At present, none of the neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease and stroke are treatable with compounds that slow or halt neuronal cell death. However, the prototype nitrone radical trap alpha-phenyl-tert-butylnitrone (PBN) has been shown to be an effective neuroprotective agent in various models of neurodegeneration. Some of these data are briefly reviewed as an introduction to an examination of the effect of the novel nitrone radical trapping agent disodium 2,4-disulfophenyl-N-tert-butylnitrone (NXY-059) in various animal models of stroke. NXY-059 has been shown to be an effective neuroprotective agent in both transient (reperfusion) and permanent focal ischaemia models in rats. In both types of model, NXY-059 has a large window of opportunity, providing effective neuroprotection when given up to 5 hours after the start of the occlusion in transient ischaemia and 4 hours after the start of permanent ischaemia. The compound is also effective in a marmoset permanent ischaemia model when administered up to 4 hours after the start of the occlusion. In this model it has been found to attenuate the problem of spatial neglect and maintain function to the paretic arm. NXY-059 administration also improves motor function in a rat haemorrhagic stroke model and has a neuroprotective effect in a rabbit thromboembolic stroke model. The compound is also well tolerated in stroke patients at plasma levels shown to provide a maximum neuroprotective effect in animal models of stroke.NXY-059, like PBN, is a nitrone with free radical trapping properties and this may be the basis of its neuroprotective action. However, experiments with PBN and NXY-059 suggest the possibility of other mechanisms being involved and these are also reviewed. Further experiments are required to fully elucidate the mechanism of action of these very effective neuroprotective agents.
Clobazam was initially developed in the early 1970s as a nonsedative anxiolytic agent, and is currently available as adjunctive therapy for epilepsy and anxiety disorders in more than 100 countries. In October 2011, clobazam (Onfi™; Lundbeck Inc., Deerfield, IL, USA) was approved by the US FDA for use as adjunctive therapy for the treatment of seizures associated with Lennox-Gastaut syndrome in patients aged 2 years and older. It is a long-acting 1,5-benzodiazepine whose structure distinguishes it from the classic 1,4-benzodiazepines, such as diazepam, lorazepam and clonazepam. Clobazam is well absorbed, with peak concentrations occurring linearly 1-4 hours after administration. Both clobazam and its active metabolite, N-desmethylclobazam, are metabolized in the liver via the cytochrome P450 pathway. The mean half-life of N-desmethylclobazam (67.5 hours) is nearly double the mean half-life of clobazam (37.5 hours). Clobazam was synthesized with the anticipation that its distinct chemical structure would provide greater efficacy with fewer benzodiazepine-associated adverse effects. Frequently reported adverse effects of clobazam therapy include dizziness, sedation, drowsiness and ataxia. Evidence gathered from approximately 50 epilepsy clinical trials in adults and children indicated that the sedative effects observed with clobazam treatment were less severe than those reported with 1,4-benzodiazepines. In several studies of healthy volunteers and patients with anxiety, clobazam appeared to enhance participants' performance in cognitive tests, further distinguishing it from the 1,4-benzodiazepines. The anxiolytic and anticonvulsant effects of clobazam are associated with allosteric activation of the ligand-gated GABA(A) receptor. GABA(A) receptors are found extensively throughout the CNS, occurring synaptically and extrasynaptically. GABA(A) receptors are composed of five protein subunits, two copies of a single type of α subunit, two copies of one type of β subunit and a γ subunit. This arrangement results in a diverse assortment of receptor subtypes. As benzodiazepine pharmacology is influenced by differences in affinity for particular GABA(A) subtypes, characterizing the selectivity of different benzodiazepines is a promising avenue for establishing appropriate use of these agents in neurological disorders. Molecular techniques have significantly advanced since the inception of clobazam as a clinical agent, adding to the understanding of the GABA(A) receptor, its subunits and benzodiazepine pharmacology. Transgenic mouse models have been particularly useful in this regard. Comparative studies between transgenic and wild-type mice have further defined relationships between GABA(A) receptor composition and drug effects. From such studies, we have learned that sedating and amnesic effects are mediated by the GABA(A) α(1) subunit, α(2) receptors mediate anxiolytic effects, α subunits are involved with anticonvulsant activity, α(5) may be implicated in learning and memory, and β(3) subunit deficiency decreases GABA inhibition. Despite progress in determining the role of various subunits to specific benzodiazepine pharmacological actions, the precise mechanism of action of clobazam, and more importantly, how that mechanism of action translates into clinical consequences (i.e. efficacy, tolerability and safety) remain unknown. Testing clobazam and 1,4-benzodiazepines using a range of recombinant GABA(A) receptor subtypes would hopefully elucidate the subunits involved and strengthen our understanding of clobazam and its mechanism of action.
