CBD products must not contain more than 0.2% THC. Several companies within the EU produce and distribute CBD-based products obtained from inflorescences of industrial hemp varieties. No analytical controls are mandatory and no legal protection or guarantees regarding the composition and quality is required. An obligatory testing and basic regulatory framework to determine the indication area, daily dosage, route of administration, maximum recommended daily dose, packaging, shelf life, and stability is also not required. Much of the ongoing confusion results from whether such products should be regulated as a food, a supplement, or medicine.

It is beyond the scope of this review to provide details for individual countries. However, physicians considering prescribing cannabis related products should be fully aware of the relevant legislation in relation to the heath care service for their specific geographical location. Since the situation can be complex, provision and use of guidelines from recognised national professional associations and or governmental bodies can be extremely helpful. For example, in the UK, such guidelines have been provided by the British Paediatric Neurology Association (BPNA, 2018) and the National Institute for Health and Care Excellence (NICE, 2019). In both, to prescribe a cannabis related product for medicinal use for epilepsy, the prescriber must be on the Specialist Register (Reference: Section 34D of the Medical Act 1983) and the prescription should be made by a consultant paediatric neurologist. Within the UK, responsibility for the prescribing and potential adverse effects of a cannabis related product remain with the prescribing clinician. Thus, clinicians are advised to be aware of the General Medical Council (GMC) guidance on prescribing unlicensed medication (GMC, 2019), and to investigate whether medical protection insurance and hospital indemnity will cover them for prescription of unlicensed cannabis related products. Should a doctor feel under pressure to prescribe a medication that they believe is not in the patient’s interests, then paragraph 5d of the GMC guidance “Consent: patients and doctors making decisions together” is relevant (GMC, 2008). It states: “If the patient asks for a treatment that the doctor considers would not be of overall benefit to them, the doctor should discuss the issues with the patient and explore the reasons for their request. If, after discussion, the doctor still considers that the treatment would not be of overall benefit to the patient, they do not have to provide the treatment. But they should explain their reasons to the patient, and explain any other options that are available, including the option to seek a second opinion”.

ARTISANAL PRODUCTS ADVERTISED WITH CBD CONTENT

The known physiologically active components of cannabis include cannabinoids, terpenoids, and flavonoids. Plant or phyto cannabinoids are unique to the cannabis plant. Over a hundred different cannabinoid compounds have been isolated from the cannabis plant, for which various chemovars exist (Cannabis indicaruderalis, and particularly sativa being the most common). Of these compounds, only 16 exist in meaningful concentrations; these include THC, CBD, cannabichromene (CBC), and cannabigerol (CBG) (as both acid and varin forms). The majority of animal and in vitro studies have focussed on THC and CBD, and whereas the effect of THC is less clear and appears to exhibit both proconvulsant and anticonvulsant properties under different conditions, CBD demonstrates clear anti-convulsant properties, making it a focus as a potential treatment for epilepsy.

An abundance of CBD-related products is currently commercially available, ranging extensively in purity, content of effective compounds and price. The global market for these products is considerable and according to the Centre for Medicinal Cannabis (2019) in the UK, at the current rate, the market will be worth one billion pounds/year in 2025.

Importantly, the content of CBD-related products is dependent on the type of cannabis plant as well as the different parts of the plant and growing conditions. Hemp and marijuana may be considered as different varieties of the same cannabis plant; whereas hemp is low in all cannabinoids including THC (≤0.3%), marijuana has a higher THC content (>0.3%).

Hemp seed oils (from seeds) contain minimal cannabinoids (i.e. THC); this depends principally on the extent of washing prior to subsequent processing, as cannabinoids in the flowers and leaves appear to transfer to the outer coating or husk of the seed during harvesting and preparation. Cannabis oils (from flowers and leaves of marijuana) contain variable levels of CBD and THC, depending on the chemovars. CBD-enriched oils (from flowers and leaves of hemp) contain high levels of CBD and some THC. The maximum ratio of CBD to THC that can be achieved without subsequent purification, irrespective of the chemovar, is 20:1, however, it should be noted that THC is significantly more potent (50-100-fold) than CBD. Moreover, for CBD-enriched oils advertised as “high CBD/low THC” content, in order to obtain CBD at similar doses to those used in randomised controlled trials (see below), the meaningful amount of THC may be higher than expected. For a child of 18 kg taking 300 mg CBD/day, this equates to 15 mg THC/day, based on a 20:1 CBD:THC ratio in preparations, which is similar to the maximum daily dosage of marinol or dronabinol, a synthetic Δ-9-THC (prescribed for chemotherapy-induced nausea and vomiting as well as weight loss in cancer or AIDS/HIV patients).

Galenic products are available in the form of cannabis decoction filter bags and cannabis extracts as oils, creams, and supplement capsules. Supplements appear to be the most common form, often referred to as “CBD dietary supplements” or “CBD-enriched oils”, obtained from extraction of different Cannabis sativa L. chemovars with high CBD content. Of the CBD-enriched oils, there are six main varieties available on the market in Europe: Bedrocan, Bedrobinol, Bediol, Bedica, Bedrolite and Bedropuur (table 1).

It is important to emphasise that these products demonstrate significant variation with regards to content, which is dependent not only on the initial source of the plant (e.g. the use of fertilisers and pesticides) but also the method by which they are prepared (Carcieri et al., 2018; Pegoraro et al., 2019; Bettiol et al., 2019). There are a number of different methods to prepare such oils, the most common being “supercritical CO2 extraction”. This leads to an extract rich in lipophilic cannabis components plus waxes, however, different biologically active compounds can be isolated during subsequent procedures, including omega-3 fatty acids, vitamins, terpenes, flavonoids, and other phytocannabinoids such as CBC, CBG, cannabidivarin (CBDV), and cannabinol (CBN) as a degradant (according to how the fresh the materials is) (Calvi et al., 2018). Terpenes represent the largest group (with more than 100 different molecules) of cannabis phytochemicals; these can easily cross cell membranes and the blood-brain barrier. Moreover, a synergistic effect between cannabinoids and terpenes has been hypothesised, but not proven (Russo, 2011; Aizpurua-Olaizola et al., 2016; Santiago et al., 2019).

It is also worth mentioning that an adequate dose of CBD based on commercially available CBD-enriched oils (up to 10-20 mg/kg/day), similar to doses used in randomised controlled trials (see below), comes at considerable financial cost to the family; in excess of 500 euros per month.

PRODUCT LABELLING

When it comes to CBD-enriched oils, there are major concerns regarding THC, CBD and terpene concentration, as well as appropriate preparation methods and storage conditions. These may vary significantly (Carcieri et al., 2018; Pavlovic et al., 2018), leading to insufficient quality control. Moreover, laboratory analyses have shown that the cannabinoid content is often not reflected on the marketing label (Vandrey et al., 2015).

Based on a report by the Centre for Medicinal Cannabis (2019) in the UK, there is an urgent need for a move towards accurate labelling regarding CBD content, as many products are sold with quantities of CBD which are well below those used in clinical trials. In the study by Bonn-Miller et al. (2017), the label accuracy of 84 products was analysed. Overall, CBD concentration ranged from 0.10 to 655.27 mg/mL (median: 9.45 mg/mL; median labelled concentration: 15.00 mg/mL). Of the products tested, 42.85% (n = 36) products were under-labelled, 26.19% (n = 22) were over-labelled, and 30.95% (n = 26) were accurately labelled. The level of CBD in the over-labelled products in the study is similar in magnitude to levels that triggered a warning from the US Food and Drug Administration (FDA) to 14 businesses in 2015-2016, indicating that there is a continued need for federal and state regulatory agencies to take steps to ensure accurate labelling of these consumer products.

Under-labelling is of less concern, as CBD itself does not appear to be susceptible to abuse and there have been no reported serious adverse effects (AEs) at high doses, however, the THC content observed may be sufficient to produce intoxication or impairment, especially among children. Clear labelling regarding the exact concentration of CBD is not yet mandatory, and there is clearly a need to introduce stricter legislation regarding accurate content labelling.

EFFECTIVENESS AS A TREATMENT FOR EPILEPSY

Anecdotal reports have fuelled public interest and, understandably, have inspired families to seek CBD-related products for the treatment of drug-resistant epilepsy (Filloux, 2015). The most well-known report is that of Charlotte, a five-year-old girl in the US who was diagnosed in 2013 with SCN1A-confirmed Dravet syndrome, with up to 50 generalised tonic-clonic seizures per day. Following three months of treatment with high-CBD-strain cannabis extract (later marketed as “Charlotte’s Web”), her seizures were reported to have reduced by more than 90% (Maa and Figi, 2014). Other anecdotal reports suggesting that CBD may improve seizure control as well as alertness, mood and sleep have also been documented (Porter and Jacobson, 2013; Hussain et al., 2015; Schonhofen et al., 2018).

A number of studies have investigated the effect of oral cannabis extracts on intractable epilepsy, based on parental reporting. These include the study by Press et al. (2015) of 75 patients (23% with Dravet syndrome and 89% with Lennox-Gastaut syndrome) in the US and Tzadok et al. (2016) of 74 patients in Israel over an average of six months; 50% seizure reduction was reported in 33%, and 50-75% seizure reduction in 34% in the two studies, respectively. In a retrospective study by Porcari et al. (2018) of 108 children with epilepsy in the US, the addition of CBD oil over an average of six months resulted in >50% seizure reduction in 29% patients, with 10% becoming seizure-free.

Based on a meta-analysis (n=670), Pamplona et al. (2018) provide evidence in support of the therapeutic value of high-content CBD treatments (CBD-rich cannabis extract or purified CBD). The results indicated a favourable effect for both patients with CBD-rich extracts (6.1 mg/kg/day CBD) and purified CBD (27.1 mg/kg/day), which was in fact more pronounced in patients taking the CBD-rich extracts. This may provide evidence in favour of the inclusion of other components within CBD-rich extracts offering beneficial entourage effects.

Overall, the studies on CBD-enriched oils indicate a 50% reduction in seizures in roughly 30-40% patients. However, it should be emphasised that these are uncontrolled studies with heterogeneous CBD preparations, the CBD content of which varied significantly (estimated at Press et al. (2015), the effect of cannabis extracts was investigated in a cohort of paediatric patients with epilepsy in a single tertiary epilepsy centre in Colorado, where the law on cannabis-related products is more relaxed. Interestingly, the overall responder rate (47%) for patients who had moved to Colorado for treatment was greater than that (22%) of those who were already living in Colorado, indicating a possible positive reporting bias and the need for appropriately controlled studies.

ADVERSE EVENTS

The studies described above reported AEs in 40-50% patients, including increased seizure frequency, gastrointestinal disturbances/diarrhoea, appetite alteration, weight changes, nausea, liver dysfunction, pancreatitis and, particularly, somnolence and fatigue. More serious effects included developmental regression, abnormal movements and status epilepticus.

More long-term effects regarding cannabis-derived products have generally been gathered based on indirect evidence, however, no hard conclusions can be drawn, mainly due to methodological limitations (dosage of THC and other cannabis-derived products, duration of exposure, concordant addiction to other drugs, genetic factors, psychiatric comorbidity, etc.). Long-term data from studies on prenatal and adolescent exposure to cannabis products indicate, however, a possible negative and lasting effect on cognitive and, particularly, behavioural functions (Lagae, 2020). Moreover, the externalisation of behavioural problems and a decrease in IQ have been reported as a result of chronic cannabis use. Clearly, long-term studies using large childhood epilepsy cohorts are needed on the chronic use of CBD and cannabis-related products.

PURIFIED CBD (EPIDIOLEX/EPIDYOLEX®)

A purified preparation of CBD is available from GW Pharmaceuticals plc, under the name of Epidiolex/Epidyolex® (>98% CBD). Interest has so far largely focussed on Epidiolex as an add-on drug for cases of epilepsy. Another product, Sativex® (also known as Nabiximol) (51% THC, 49% CBD), made by the same company as a refined extract, has been approved for cases of neuropathic pain, spasticity, overactive bladder and other symptoms of multiple sclerosis in some countries.

Purified CBD has been shown to demonstrate positive effects against a wide spectrum of seizures and epilepsy based on animal models (Rosenburg et al., 2017a). While the precise mechanism of action of CBD in the control of epileptic seizures in humans remains unknown, recent evidence suggests a role in modulating intracellular Ca2+ (including effects on neuronal Ca2+ mobilisation via GPR55 and TRPV1) and modulating adenosine-mediated signalling (Gray and Whalley, 2020).

In 2017 and 2018, the first randomised controlled trials for pharmaceutically prepared Epidiolex were published for Dravet syndrome and Lennox-Gastaut syndrome, respectively (Devinsky et al., 2017; Thiele et al., 2018), and in June 2018, the FDA approved CBD as an add-on antiepileptic drug for patients with Lennox-Gastaut syndrome or Dravet syndrome over the age of two. Epidiolex was also later approved by the EMA in September 2019 for patients over two years of age with Dravet syndrome and Lennox-Gastaut syndrome, in conjunction with clobazam. However, accessibility to Epidiolex outside of Europe and the US remains variable (e.g. only patients involved in RCTs may be eligible), due to a lack of approval and legal reform by central agencies. While such reform is clearly welcomed, it cannot come fast enough for those who may benefit.

PHARMACOLOGY AND DRUG INTERACTIONS

As a therapeutic drug, the pharmacokinetic profile of CBD exhibits low bioavailability, significant protein binding (99% protein binding capability), and interactions with various metabolic pathways in the liver, including CYPs that are susceptible to pharmacogenetic variability and drug interactions. However, as CBD interacts with many enzymes, it is cleared quickly and is therefore less susceptible to modulation by drugs that affect metabolising enzymes. Moreover, the pharmacokinetic profile of CBD seems relatively unaffected by inhibitors and inducers or genetic background. The bioavailability of oral oil formulations is limited (<6%) due to extensive first pass metabolism in the liver (Bialer et al., 2017, 2018).

CBD may exhibit numerous interactions with AEDs (Johannessen Landmark and Patsalos, 2010; Johannessen and Johannessen Landmark, 2010; Johannessen Landmark et al., 2012, 2016; Patsalos, 2013a, 2013b) including both potent enzyme inducers (such as carbamazepine and phenytoin) and inhibitors (such as stiripentol, felbamate and valproate) (table 2), however, the clinical significance of these interactions may not be meaningful. The most obvious and clinically significant interaction between CBD and other concomitantly used drugs, based on clinical trials, is that with clobazam. CBD, via enzyme inhibition (CYP2C19), may lead to an increase (up to five-fold) in its less potent metabolite, N-desmethylclobazam (Geffrey et al., 2015; Devinsky et al., 2018a), leading to toxicity (principally manifesting as sedation [Gaston et al., 2017]), which may occur at even low levels (1 mg/kg/day) (unpublished observations; Johannessen Landmark). In addition, concurrent clobazam may lead to increased 7-hydroxy-cannabidiol (an active metabolite of CBD) (Morrison et al., 2019), which arguably may lead to better seizure control by boosting the effect of CBD, however, studies with and without clobazam are needed to confirm this. Other AEDs with a similarly increased effect, concomitant with CBD, may include topiramate, rufinamide, zonisamide and eslicarbazepine (Gaston et al., 2017; Franco and Perucca, 2019). There are therefore still a number of unanswered questions regarding the pharmacology of CBD (Johannessen Landmark and Brandl, 2020; Brodie and Ben-Menachem, 2018).

The clinical impact of such interactions in the individual patient is difficult to predict. Patients should be systematically questioned about efficacy, tolerability and adherence, and serum concentrations should be measured if possible and dosages adjusted accordingly to optimise each patient’s treatment.

EFFICACY AS A TREATMENT FOR EPILEPSY

The first trials for purified CBD (Epidiolex) were launched as an expanded access programme in 2014 for patients with significant medically refractory epilepsy in the form of an open-label, non-controlled trial for compassionate use (Devinsky et al., 2016). Patients (n=214) with intractable seizures (at least four weekly) were monitored over a 12-week period (relative to a four-week baseline) with initial CBD doses of 2.5-5 mg/kg/day, increasing weekly to 25 or 50 mg/kg/day. Overall, a 36.5% median reduction of motor seizures was reported (49.8% for Dravet syndrome patients), and five patients were free of all motor seizures (of the patients with motor and atonic seizures, 39% and 56% showed a >50% reduction of seizures, respectively). This programme was continued and interim data on >600 patients over a 96-week period were published in 2018 by Szaflarski et al., revealing a reduction of median monthly convulsive seizures by 51% (52% with ≥50% seizure reduction) and total seizures by 48% at 12 weeks, with similar results over the 96-week period.

With these very encouraging results, shortly after the initial launch of this programme, controlled trials for Epidiolex were established for Dravet syndrome (Devinsky et al., 2017) and Lennox-Gastaut syndrome (Thiele et al., 2018; Devinsky et al., 2018b). For further details regarding these trials, refer to Nabbout and Thiele (2020).

Lennox Gastaut syndrome

In the two Lennox-Gastaut syndrome double-blind placebo-controlled trials, patients (n=171 and 225) were administered CBD at 20 mg/kg/day (GWPCARE4; Thiele et al., 2018) or 10 or 20 mg/kg/day (GWPCARE3; Devinsky et al., 2018b) over a 14-week treatment period (including a titration phase of two weeks starting with a dose of 2.5 mg/kg/day, titrated to 10 or 20 mg/kg/day), and data were compared relative to a four-week baseline observation period. CBD in an oral solution or placebo was administered as add-on to current AEDs. For CBD at 20 mg/kg/day, the median percentage reduction in total seizure frequency was 41% (vs 13.7% placebo) and 38.4% (vs 18.5% placebo), and monthly median decrease in drop seizures was reported to be 44% (vs 22% placebo) and 42% (vs 17% placebo) in the two trials, respectively. At 10 mg/kg/day, the median percentage reduction in total seizure frequency was similar at 36.4% (vs 18.5% placebo), and monthly median decrease in drop seizures was 37% (vs 17% placebo).

Lennox-Gastaut syndrome patients who enrolled in these RCTs were also invited to enter an open-label study (GWPCARE5; Thiele et al., 2019a). The interim data after 48 weeks of treatment revealed a 48-60% median decrease in drop seizure frequency and a 48-57% median decrease in monthly total seizure frequency relative to baseline (figure 1).