Glatiramer acetate is a US FDA category B drug with regard to use by pregnant women with multiple sclerosis (MS). There are no data currently available for the continuous use of glatiramer acetate during pregnancy.
To assess the risks and benefits of glatiramer acetate used throughout pregnancy among women with active MS.
Retrospective and multicentre case series.
Outpatient services of academic and private institutions caring for patients with MS in Brazil.
Eleven women with MS and their children were assessed.
Retrospective evaluation of women with MS who received glatiramer acetate continuously for at least 7 months during pregnancy. This evaluation was performed by the neurologist responsible for the patient. Children aged 1 year and over, born to mothers who received glatiramer acetate during pregnancy, were assessed using the Denver II developmental screening test.
Obstetric, neonatal and developmental outcomes.
No drug-related obstetric complications were observed. No specific drug-related malformations, neonatal complications or developmental abnormalities were observed in the children. Postnatal MS relapse rates remained significantly lower than antenatal rates in these patients.
No deleterious effects from glatiramer acetate were observed in these pregnant women with MS or in their offspring. No increment in postnatal relapse rate was observed. However, the use of glatiramer acetate during pregnancy should be restricted to the most difficult cases, in which the benefits clearly outweigh the risks.
Neuroprotective therapies for acute ischaemic stroke have yet to be realised despite the determined efforts of basic science and clinical investigators. Progressive elucidation of the complex pathophysiology involved in the ischaemic cascade has led to the development of numerous candidate interventions. Preliminary efficacy in animal models has repeatedly resulted in frustration after extensive clinical testing. Failure in the translation of results from animal models to humans implicates potential limitations of the current drug development process. Reflection on prior studies suggests possible flaws at several stages. Incorporation of standardised guidelines for preclinical testing of putative neuroprotective therapies and modification of clinical trial design, methodology and reporting may improve chances for success. The future of neuroprotection for stroke remains bright in spite of previous disappointments.
The major psychoactive constituent of Cannabis sativa, Δ9-tetrahydrocannabinol (Δ9-THC), and endogenous cannabinoid ligands, such as anandamide, signal through G-protein-coupled cannabinoid receptors localised to regions of the brain associated with important neurological processes. Signalling is mostly inhibitory and suggests a role for cannabinoids as therapeutic agents in CNS disease where inhibition of neurotransmitter release would be beneficial.
Anecdotal evidence suggests that patients with disorders such as multiple sclerosis smoke cannabis to relieve disease-related symptoms. Cannabinoids can alleviate tremor and spasticity in animal models of multiple sclerosis, and clinical trials of the use of these compounds for these symptoms are in progress. The cannabinoid nabilone is currently licensed for use as an antiemetic agent in chemotherapy-induced emesis. Evidence suggests that cannabinoids may prove useful in Parkinson’s disease by inhibiting the excitotoxic neurotransmitter glutamate and counteracting oxidative damage to dopaminergic neurons. The inhibitory effect of cannabinoids on reactive oxygen species, glutamate and tumour necrosis factor suggests that they may be potent neuroprotective agents. Dexanabinol (HU-211), a synthetic cannabinoid, is currently being assessed in clinical trials for traumatic brain injury and stroke. Animal models of mechanical, thermal and noxious pain suggest that cannabinoids may be effective analgesics. Indeed, in clinical trials of postoperative and cancer pain and pain associated with spinal cord injury, cannabinoids have proven more effective than placebo but may be less effective than existing therapies. Dronabinol, a commercially available form of Δ9-THC, has been used successfully for increasing appetite in patients with HIV wasting disease, and cannabinoid receptor antagonists may reduce obesity.
Acute adverse effects following cannabis usage include sedation and anxiety. These effects are usually transient and may be less severe than those that occur with existing therapeutic agents. The use of nonpsychoactive cannabinoids such as cannabidiol and dexanabinol may allow the dissociation of unwanted psychoactive effects from potential therapeutic benefits. The existence of other cannabinoid receptors may provide novel therapeutic targets that are independent of CB1 receptors (at which most currently available cannabinoids act) and the development of compounds that are not associated with CB1 receptor-mediated adverse effects. Further understanding of the most appropriate route of delivery and the pharmacokinetics of agents that act via the endocannabinoid system may also reduce adverse effects and increase the efficacy of cannabinoid treatment.
This review highlights recent advances in understanding of the endocannabinoid system and indicates CNS disorders that may benefit from the therapeutic effects of cannabinoid treatment. Where applicable, reference is made to ongoing clinical trials of cannabinoids to alleviate symptoms of these disorders.
Parkinson's disease is the second most common age-related neurodegenerative disorder, typified by the progressive loss of substantia nigra pars compacta dopamine neurons and the consequent decrease in the neurotransmitter dopamine. Patients exhibit a range of clinical symptoms, with the most common affecting motor function and including resting tremor, rigidity, akinesia, bradykinesia and postural instability. Current pharmacological interventions are palliative and largely aimed at increasing dopamine levels through increased production and/or inhibition of metabolism of this key neurotransmitter. The gold standard for treatment of both familial and sporadic Parkinson's disease is the peripheral administration of the dopamine precursor, levodopa. However, many patients gradually develop levodopa-induced dyskinesias and motor fluctuations. In addition, dopamine enhancement therapies are most useful when a portion of the nigrostriatal pathway is intact. Consequently, as the number of substantia nigra dopamine neurons and striatal projections decrease, these treatments become less efficacious. Current translational research is focused on the development of novel disease-modifying therapies, including those utilizing gene therapeutic approaches. Herein we present an overview of current gene therapy clinical trials for Parkinson's disease. Employing either recombinant adeno-associated virus type 2 (rAAV2) or lentivirus vectors, these clinical trials are focused on three overarching approaches: augmentation of dopamine levels via increased neurotransmitter production; modulation of the neuronal phenotype; and neuroprotection. The first two therapies discussed in this article focus on increasing dopamine production via direct delivery of genes involved in neurotransmitter synthesis (amino acid decarboxylase, tyrosine hydroxylase and GTP [guanosine triphosphate] cyclohydrolase 1). In an attempt to bypass the degenerating nigrostriatal pathway, a third clinical trial utilizes rAAV2 to deliver glutamic acid decarboxylase to the subthalamic nucleus, converting a subset of excitatory neurons to GABA-producing cells. In contrast, the final clinical trial is aimed at protecting the degenerating nigrostriatum by striatal delivery of rAAV2 harbouring the neuroprotective gene, neurturin. Based on preclinical studies, this gene therapeutic approach is posited to slow disease progression by enhancing neuronal survival. In addition, we discuss the outcome of each clinical trial and discuss the potential rationale for the marginal yet incremental clinical advancements that have thus far been realized for Parkinson's disease gene therapy.
Bipolar patients with comorbid substance abuse or dependence (‘dual diagnosis’ patients) represent a major public health problem. Substance abuse generally predicts poor outcome and higher morbidity/mortality in bipolar disorder. For the purposes of this review, open and controlled studies of dual diagnosis assessment and treatment were located through electronic searches of several databases. Pertinent case reports were also evaluated. The results of the search were evaluated in light of the authors’ own research on dual diagnosis patients.
Literature searching revealed few controlled studies to guide pharmacotherapy of bipolar patients with comorbid substance abuse or dependence. However, preliminary evidence suggests that the best outcomes are usually achieved with antiepileptic mood stabilisers and/or atypical antipsychotics, combined with appropriate psychosocial interventions. The latter may include classical 12-step groups, integrated group therapy or individual psychotherapy. While it is often difficult to determine the precise pathway to comorbid bipolar disorder/substance abuse, it is clear that both disorders must be vigorously treated. This requires a carefully integrated biopsychosocial approach, involving appropriate mood stabilisers and psychosocial interventions. Many more controlled studies of these combined treatment approaches are needed.