Based on the patient or caregiver Clinical Global Impression (CGI) scale, overall improvements were reported in patients of each trial: 58% patients (compared to 34% in the placebo group) in the study of Thiele et al. (2018), 57% and 66% in the 20 mg/kg/day and 10 mg/kg/day group, respectively (compared to 44% in the placebo group) in the study of Devinsky et al. (2018b), and 88% at 24 weeks (also similar at 38 and 48 weeks) in the open-label study of Thiele et al. (2019a).

Dravet syndrome

For Dravet syndrome, two trials involved an initial double-blind placebo-controlled trial (n=120) (GWPCARE1B; Devinsky et al., 2017) and a later open-label extension programme (GWPCARE5; Devinsky et al., 2019). An additional trial has also recently been completed (GWPCARE2; Miller et al., 2019). For the former, similar to the Lennox-Gastaut syndrome trials, patients were administered 20 mg/kg/day CBD over a 14-week treatment period, and data were compared relative to a four-week baseline period. For the open-label extension programme, a subset of these patients together with participants from the recently completed GWPCARE2 trial were enlisted (n=189) and followed over 48 weeks. For the controlled trial, during the treatment period, the median percent reduction of convulsive seizures and total seizures was 39% and 29% in the CBD arm relative to 13% and 9% in the placebo arm, respectively. The difference in median percent reduction in non-convulsive seizures was not significant. During the open-label extension programme, the median percent reduction of total seizures continued at between 39% and 51% over a 48-week period (figure 2).

As part of the expanded access programme mentioned above, the long-term effect of add-on CBD at up to 25-50 mg/kg/day over a period of 144 weeks was reported for Dravet syndrome and Lennox-Gastaut syndrome patients (Laux et al., 2019). Monthly major motor seizures were reduced by 50% and total seizures by 44%, with consistent reductions in both seizure types across the treatment period, thus supporting CBD as a long-term treatment option.

Based on the patient or caregiver CGI scale, overall improvements were reported for both trials: 62% patients (compared to 34% in the placebo arm) in the study of Devinsky et al. (2017), and 85% at 48 weeks in the open-label study of Devinsky et al. (2019).

Tuberous sclerosis complex

A clinical trial (GWPCARE6) for Epidiolex as add-on treatment in patients with tuberous sclerosis complex (TSC) was completed earlier this year and has also revealed promising results (Thiele et al., 2019b). Patients were randomised into two groups with Epidiolex (25 or 50 mg/kg/day) or placebo. Of the 201 patients who completed the study, total seizure frequency was decreased by 48% (p=0.0013), 48% (p=0.0018) and 27%, and 50% seizure reduction in 36% (p=0.0692), 40% (p=0.0245), and 22% in the 20 mg/kg/day, 50 mg/kg/day and placebo groups, respectively. An overall improvement, based on the caregiver CGI scale, was reported for 69% (p=0.0074), 62% (p=0.580) and 40% in the three groups, respectively. In conclusion, Epidiolex significantly reduced seizures in TSC patients. The therapeutic effect of the lower 25 mg/kg/day concentration was similar to that of the higher 50 mg/kg/day dose, and since the latter was associated with more AEs (see below), the 25 mg/kg/day dose would therefore be indicated for these patients.

Other syndromes

Based on an open-label trial for compassionate use, CBD was tested as a treatment for CDKL5 deficiency disorder and Aicardi, Doose, and Dup15q syndromes over a 12-week period (n=55) (Devinsky et al., 2018c). The mean decrease in convulsive seizure frequency was 51.4% (n=35). Studies are underway to evaluate CBD efficacy for a broader range of epilepsy syndromes and more than 20 trials are currently listed at ClinicalTrials.gov.

Overall, evidence from open-label studies suggests a favourable effect of CBD as an add-on treatment for a number of severe epileptic conditions and the controlled trials for Lennox-Gastaut syndrome, Dravet syndrome and TSC provide a clearer picture of the positive effect of CBD, in some cases even correlating with seizure freedom. A general positive trend for quality of life (particularly in Lennox-Gastaut syndrome patients), sleep behaviour (particularly in Dravet syndrome patients) and adaptive behaviour was reported. There were also particular improvements in the socialisation domain and communication domain for Dravet syndrome and Lennox-Gastaut syndrome patients, respectively. In the prospective, open-label clinical study by Rosenberg et al. (2017b), in which caregiver-reported quality of life (n=48) was evaluated for a subset of patients treated with CBD for 12 weeks, improvements (in energy/fatigue, memory, control/helplessness, other cognitive functions, social interactions, behaviour and global QOL) were not related to changes in seizure frequency or AEs, suggesting that CBD may have beneficial effects on patient QOL, distinct from anti-seizure effects, however, this should be confirmed in controlled studies.

ADVERSE EFFECTS

In contrast to artisanal CBD-related products, the AEs associated with purified CBD have been more clearly demonstrated based on the open-label trials and, particularly, the randomised, double-blind placebo-controlled trials (Anciones and Gil-Nagel, 2020).

Based on the collective data from the controlled trials, AEs were frequently reported (86% in CBD groups and 76% in placebo groups), however, the vast majority of AEs were mild and moderate. These included somnolence, decreased appetite, pyrexia and diarrhoea, followed by other less frequent AEs such as vomiting, fatigue and upper respiratory infections (table 3). Most AEs appeared within the first two weeks of treatment. Serious AEs were far less common (affecting 19% of CBD groups and 9% of placebo groups). These included, in particular, somnolence, pyrexia, convulsion, rash, lethargy and elevated transaminases (>three times the normal upper limit). The latter occurred in 16% patients in the CBD groups and 1% in the placebo groups. Moreover, in >79-100% of the cases with elevated transaminases, patients were concomitantly taking valproate.

No seizure worsening, suicidal ideation or deaths related to the treatment were reported. It should be emphasised, however, given the novelty of Epidiolex, that long-term AEs are currently unknown.

In the recent TSC trial with the higher dose of 50 mg/kg/day CBD (Thiele et al., 2019b), AEs were common but similarly overall reported as mild and moderate (93%, 100% and 95% in the 25 mg/kg/day; 50 mg/kg/day and placebo groups, respectively). The most common AEs were diarrhoea, decreased appetite, and somnolence, and treatment discontinuation due to AEs occurred in 11%, 14% and 3%, respectively. Elevated liver enzymes were reported in 12% (n=9) and 25% (n=18) in the 25 mg/kg/day and 50 mg/kg/day, respectively (of those, 81% were also taking valproate).

RECOMMENDATIONS FOR USE

CBD is administered orally as an oil solution. In open-label studies, doses mostly up to 25 mg/kg/day were used, and in the controlled studies, higher doses up to 50 mg/kg/day were used. The studies on Lennox-Gastaut syndrome, however, show that a significant proportion of children respond to doses of as little as 10 mg/kg/day. Therefore a “start slow” and “increase on a case-by-case basis” strategy is recommended. A starting dose of 5 mg/kg/day, divided in two doses, would appear to be adequate. This dose should be increased to 10 mg/kg/day after two weeks of treatment. Thereafter, the individual’s response should be carefully observed. The required observation time strictly depends on baseline seizure frequency before the administration of CBD. If the drug is well tolerated but not sufficiently effective, the dose should be slowly increased in increments of 5 mg/kg/day, as long as it is tolerated, up to a maximum of 20-25 mg/kg/day (table 4).

As mentioned above, special care should be taken if both CBD and clobazam are administered, since the addition of CBD may lead to an increase (up to five-fold) in its less potent metabolite, N-desmethylclobazam. A toxic benzodiazepine level may manifest as fatigue, somnolence, ataxia, a decrease in cognitive function or behavioural changes. Clinically, these are difficult to distinguish from the possible AEs of CBD itself and monitoring of clobazam/N-desmethylclobazam levels is therefore recommended. Baseline therapeutic drug monitoring should be performed before administration of CBD and subsequently after each increase. If a significant increase in benzodiazepine level is observed, the dose of clobazam should be reduced (and then checked), according to an estimate based on linear kinetics. Like CBD, however, stiripentol inhibits the same P450 subtype 2C19 (CYP2C19), and an increase in benzodiazepine level may not, therefore, occur if the patient is already on stiripentol (Devinsky et al., 2018b). It is highly recommended to follow serum concentrations of all drugs when initiating CBD as a basis for appropriate dosage adjustment. This includes psychotropic drugs (mood stabilisers, antidepressants, and antipsychotics) in order to reveal possible pharmacokinetic interactions or reasons for poor clinical effects or observed AEs.

Pharmacogenetic testing for CYP2C19 could be performed if a poor metabolizer genotype is suspected based on unexpectedly high levels of CBD relative to the dose.

Finally, biochemical markers of toxicity should be measured, particularly regarding liver enzymes in conjunction with valproate (Gaston et al., 2017; Devinsky et al., 2018a). In the controlled studies, increased liver enzymes led to withdrawal of CBD if levels were more than three times the upper normal limit in the presence of any symptoms (fever, rash, nausea, abdominal pain or increased bilirubin) or eight times higher in the absence of such symptoms. In rare cases, an increase in enzymes was observed with 20 mg/kg/day CBD without concomitant use of valproate, but not with lower doses of CBD. Overall, the increase in liver enzymes was reversible in about half the cases, without taking any action; in the remaining cases, CBD was withdrawn, leading to normalisation of levels (Devinsky et al., 2018b). A mild increase in enzyme levels may be observed over a few weeks before taking any action, however, as levels become too high, CBD or valproate should be withdrawn or reduced, according to the benefit of each.