The use of anabolic androgenic steroids (AAS) for gains in strength and muscle mass is relatively common among certain subpopulations, including athletes, bodybuilders, adolescents and young adults. Adverse physical effects associated with steroid abuse are well documented, but more recently, increased attention has been given to the adverse psychiatric effects of these compounds. Steroids may be used in oral, 17alpha-alkylated, or intramuscular, 17beta-esterified, preparations. Commonly, steroid users employ these agents at levels 10- to 100-fold in excess of therapeutic doses and use multiple steroids simultaneously, a practice known as 'stacking'. Significant psychiatric symptoms including aggression and violence, mania, and less frequently psychosis and suicide have been associated with steroid abuse. Long-term steroid abusers may develop symptoms of dependence and withdrawal on discontinuation of AAS. Treatment of AAS abusers should address both acute physical and behavioural symptoms as well as long-term abstinence and recovery. To date, limited information is available regarding specific pharmacological treatments for individuals recovering from steroid abuse. This paper reviews the published literature concerning the recognition and treatment of behavioural manifestations of AAS abuse.
Acamprosate is an abstinence-promoting drug widely used in the treatment of alcohol dependence but which has a mechanism of action that has remained obscure for many years. Recently, evidence has emerged that this drug may interact with excitatory glutamatergic neurotransmission in general and as an antagonist of the metabotropic glutamate receptor subtype 5 (mGluR5) in particular. These findings provide, for the first time, a satisfactory, unifying hypothesis that can bring together and explain the diverse neurochemical effects of acamprosate. Glutamic acid is involved in several aspects of alcohol dependence and withdrawal, many of which can be modified by acamprosate. For example, during chronic exposure to alcohol, the glutamatergic system becomes upregulated, leaving the brain exposed to excessive glutamatergic activity when alcohol is abruptly withdrawn. The surge in glutamic acid release that occurs following alcohol withdrawal can be attenuated by acamprosate. The elevated extracellular levels of glutamic acid observed in withdrawal, together with supersensitivity of NMDA receptors, may expose vulnerable neurons to excitotoxicity, possibly contributing to the neuronal loss sometimes observed in chronic alcohol dependence. In vitro studies suggest that the excitotoxicity produced by ethanol can effectively be blocked by acamprosate. Moreover, glutamatergic neurotransmission plays an important role in the acquisition of cue-elicited drinking behaviours, which again can be modulated by acamprosate. In conclusion, the glutamatergic hypothesis of the mechanism of action of acamprosate helps explain many of its effects in human alcohol dependence and points the way to potential new activities, such as neuroprotection, that merit exploration in the clinic.
Peginterferon beta-1a (Plegridy™), an interferon beta-1a conjugated to a methoxy polyethylene glycol (PEG) molecule, is available in the EU and the USA for the treatment of adults with relapsing-remitting multiple sclerosis (RRMS). In a 96-week multinational, phase III study in this patient population (ADVANCE), subcutaneous peginterferon beta-1a 125 µg every 2 weeks significantly reduced the adjusted annualized relapse rate over 48 weeks, compared with placebo, corresponding to 36 % fewer relapses per patient-year. Significant reductions versus placebo were also observed in the risk of relapse and disability progression, the number of new or newly enlarging T2-weighted hyperintense lesions, and various other magnetic resonance imaging endpoints. The efficacy of peginterferon beta-1a was sustained over 96 weeks, with preliminary data from the first year of an ongoing 2-year extension of ADVANCE indicating continued benefit longer-term. In ADVANCE, peginterferon beta-1a had an acceptable tolerability profile that was consistent with that of established interferon beta treatments. Adverse events were generally mild or moderate in severity, with injection-site erythema and influenza-like illness reported most commonly. Amongst other adverse events of special interest, peginterferon beta-1a was not associated with an increased risk of autoimmune disorders, depression/suicidal ideation, infections or seizures. In the absence of head-to-head studies, definitive conclusions on the comparative efficacy and tolerability of peginterferon beta-1a versus existing therapies are not yet possible. Although final data from the extension of ADVANCE are awaited, current evidence suggests subcutaneous peginterferon beta-1a every 2 weeks extends the treatment options currently available for adults with RRMS, with the dosing regimen imparting potential compliance advantages over non-PEGylated interferon beta formulations that require more frequent administration.