CONCLUSIONS

Given the range of, and easy access to CBD-enriched oils on the market, alongside the fallacious perception that “natural” products may be safer with fewer AEs than conventional AEDs, it is clear to see why such products are popular. However, analytical controls for CBD-enriched products are not mandatory, leaving consumers with no legal protection or guarantees about the composition and quality of the product they are acquiring. Currently, CBD-enriched products are not subject to any obligatory testing or basic regulatory framework to determine the indication area, daily dosage, route of administration, maximum recommended daily dose, packaging, shelf life or stability. The content of these products is therefore highly variable and although components other than CBD are present which may even be beneficial, there is currently no way this can be ascertained or controlled.

In contrast, purified CBD, in the form of Epidiolex/Epidyolex, is a standardised pharmaceutical preparation that is subject to minimal variability. Based on controlled trials, Epidiolex appears to be an effective treatment option for patients with Dravet syndrome, Lennox-Gastaut syndrome and TSC and has a relatively good safety profile, although it should be emphasised that, at least from the controlled trials, CBD does not outperform other drugs and will by no means represent a silver bullet for everyone. It does, however, add to the arsenal of available add-on drugs against these severe forms of epilepsy, in some cases offering substantial benefits.

Given the range of different seizure types associated with Dravet syndrome, Lennox-Gastaut syndrome and TSC, CBD would appear to have a favourable effect on a large spectrum of convulsive (consistent with preclinical data), rather than non-convulsive seizures (Devinsky et al., 2017), namely clonic, myoclonic, myoclonic-astatic, and generalised tonic-clonic seizures. It should be noted, however, that the effect of CBD on specific types of seizures was not described in detail in the controlled trials and further studies will therefore be required to address this. Other forms of intractable epilepsy cases have been investigated in open-label trials (CDKL5 deficiency disorder and Aicardi, Dup15q and Doose syndromes; Devinsky et al., [2018c]), and more than 20 trials are currently listed at ClinicalTrials.gov (including Rett syndrome and other forms of intractable epilepsy). Although these syndromes collectively represent a small fraction of the epilepsy population, clinical trials in the future may lead to CBD or indeed other cannabinoids being indicated more broadly across the spectrum of epilepsy syndromes.

DISCLOSURES

A. Arzimanoglou receives salary support from the University Hospitals of Lyon (HCL). His work is also partly supported by the European Union grant for the coordination of the EpiCARE European Reference Network. He has a mission of Editor-in-Chief for the ILAE educational journal Epileptic Disorders and of Associate Editor for the European Journal of Paediatric Neurology. He is an investigator on research grants awarded to HCL, France and Sant Joan de Deu Hospital Barcelona from the Caixa Foundation, GW Pharma and UCB; he has received travel expenses or consulting fees from Advicenne Pharma, Amzell, Arvelle, Biomarin, Eisai, GW Pharma, Lündbeck, Sanofi, Shire, Takeda, UCB Pharma, Zogenix. R. Nabbout receives salary from APHP and university Paris Descartes. She reports grants from EU (EJP-RD, Horizons 2020, and FP7), research grants from Shire, Livanova, Eisai and UCB, consulting and lecturer fees from Eisai, Advicenne Pharma, Takeda, Biomarin, Lundbeck, Zogenix, novartis, and GW pharma, outside the submitted work. Antonio Gil-Nagel has received support from Zogenix, Bilal, Stoke Therapeutics, GW, UCB, Arvelle Therapeutics, Sanofi, Marinus Pharma. Nicola Specchio has received grant support and fees for advisory board participation from GW Pharma. J. Helen Cross has acted as an investigator for studies with GW Pharma, Zogenix, Vitaflo and Marinius. She has been a speaker and on advisory boards for GW Pharma, Zogenix, and Nutricia; all remuneration has been paid to her department. Her work is supported by the NIHR Biomedical Research Centre at Great Ormond Street Hospital & University College London. U. Brandl, Lieven Lagae, Cecilie Johannessen Landmark, Oliver Gubbay, and EA. Thiele have no disclosures. The workshop was supported by an educational grant from the Fundació Sant Joan de Déu (Barcelona, Spain) and the Association ESEFNP (Lyon, France).

a Collaborators, Members of The Cannabinoids International Experts Panel: Stéphane Auvin (France), Mar Carreno (Spain), Richard Chin (UK), Roberta Cilio (Belgium), Vincenzo Di Marzo (Italy), Maria Del Carmen Fons (Spain), Elaine Hughes (USA), Floor Janssen (The Netehrlands), Reetta Kalvilainen (Finland), Tally Lerman-Sagie (Israel), Maria Mazurkiewicz-Bełdzińska (Poland), Nicola Pietrafusa (Italy), Georgia Ramantani (Switzerland), Sylvain Rheims (France), Rocio Sánchez-Carpintero (Spain), Pasquale Striano (Italy), Ben Whalley (UK).

via John Libbey Eurotext – Epileptic Disorders – Epilepsy and cannabidiol: a guide to treatment

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[WEB PAGE] Antidepressant Approvals Could Herald New Era in Psychiatric Drugs

Antidepressant Approvals Could Herald New Era in Psychiatric Drugs

The FDA has given the green light to the first major new classes of antidepressant therapies in decades, opening up new avenues for therapeutic development.

Bianca Nogrady, Oct 1, 2019

 

As droughts go, the one plaguing the antidepressant drug development landscape for the past few decades has been noteworthy. Since the advent of serotonin and norepinephrine reuptake inhibitors in the 1980s and 1990s, there has been a dearth of new pharmacological therapies for mood disorders, says psychiatrist Samantha Meltzer-Brody, director of the University of North Carolina’s Perinatal Psychiatry Program. “The same medications largely that were there when I went to medical school a long time ago were still the ones we’ve been using.”

Given this state of affairs, Meltzer-Brody says she had the “most modest” of expectations a few years ago when she got involved in the first clinical trial testing a new drug, SAGE-547, for postpartum depression. Developed by Massachusetts-based Sage Therapeutics, SAGE-547 is a solution of allopregnanolone, a neuroactive metabolite of the sex hormone progesterone, which plays key roles in the female reproductive system.

Progesterone and allopregnanolone levels peak during the third trimester of pregnancy, then crash immediately after delivery. Preclinical data suggested the drop in allopregnanolone could be a trigger for postpartum depression in some women. The company-funded trial involved administering SAGE-547 to a handful of patients with postpartum depression as an intravenous infusion over 48 hours.

The response in the first patient treated with SAGE-547 was dramatic. From being withdrawn and depressed with no appetite before treatment, she began smiling, talking, eating, and interacting, Meltzer-Brody says. “After that first patient, we thought either that’s one heck of a placebo or maybe there’s a signal.” Three more patients were treated, with similar results. Known by the generic name brexanolone, the drug sped through Phase 2 and Phase 3 trials before being approved by the US Food and Drug Administration (FDA) on March 19.

Now marketed by Sage Therapeutics as Zulresso, the therapy is the vanguard of a new wave of antidepressants. Although the path to market hasn’t been straightforward for all drug candidates, these treatments are known for being fast-acting and effective, and have fewer side effects than previous therapies. These improvements are reflected in the price tag: the first of these new antidepressants to reach the market—Zulresso and Janssen Pharmaceuticals’ Spravato (esketamine), approved just two weeks earlier for major depressive disorder—cost up to tens of thousands of dollars for a course of treatment.

But what really sets these new depression-treating drugs apart is the “circuit-driven” approach to their development, says Sage Therapeutics’ chief research officer Jim Doherty. A research focus on basic neuroscience has expanded understanding of how different neural circuits are involved in brain function—and how to target those circuits therapeutically. “The purpose of the brain is as a communication network,” Doherty says. Instead of thinking only in terms of candidate drug molecules and receptors, “we try to think as much as we can at that level [of the whole communication network] to understand what are going to be the circuit-level consequences of our molecules.”

A better understanding of depression

For a long time, the only treatments available for depression were two classes of antidepressants known as tricyclics and monoamine oxidase inhibitors (MAOIs), both of which were discovered in the 1950s. Three decades passed before a new class emerged—the SSRIs, with the first drug Prozac (fluoxetine) launched on the market by pharma giant Eli Lilly in 1988. (See timeline on page 65.) Still the most widely prescribed antidepressants in the world, SSRIs are thought to influence mood by increasing levels of the neurotransmitter serotonin in the brain’s synapses. But their exact mechanism of action is unknown. They’re also ineffective for many people, and even when they help, can require weeks or even months to alleviate patients’ symptoms. Researchers began to ask whether approaches to antidepressant development based on more-recent neuroscience might prove more successful.

“The exciting thing for a clinician-researcher like me is to be able to see that the field is broadening in the understanding of what’s creating depression,” says Jayashri Kulkarni, psychiatrist and director of the Monash Alfred Psychiatry Research Centre in Melbourne, Australia, who is involved in a clinical trial of esketamine funded by Janssen. “The move in the last ten years has been to look at causes of depression in terms of brain chemistry as well as brain circuitry or brain physiology, and when you do that, you actually come out with some options that are really good” as potential targets for antidepressant drugs.

Brexanolone, for example, is the product of research on how to modulate the function of the brain’s gamma-aminobutyric acid type A (GABAA) receptors, which normally interact with allopregnanolone and other neuroactive hormones. The drug began life as an epilepsy therapy, but Sage soon realized its potential for treating postpartum depression.

Esketamine, meanwhile, is one of another new class of antidepressants, based on a drug that has been in clinical use for half a century. The general anesthetic and painkiller ketamine is one of the World Health Organization’s essential medicines because of its safety and efficacy in both adults and children.  A couple of decades ago, with growing awareness of the role that the neurotransmitter glutamate and its interactions with the N-methyl-D-aspartate (NMDA) receptor play in mood disorders, researchers began to investigate whether ketamine, which blocks the NMDA receptor, might also be effective in treating depression.

After that first patient, we thought either that’s one heck of a placebo or maybe there’s a signal.

 —Samantha Meltzer-Brody, University of North Caro­lina

The first clinical study of ketamine for depression, published in 2000, found significant and rapid improvement in depression symptoms in seven individuals with major depression. A second randomized, placebo-controlled, double-blind crossover study in 2006 confirmed the benefits, and showed that they could be delivered within just two hours of an intravenous infusion, based on patient questionnaires. “You don’t have a suicidal patient sitting around for weeks or months trying to see if the next medication is actually going to work,” says psychiatrist and neuroscientist Ronald Duman, director of the Abraham Ribicoff Research Facilities at Yale University School of Medicine who researches ketamine but wasn’t involved in the 2006 study.

Since that research was published, interest has surged in developing new ketamine-based therapies for depression, and esketamine is the first ketamine-derived product on the market. It’s the s-enantiomer of ketamine—one of two mirror-image molecules that together make up ketamine—and is administered in a nasal spray formulation. The drug was approved by the FDA last March as an add-on therapy for treatment-resistant major depression, but not without some controversy. “The FDA gave Janssen quite a bit of flexibility,” says Todd Gould, a neuropharmacologist at the University of Maryland School of Medicine. “They only met their primary outcome in one of three acute studies.”

A typical course of esketamine involves four weeks of twice-weekly treatments, followed by maintenance doses once every one or two weeks in patients who respond, continuing for up to nine months based on clinical judgement. The choice of nasal delivery was deliberate, says Ella Daly, therapeutic area lead for mood in US Scientific Affairs at Janssen. “Unlike the intravenous formulation, the intranasal route is noninvasive, [and] we felt it would facilitate outpatient access and administration,” Daly says.

However, because esketamine, like ketamine, can have cognitive, dissociative, and even psychedelic side effects, the nasal spray must be administered in a supervised medical setting, and the patient has to remain at the clinic for at least two hours after administration. “Generally [side effects attenuate], though, with repeated dosing, so we see that reducing and being less significant,” Daly says.

Neither esketamine nor brexanolone are cheap. The list price for Spravato is $590–$885 per treatment session, or up to more than $30,000 for a full nine months of treatment at maximum dosage, while a one-time, 60-hour intravenous  infusion of Zulresso costs around $34,000. But their success has caught the attention of the pharmaceutical industry, which had been moving away from psychiatric drug development due to challenges in translating animal findings into humans, says Duman, who has received fees and grant support from Johnson & Johnson, the parent company of Janssen. “There’s a very renewed interest now because of ketamine and Spravato,” he says. “This is going to help bring big pharma back to the table.”

More new antidepressants on the horizon

Esketamine’s mirror twin, the r-enantiomer of ketamine, is also being investigated as a potential therapeutic molecule. “The preclinical data from our lab and other labs indicates that the r-ketamine is the more potent antidepressant, [but] that remains to be tested in humans,” says Gould. While the s-enantiomer is a more potent antagonist of the NMDA receptor, Gould says that doesn’t necessarily translate to stronger antidepressant effects.

Gould and others are also interested in the metabolites that result from ketamine’s breakdown in the body, after research in animals found that ketamine’s metabolites were not only necessary for its antidepressant effects but could, by themselves, induce ketamine-like responses. One of those metabolites, known as (2R,6R)-hydroxynorketamine and patented by Gould and others, is about to start Phase 1 clinical trials funded by the National Institutes of Health.

At dosages that relieve depression-like symptoms in animals, the compound “does not block the NMDA receptor, it does not produce the side effects of ketamine, and it does not appear to have the potential for addiction or abuse,” says clinical pharmacologist Carlos Zarate, chief of the section on the Neurobiology and Treatment of Mood Disorders at the National Institute of Mental Health who, with colleagues, also has patents for ketamine and its metabolites for the treatment of mood disorders.

Zarate believes that ketamine-based drugs have great potential, especially if the abuse potential and dissociative side effects are reduced. “What we do know is that ketamine, at least in our research, seems to have more-broad therapeutic effects, called pan-therapeutic effects,” Zarate says. “It seems to work very well in anxiety,  [post-traumatic stress disorder] symptoms, anhedonia or lack of pleasure, suicidal thinking, and in fact sometimes even in people who have failed electroconvulsive therapy.”

The drug development pipeline for treatments that, like brexanolone, target the GABA receptor system may also be opening up. Sage Therapeutics is starting Phase 3 trials of another GABAA receptor modulator, called SAGE-217, for adults with major depressive disorder. A recent placebo-controlled Phase 2 study showed that the compound achieved significant improvements in depressive symptoms, without any major safety signals. “That molecule was designed to have the same pharmacology of Zulresso but to have an oral once-a-day pharmacokinetic profile,” Doherty says. The company also has other drugs in early development that target the same NMDA receptor system as ketamine.

It hasn’t all been smooth sailing. Pharmaceutical company Allergan had a high-profile failure of three Phase 3 placebo-controlled clinical trials of its NMDA receptor–targeting drug rapastinel, which did not meet the primary endpoint of preventing relapses of major depression. And both the brexanolone and esketamine Phase 3 trials detected high placebo response rates, a common feature of late-stage trials in depression that can make it difficult to demonstrate that a treatment is achieving a clinical benefit.

In the case of esketamine, one of its Phase 3 trials, carried out in patients aged 65 years and older with treatment-resistant depression, failed to show statistically significant efficacy compared to placebo. “It’s fair to say that studies in the elderly population in depression are more challenging because response rates typically are lower,” Daly says. That study also used a lower starting dose, she notes, adding that an older population may need a longer duration of treatment to show benefit.

Despite the setbacks, there is general agreement that the antidepressant landscape is undergoing a profound change for the better. “It’s going to be the new norm, in that next-generation treatments will be required to have a rapid onset of action unless they’re special or unique in some other therapeutic property,” Zarate says. “Imagine, for every episode of depression you intervene [in] very early, you could significantly reduce the amount of time our patients spend in depression, [are] not able to function, have poor quality of life, and are at risk of suicide.”

A HISTORY OF ANTIDEPRESSANTS

Researchers have been working for decades on new ways to treat depression, but the US market is still dominated by drugs that were developed in the late 1980s and early 1990s.

1952

Iproniazid, the first of the monoamine oxidase inhibitors (MAOIs), is developed, after doctors realize that isoniazid, a tuberculosis drug with a similar structure, has an unexpected euphoric effect on patients. The drug inhibits the monoamine oxidase enzyme, which interacts with several neurotransmitters in the brain, including serotonin.

1957

Imipramine, the first tricyclic antidepressant, is introduced for medical use. Derived from antihistamine compounds, this drug class blocks the reuptake of serotonin and norepinephrine into presynaptic neurons, thereby increasing extracellular levels of the neurotransmitters in the brain.

1988

Fluoxetine, better known as Prozac, makes its debut on the market as the first selective serotonin reuptake inhibitor (SSRI)—still the class of antidepressants most commonly prescribed today. By reducing the reuptake of serotonin, the drug increases the extracellular concentration of the neurotransmitter.

1989

Bupropion, a type of antidepressant that doesn’t fit into existing drug classes, is approved as a treatment for major depressive disorder. It increases dopamine and norepinephrine levels in the brain by inhibiting the neurotransmitters’ reuptake.

1993

Venlafaxine, the first of the serotonin-norepinephrine reuptake inhibitors (SNRIs), hits the market. Like the SSRIs, these drugs inhibit the reuptake of serotonin, but they additionally do the same for norepinephrine.

2013

Vortioxetine, another atypical antidepressant, is approved. In addition to inhibiting the reuptake of serotonin, vortioxetine acts as an agonist and antagonist of different serotonin receptors, with the net effect of increasing extracellular amounts of serotonin and modulating the release of other, downstream neurotransmitters.

2019

Brexanolone and esketamine, the first of a new wave of drugs born of research into the underlying brain circuitry of depression, are approved and put on the market.

via Antidepressant Approvals Could Herald New Era in Psychiatric Drugs | The Scientist Magazine®

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[Abstract] Composite active range of motion (CXA) and relationship with active function in upper and lower limb spastic paresis

The aim of this study is to evaluate a novel composite measure of active range of motion (XA) and determine whether this measure correlates with active function.

Post hoc analysis of two randomized, placebo-controlled, double-blind studies with open-label extensions exploring changes in active function with abobotulinumtoxinA.

Tertiary rehabilitation centers in Australia, Europe, and the United States.

Adults with upper (n = 254) or lower (n = 345) limb spastic paresis following stroke or brain trauma.

AbobotulinumtoxinA (⩽5 treatment cycles) in the upper or lower limb.

XA was used to calculate a novel composite measure (CXA), defined as the sum of XA against elbow, wrist, and extrinsic finger flexors (upper limb) or soleus and gastrocnemius muscles (lower limb). Active function was assessed by the Modified Frenchay Scale and 10-m comfortable barefoot walking speed in the upper limb and lower limb, respectively. Correlations between CXA and active function at Weeks 4 and 12 of open-label cycles were explored.

CXA and active function were moderately correlated in the upper limb (P < 0.0001–0.0004, r = 0.476–0.636) and weakly correlated in the lower limb (P < 0.0001–0.0284, r = 0.186–0.285) at Weeks 4 and 12 of each open-label cycle. Changes in CXA and active function were weakly correlated only in the upper limb (Cycle 2 Week 12, P = 0.0160, r = 0.213; Cycle 3 Week 4, P = 0.0031, r = 0.296). Across cycles, CXA improvements peaked at Week 4, while functional improvements peaked at Week 12.

CXA is a valid measure for functional impairments in spastic paresis. CXA improvements following abobotulinumtoxinA injection correlated with and preceded active functional improvements.

via Composite active range of motion (CXA) and relationship with active function in upper and lower limb spastic paresis – Nicolas Bayle, Pascal Maisonobe, Romain Raymond, Jovita Balcaitiene, Jean-Michel Gracies,

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[Abstract] Pharmacological and Non-Pharmacological Interventions for Depression after Moderate-to-Severe Traumatic Brain Injury: A Systematic Review and Meta-Analysis

The objective of this study was to systematically review the literature and perform a meta-analysis of randomized controlled trials (RCTs) on the effectiveness of pharmacological and non-pharmacological interventions for depression in patients with moderate-to-severe traumatic brain injury.

Databases searched were: Embase, PubMed, PsycInfo, Cochrane Central, Web of Science, and Google Scholar. Depression score on a self-report questionnaire was the outcome measure. Outcomes were collected at baseline and at the first follow-up moment. Data extraction was executed independently by two researchers. Thirteen RCTs were identified: five pharmacological and eight non-pharmacological. Although not all individual studies had significant results, the overall standardized mean difference (SMD) was −0.395, p ≤ 0.001, indicating that interventions improved the depression scores in patients with TBI.

The difference in effectiveness between pharmacological interventions and non-pharmacological interventions was not significant (ΔSMD: 0.203, p = 0.238). Further subdivision into methylphenidate, sertraline, psychological, and other interventions showed a significant difference in effectiveness between methylphenidate (ΔSMD: −0.700, p = 0.020) and psychological interventions (reference). This difference was not found if other depression outcomes in four of the included studies were analyzed. The SMD of low-quality studies did not differ significantly from moderate- and high-quality studies (ΔSMD: 0.321, p = 0.050).

Although RCTs targeting interventions for depression after TBI are scarce, both pharmacological and non-pharmacological interventions appear to be effective in treating depressive symptoms/depression after moderate-to-severe TBI. There is a need for high-quality RCTs in which the add-on effects of pharmacological and non-pharmacological interventions are investigated.

via Pharmacological and Non-Pharmacological Interventions for Depression after Moderate-to-Severe Traumatic Brain Injury: A Systematic Review and Meta-Analysis | Journal of Neurotrauma

 

 

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[Abstract] Does Casting After Botulinum Toxin Injection Improve Outcomes in Adults With Limb Spasticity? A Systematic Review – Full Text PDF

Abstract

Objective: To determine current evidence for casting as an adjunct therapy following botulinum toxin injection for adult limb spasticity.

Design: The databases MEDLINE, EMBASE, CINAHL and Cochrane Central Register of Controlled Trials were searched for English language studies from 1990 to August 2018. Full-text studies using a casting protocol following botulinum toxin injection for adult participants for limb spasticity were included. Studies were graded according to Sackett’s levels of evidence, and outcome measures were categorized using domains of the International Classification of Disability, Functioning and Health. The review was prepared and reported according to PRISMA guidelines.

Results: Five studies, involving a total of 98 participants, met the inclusion criteria (2 randomized controlled trials, 1 pre-post study, 1 case series and 1 case report). Casting protocols varied widely between studies; all were on casting of the lower limbs. There is level 1b evidence that casting following botulinum toxin injection improves spasticity outcomes compared with stretching and taping, and that casting after either botulinum toxin or saline injections is better than physical therapy alone.

Conclusion: The evidence suggests that adjunct casting of the lower limbs may improve outcomes following botulinum toxin injection. Casting protocols vary widely in the literature and priority needs to be given to future studies that determine which protocol yields the best results.

Full Text PDF

via Does Casting After Botulinum Toxin Injection Improve Outcomes in Adults With Limb Spasticity? A Systematic Review – PubMed

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[NEWS] Brain-wave pattern can identify people likely to respond to antidepressant, study finds.

Researchers used electroencephalography and artificial intelligence to identify individuals who would likely respond to sertraline, the antidepressant marketed as Zoloft.

brain wave graphic

Researchers used electroencephalography and an algorithm to identify a brain-wave signature in individuals with depression who will most likely respond to a medication.
Andrea Danti/Shutterstock.comA new method of interpreting brain activity could potentially be used in clinics to help determine the best treatment options for depression, according to a study led by researchers at the Stanford School of Medicine.      

Stanford researchers and their collaborators used electroencephalography, a tool for monitoring electrical activity in the brain, and an algorithm to identify a brain-wave signature in individuals with depression who will most likely respond to sertraline, an antidepressant marketed as Zoloft.

paper describing the work was published today in Nature Biotechnology.

The study emerged from a decades-long effort funded by the National Institute of Mental Health to create biologically based approaches, such as blood tests and brain imaging, to help personalize the treatment of depression and other mental disorders. Currently, there are no such tests to objectively diagnose depression or guide its treatment.

“This study takes previous research showing that we can predict who benefits from an antidepressant and actually brings it to the point of practical utility,” said Amit Etkin, MD, PhD, professor of psychiatry and behavioral sciences at Stanford. “I will be surprised if this isn’t used by clinicians within the next five years.”

Instead of functional magnetic resonance imaging, an expensive technology often used in studies to image brain activity, the scientists turned to electroencephalography, or EEG, a much less costly technology.

Etkin shares senior authorship of the paper with Madhukar Trivedi, MD, professor of psychiatry at the University of Texas-Southwestern. Wei Wu, PhD, an instructor of psychiatry at Stanford, is the lead author.

The paper is one of several based on data from a federally funded depression study launched in 2011 — the largest randomized, placebo-controlled clinical trial on antidepressants ever conducted with brain imaging — which tested the use of sertraline in 309 medication-free patients. The multicenter trial was called Establishing Moderators and Biosignatures of Antidepressant Response for Clinical Care, or EMBARC. Led by Trivedi, it was designed to advance the goal of improving the trial-and-error method of treating depression that is still in use today.

“It often takes many steps for a patient with depression to get better,” Trivedi said. “We went into this thinking, ‘Wouldn’t it be better to identify at the beginning of treatment which treatments would be best for which patients?’”

Most common mental disorder

Major depression is the most common mental disorder in the United States, affecting about 7% of adults in 2017, according to the National Institute of Mental Health. Among those, about half never get diagnosed. For those who do, finding the right treatment can take years, Trivedi said. He pointed to one of his past studies that showed only about 30% of depressed patients saw any remission of symptoms after their first treatment with an antidepressant.

Amit Etkin

Amit Etkin

Current methods for diagnosing depression are simply too subjective and imprecise to guide clinicians in quickly identifying the right treatment, Etkin said. In addition to a variety of antidepressants, there are several other types of treatments for depression, including psychotherapy and brain stimulation, but figuring out which treatment will work for which patients is based on educated guessing. 

    

To diagnose depression, clinicians rely on a patient reporting at least 5 of 9 common symptoms of the disease. The list includes symptoms such as feelings of sadness or hopelessness, self-doubt, sleep disturbances — ranging from insomnia to sleeping too much — low energy, unexplained body aches, fatigue, and changes in appetite, ranging from overeating to undereating. Patients often vary in both the severity and types of symptoms they experience, Etkin said.

“As a psychiatrist, I know these patients differ a lot,” Etkin said. “But we put them all under the same umbrella, and we treat them all the same way.” Treating people with depression often begins with prescribing them an antidepressant. If one doesn’t work, a second antidepressant is prescribed. Each of these “trials” often takes at least eight weeks to assess whether the drug worked and symptoms are alleviated. If an antidepressant doesn’t work, other treatments, such as psychotherapy or occasionally transcranial magnetic stimulation, may also be tried. Often, multiple treatments are combined, Etkin said, but figuring out which combination works can take a while.

“People often feel a lot of dejection each time a treatment doesn’t work, creating more self-doubt for those whose primary symptom is most often self-doubt,” Trivedi said.

Looking for a biomarker

The EMBARC trial enrolled 309 people with depression who were randomized to receive either sertraline or a placebo.

For their study, Etkin and his colleagues set out to find a brain-wave pattern to help predict which depressed participants would respond to sertraline. First, the researchers collected EEG data on the participants before they received any drug treatment. The goal was to obtain a baseline measure of brain-wave patterns.

Next, using insights from neuroscience and bioengineering, the investigators analyzed the EEG using a novel artificial intelligence technique they developed and identified signatures in the data that predicted which participants would respond to treatment based on their individual EEG scans. The researchers found that this technique reliably predicted which of the patients did, in fact, respond to sertraline and which responded to placebo. The results were replicated at four different clinical sites.

Further research suggested that participants who were predicted to show little improvement with sertraline were more likely to respond to treatment involving transcranial magnetic stimulation, or TMS, in combination with psychotherapy.

“Using this method, we can characterize something about an individual person’s brain,” Etkin said. “It’s a method that can work across different types of EEG equipment, and thus more apt to reach the clinic.”

Etkin is on leave from Stanford, working as the founder and CEO of the startup Alto Neuroscience, a company based in Los Altos, California, that aims to build on these findings and develop a new generation of biologically based diagnostic tests to personalize mental health treatments with a high degree of clinical utility. “Part of getting these study results used in clinical care is, I think, that society has to demand it,” Trivedi said. “That is the way things get put into practice. I don’t see a downside to putting this into clinical use soon.”

Broad effort

When EMBARC was launched, it was part of a broader effort by the NIMH to push for improvements in mental health care by using advances in fields such as genetics, neuroscience and biotechnology, said Thomas Insel, MD, who served as director of that institute from 2002 to 2015.

“We went into EMBARC saying anything is possible,” Insel said. “Let’s see if we can come up with clinically actionable techniques.” He didn’t think it would take this long, but he remains optimistic.

“I think this study is a particularly interesting application of EMBARC,” he said. “It leverages the power of modern data science to predict at the individual level who is likely to respond to an antidepressant.”

In addition to improving care, the researchers said they see a possible side benefit to the use of biologically based approaches: It could reduce the stigma associated with depression and other mental health disorders that prevents many people from seeking appropriate medical care.

“I’d love to think scientific evidence will help to counteract this stigma, but it hasn’t so far,” said Insel. “It’s been over 160 years since Abraham Lincoln said that melancholy ‘is a misfortune, not a fault.’ We still have a long way to go before most people will understand that depression is not someone’s fault.” (President Lincoln suffered bouts of depression.)

Other Stanford co-authors of the paper are postdoctoral scholars Yu Zhang, PhD, and Jing Jiang, PhD; former postdoctoral scholar Gregory Fonzo, PhD; neuroscience graduate students Molly Lucas and Camarin Rolle; research assistants Carena Cornelssen and Kamron Sarhadi; clinical research coordinator Trevor Caudle; former clinical research coordinators Rachael Wright, Karen Monuszko and Hersh Trivedi; and former neuroscience graduate student Russell Toll. All Stanford authors, including Etkin, are affiliated with Veterans Affairs Palo Alto Healthcare System and the Sierra Pacific Mental Illness, Research, Education and Clinical Center in Palo Alto.

Etkin is a member of the Wu Tsai Neurosciences Institute at Stanford.

Researchers at South China University of Technology, the Netherlands Research Institute, Harvard Medical School, the New York State Psychiatric Institute, Columbia University and the Netherlands neuroCare Group also contributed to the work.

Insel is an investor in Alto Neuroscience.

The EMBARC study data are publicly available through the NIMH Data Archive.

The study was funded by the National Institutes of Health (U01MH092221, U01MH092250, R01MH103324, DP1 MH116506), the Stanford Neurosciences Institute, the Hersh Foundation, the National Key Research and Development Plan of China, and the National Natural Science Foundation of China.


Stanford Medicine integrates research, medical education and health care at its three institutions – Stanford University School of MedicineStanford Health Care (formerly Stanford Hospital & Clinics), and Lucile Packard Children’s Hospital Stanford. For more information, please visit the Office of Communication & Public Affairs site at http://mednews.stanford.edu.

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[WEB PAGE] The ABCs of CBD: Separating fact from fiction – NIH MedlinePlus Magazine

CBD. Cannabidiol. No matter what you call it, you may have heard health claims about this little-known part of the marijuana plant, which comes from the plant’s flowers. Some say it treats muscle aches, anxiety, sleeping troubles, chronic pain, and more.

But what does the science say?

We spoke to NIH expert Susan Weiss, Ph.D., to learn more and find out why consumers should be careful. Dr. Weiss is the director of the division of extramural research at the National Institute on Drug Abuse (NIDA).

What is CBD?

CBD (or cannabidiol) comes from the cannabis (or marijuana) plant.

The chemical compound THC [tetrahydrocannabinol] is the part of the cannabis plant that most people are familiar with because that is the part that makes people “high.” Most effects of marijuana that people think of are caused by THC.

Most recreational marijuana has very little CBD in it. CBD products are available through dispensaries, health food and convenience stores, and the internet. It’s a widely used product that’s not regulated—and is not legal to sell for its largely unproven health benefits.

How does CBD work?

Nobody really knows what is responsible for the mental and physical health benefits that have been attributed to it. CBD affects the body’s serotonin system, which controls our moods. It also affects several other signaling pathways, but we really don’t understand its mechanisms of action yet.

How much do we know about CBD as a potential treatment?

There are over 50 conditions that CBD is claimed to treat.

We do know that CBD can help control serious seizure disorders in some children (e.g., Dravet and Lennox-Gastaut syndromes) that don’t respond well to other treatments. Epidiolex is an FDA [Food and Drug Administration] approved medication containing CBD that can be used for this purpose.

There’s also data to suggest the potential of CBD as a treatment for schizophrenia and for substance use disorders. But these potential uses are in extremely early stages of development.

Are there side effects?

We don’t know of any severe side effects at this time. But there were mild side effects reported in the epilepsy studies, mostly gastrointestinal issues like diarrhea. There were also some reported drug-to-drug interactions. That’s why, for safety reasons, it’s important that CBD or any cannabis product go through the FDA review process.

Are there any specific CBD studies that you are focused on?

We are interested in CBD as a potential treatment of substance use disorders.

There is some research looking at it for opioid, tobacco, and alcohol use disorders. If CBD can help prevent relapse in those areas, that would be really interesting. We’re also interested in it for pain management. Trying to find less addictive medications for pain would help a lot of people.

What else would you like people to know?

Buyer beware.

We are concerned about the health claims being exaggerated or incorrect. The FDA issued warning letters to several companies because of untested health claims. And the CBD products themselves didn’t always contain the amount of CBD that they were reported to have—some actually had THC in them.

Another concern is that people are using CBD to treat ailments for which we have FDA-approved medications. Thus, they may be missing out on better treatments. And when they’re using CBD or other cannabis products for conditions we don’t know very much about, that’s worrisome.

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[Abstract + References] Therapeutic Drug Monitoring of Antiepileptic Drugs in Women with Epilepsy Before, During, and After Pregnancy – Review

Abstract

During pregnancy, the pharmacokinetics of an antiepileptic drug is altered because of changes in the clearance capacity and volume of distribution. These changes may have consequences for the frequency of seizures during pregnancy and fetal exposure to antiepileptic drugs. In 2009, a review was published providing guidance for the dosing and therapeutic drug monitoring of antiepileptic drugs during pregnancy. Since that review, new drugs have been licensed and new information about existing drugs has been published. With this review, we aim to provide an updated narrative overview of changes in the pharmacokinetics of antiepileptic drugs in women during pregnancy. In addition, we aim to formulate advice for dose modification and therapeutic drug monitoring of antiepileptic drugs. We searched PubMed and the available literature on the pharmacokinetic changes of antiepileptic drugs and seizure frequency during pregnancy published between January 2007 and September 2018. During pregnancy, an increase in clearance and a decrease in the concentrations of lamotrigine, levetiracetam, oxcarbazepine’s active metabolite licarbazepine, topiramate, and zonisamide were observed. Carbamazepine clearance remains unchanged during pregnancy. There is inadequate or no evidence for changes in the clearance or concentrations of clobazam and its active metabolite N-desmethylclobazam, gabapentin, lacosamide, perampanel, and valproate. Postpartum elimination rates of lamotrigine, levetiracetam, and licarbazepine resumed to pre-pregnancy values within the first few weeks after pregnancy. We advise monitoring of antiepileptic drug trough concentrations twice before pregnancy. This is the reference concentration. We also advise to consider dose adjustments guided by therapeutic drug monitoring during pregnancy if the antiepileptic drug concentration decreases 15–25% from the pre-pregnancy reference concentration, in the presence of risk factors for convulsions. If the antiepileptic drug concentration changes more than 25% compared with the reference concentration, dose adjustment is advised. Monitoring of levetiracetam, licarbazepine, lamotrigine, and topiramate is recommended during and after pregnancy. Monitoring of clobazam, N-desmethylclobazam, gabapentin, lacosamide, perampanel, and zonisamide during and after pregnancy should be considered. Because of the risk of teratogenic effects, valproate should be avoided during pregnancy. If that is impossible, monitoring of both total and unbound valproate is recommended. More research is needed on the large number of unclear pregnancy-related effects on the pharmacokinetics of antiepileptic drugs.

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[ARTICLE] Endocannabinoids: A Promising Impact for Traumatic Brain Injury – Full Text

Abstract

The endogenous cannabinoid (endocannabinoid) system regulates a diverse array of physiological processes and unsurprisingly possesses considerable potential targets for the potential treatment of numerous disease states, including two receptors (i.e., CB1 and CB2 receptors) and enzymes regulating their endogenous ligands N-arachidonoylethanolamine (anandamide) and 2-arachidonyl glycerol (2-AG). Increases in brain levels of endocannabinoids to pathogenic events suggest this system plays a role in compensatory repair mechanisms. Traumatic brain injury (TBI) pathology remains mostly refractory to currently available drugs, perhaps due to its heterogeneous nature in etiology, clinical presentation, and severity. Here, we review pre-clinical studies assessing the therapeutic potential of cannabinoids and manipulations of the endocannabinoid system to ameliorate TBI pathology. Specifically, manipulations of endocannabinoid degradative enzymes (e.g., fatty acid amide hydrolase, monoacylglycerol lipase, and α/β-hydrolase domain-6), CB1 and CB2 receptors, and their endogenous ligands have shown promise in modulating cellular and molecular hallmarks of TBI pathology such as; cell death, excitotoxicity, neuroinflammation, cerebrovascular breakdown, and cell structure and remodeling. TBI-induced behavioral deficits, such as learning and memory, neurological motor impairments, post-traumatic convulsions or seizures, and anxiety also respond to manipulations of the endocannabinoid system. As such, the endocannabinoid system possesses potential drugable receptor and enzyme targets for the treatment of diverse TBI pathology. Yet, full characterization of TBI-induced changes in endocannabinoid ligands, enzymes, and receptor populations will be important to understand that role this system plays in TBI pathology. Promising classes of compounds, such as the plant-derived phytocannabinoids, synthetic cannabinoids, and endocannabinoids, as well as their non-cannabinoid receptor targets, such as TRPV1 receptors, represent important areas of basic research and potential therapeutic interest to treat TBI.

 

Introduction

Traumatic brain injury accounts for approximately 10 million deaths and/or hospitalizations annually in the world, and approximately 1.5 million annual emergency room visits and hospitalizations in the US (). Young men are consistently over-represented as being at greatest risk for TBI (). While half of all traumatic deaths in the USA are due to brain injury (), the majority of head injuries are considered mild and often never receive medical treatment (). Survivors of TBI are at risk for lowered life expectancy, dying at a 3⋅2 times more rapid rate than the general population (). Survivors also face long term physical, cognitive, and psychological disorders that greatly diminish quality of life. Even so-called mild TBI without notable cell death may lead to enduring cognitive deficits (). A 2007 study estimated that TBI results in $330,827 of average lifetime costs associated with disability and lost productivity, and greatly outweighs the $65,504 estimated costs for initial medical care and rehabilitation (), demonstrating both the long term financial and human toll of TBI.

The development of management protocols in major trauma centers () has improved mortality and functional outcomes (). Monitoring of intracranial pressure is now standard practice (), and advanced MRI technologies help define the extent of brain injury in some cases (). Current treatment of major TBI is primarily managed through surgical intervention by decompressive craniotomy () which involves the removal of skull segments to reduce intracranial pressure. Delayed decompressive craniotomy is also increasingly used for intractable intracranial hypertension (). The craniotomy procedure is associated with considerable complications, such as hematoma, subdural hygroma, and hydrocephalus (). At present, the pathology associated with TBI remains refractive to currently available pharmacotherapies () and as such represents an area of great research interest and in need of new potential targets. Effective TBI drug therapies have yet to be proven, despite promising preclinical data () plagued by translational problems once reaching clinical trials ().

The many biochemical events that occur in the hours and months following TBI have yielded preclinical studies directed toward a single injury mechanism. However, an underlying premise of the present review is an important need to address the multiple targets associated with secondary injury cascades following TBI. A growing body of published scientific research indicates that the endogenous cannabinoid (endocannabinoid; eCB) system possesses several targets uniquely positioned to modulate several key secondary events associated with TBI. Here, we review the preclinical work examining the roles that the different components of the eCB system play in ameliorating pathologies associated with TBI.

The Endocannabinoid (eCB) System

Originally, “Cannabinoid” was the collective name assigned to the set of naturally occurring aromatic hydrocarbon compounds in the Cannabis sativa plant (). Cannabinoid now more generally refers to a much more broad set of chemicals of diverse structure whose pharmacological actions or structure closely mimic that of plant-derived cannabinoids. Three predominant categories are currently in use; plant-derived phytocannabinoids (reviewed in ), synthetically produced cannabinoids used as research () or recreational drugs (), and the endogenous cannabinoids, N-arachidonoylethanolamine (anandamide) () and 2-AG ().

These three broad categories of cannabinoids generally act through cannabinoid receptors, two types of which have so far been identified, CB1 () and CB2 (). Both CB1 and CB2 receptors are coupled to signaling cascades predominantly through Gi/o-coupled proteins. CB1 receptors mediate most of the psychomimetic effects of cannabis, its chief psychoactive constituent THC, and many other CNS active cannabinoids. These receptors are predominantly expressed on pre-synaptic axon terminals (), are activated by endogenous cannabinoids that function as retrograde messengers, which are released from post-synaptic cells, and their activation ultimately dampens pre-synaptic neurotransmitter release (). Acting as a neuromodulatory network, the outcome of cannabinoid receptor signaling depends on cell type and location. CB1 receptors are highly expressed on neurons in the central nervous system (CNS) in areas such as cerebral cortex, hippocampus, caudate-putamen (). In contrast, CB2 receptors are predominantly expressed on immune cells, microglia in the CNS, and macrophages, monocytes, CD4+ and CD8+ T cells, and B cells in the periphery (). Additionally, CB2 receptors are expressed on neurons, but to a much less extent than CB1 receptors (). The abundant, yet heterogeneous, distribution of CB1 and CB2 receptors throughout the brain and periphery likely accounts for their ability to impact a wide variety of physiological and psychological processes (e.g., memory, anxiety, and pain perception, reviewed in ) many of which are impacted following TBI.

Another unique property of the eCB system is the functional selectivity produced by its endogenous ligands. Traditional neurotransmitter systems elicit differential activation of signaling pathways through activation of receptor subtypes by one neurotransmitter (). However, it is the endogenous ligands of eCB receptors which produce such signaling specificity. Although several endogenous cannabinoids have been described () the two most studied are anandamide () and 2-AG (). 2-AG levels are three orders of magnitude higher than those of anandamide in brain (). Additionally, their receptor affinity () and efficacy differ, with 2-AG acting as a high efficacy agonist at CB1 and CB2 receptors, while anandamide behaves as a partial agonist (). In addition, anandamide binds and activates TRPV1 receptors (), whereas 2-AG also binds GABAA receptors (). As such, cannabinoid ligands differentially modulate similar physiological and pathological processes.

Distinct sets of enzymes, which regulate the biosynthesis and degradation of the eCBs and possess distinct anatomical distributions (see Figure Figure11), exert control over CB1 and CB2 receptor signaling. Inactivation of anandamide occurs predominantly through FAAH (), localized to intracellular membranes of postsynaptic somata and dendrites (), in areas such as the neocortex, cerebellar cortex, and hippocampus (). Inactivation of 2-AG proceeds primarily via MAGL (), expressed on presynaptic axon terminals (), and demonstrates highest expression in areas such as the thalamus, hippocampus, cortex, and cerebellum (). The availability of pharmacological inhibitors for eCB catabolic enzymes has allowed the selective amplification of anandamide and 2-AG levels following brain injury as a key strategy to enhance eCB signaling and to investigate their potential neuroprotective effects.

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FIGURE 1
Endocannabinoid system cell localization by CNS cell type. Endocannabinoid functional specialization among CNS cell types is determined by the cellular compartmentalization of biosynthetic and catabolic enzymes (biosynthesis by NAPE and DAGL-α, -β, catabolism by FAAH and MAGL). Cellular level changes in eCB biosynthetic and catabolic enzymes as a result of brain injury have yet to be investigated, though morphological and molecular reactivity by cell type is well documented.

[…]

 

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[Abstract] Exploratory Randomized Double-Blind Placebo-Controlled Trial of Botulinum Therapy on Grasp Release After Stroke (PrOMBiS)

Background. OnabotulinumtoxinA injections improve upper-limb spasticity after stroke, but their effect on arm function remains uncertain.

Objective. To determine whether a single treatment with onabotulinumtoxinA injections combined with upper-limb physiotherapy improves grasp release compared with physiotherapy alone after stroke.

Methods. A total of 28 patients, at least 1 month poststroke, were randomized to receive either onabotulinumtoxinA or placebo injections to the affected upper limb followed by standardized upper-limb physiotherapy (10 sessions over 4 weeks). The primary outcome was time to release grasp during a functionally relevant standardized task. Secondary outcomes included measures of wrist and finger spasticity and strength using a customized servomotor, clinical assessments of stiffness (modified Ashworth Scale), arm function (Action Research Arm Test [ARAT], Nine Hole Peg Test), arm use (Arm Measure of Activity), Goal Attainment Scale, and quality of life (EQ5D).

Results. There was no significant difference between treatment groups in grasp release time 5 weeks post injection (placebo median = 3.0 s, treatment median = 2.0 s; t(24) = 1.20; P = .24; treatment effect = −0.44, 95% CI = −1.19 to 0.31). None of the secondary measures passed significance after correcting for multiple comparisons. Both groups achieved their treatment goals (placebo = 65%; treatment = 71%), and made improvements on the ARAT (placebo +3, treatment +5) and in active wrist extension (placebo +9°, treatment +11°).

Conclusions. In this group of stroke patients with mild to moderate spastic hemiparesis, a single treatment with onabotulinumtoxinA did not augment the improvements seen in grasp release time after a standardized upper-limb physiotherapy program.

 

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