Achieving optimal patient benefit from biological therapies can be hindered by drug instability, rapid clearance requiring frequent dosing or potential immune reactions. One strategy for addressing these challenges is drug modification through PEGylation, a well established process by which one or more molecules of polyethylene glycol (PEG) are covalently attached to a biological or small-molecule drug, effectively transforming it into a therapy with improved pharmacokinetic and pharmacodynamic properties. Numerous PEGylated therapeutics are currently available, all of which have at least comparable efficacy, safety and tolerability to their unmodified forms. A PEGylated form of interferon-β-1a (PEG-IFNβ-1a) is being developed to address an unmet medical need for safer, more effective and more convenient therapies for multiple sclerosis (MS). Phase I study data suggest that PEG-IFNβ-1a should provide patients with a first-line therapy with a more convenient dosing regimen while maintaining the established efficacy, safety and tolerability of presently available IFNβ-1a. The ongoing global ADVANCE phase III study will determine the clinical efficacy of PEG-IFNβ-1a in patients with relapsing MS.
Objective:
The aim of the study was to compare the cost effectiveness of fingolimod, teriflunomide, dimethyl fumarate, and intramuscular (IM) interferon (IFN)-β(1a) as first-line therapies in the treatment of patients with relapsing-remitting multiple sclerosis (RRMS).
Methods:
A Markov model was developed to evaluate the cost effectiveness of disease-modifying drugs (DMDs) from a US societal perspective. The time horizon in the base case was 5 years. The primary outcome was incremental net monetary benefit (INMB), and the secondary outcome was incremental cost-effectiveness ratio (ICER). The base case INMB willingness-to-pay (WTP) threshold was assumed to be US$150,000 per quality-adjusted life year (QALY), and the costs were in 2012 US dollars. One-way sensitivity analyses and probabilistic sensitivity analysis were conducted to test the robustness of the model results.
Results:
Dimethyl fumarate dominated all other therapies over the range of WTPs, from US$0 to US$180,000. Compared with IM IFN-β(1a), at a WTP of US$150,000, INMBs were estimated at US$36,567, US$49,780, and US$80,611 for fingolimod, teriflunomide, and dimethyl fumarate, respectively. The ICER of fingolimod versus teriflunomide was US$3,201,672. One-way sensitivity analyses demonstrated the model results were sensitive to the acquisition costs of DMDs and the time horizon, but in most scenarios, cost-effectiveness rankings remained stable. Probabilistic sensitivity analysis showed that for more than 90% of the simulations, dimethyl fumarate was the optimal therapy across all WTP values.
Conclusion:
The three oral therapies were favored in the cost-effectiveness analysis. Of the four DMDs, dimethyl fumarate was a dominant therapy to manage RRMS. Apart from dimethyl fumarate, teriflunomide was the most cost-effective therapy compared with IM IFN-β(1a), with an ICER of US$7,115.
Intramuscular interferon-beta-1a, a recombinant interferon-beta approved in the US for the treatment of relapsing forms of multiple sclerosis (MS), has also been evaluated in the treatment of patients with a first clinical demyelinating episode and brain lesions consistent with MS confirmed by magnetic resonance imaging (MRI). In a randomised, double-blind trial, patients at high risk of developing clinically definite MS who received intramuscular interferon-beta-1a 30 microg once weekly had a 44% reduction in the cumulative probability of developing MS, compared with placebo recipients (rate ratio 0.56; p = 0.002), over a 3-year period after a first, MRI-confirmed demyelinating event. These results were supported by MRI findings that showed significantly smaller increases in the volume of brain lesions and the number of new/enlarging and gadolinium-enhancing lesions in interferon-beta-1a recipients than in those receiving placebo. A nonblind extension of this trial demonstrated that early treatment with interferon-beta-1a significantly reduced the probability of developing MS by 35% (p = 0.03), compared with delayed treatment, over a 5-year period. Intramuscular interferon-beta-1a was generally well tolerated; however, influenza-like syndrome was documented in >50% of patients at high risk of developing clinically definite MS who received the drug.
The new formulation of subcutaneous interferon-beta-1a was developed without serum-derived components with the aim of improving immunogenicity and injection tolerability in patients with relapsing forms of multiple sclerosis (MS). In a prospectively defined interim analysis at 48 weeks of an ongoing, single-arm, phase IIIb trial, 13.9% of MS patients receiving the new formulation of subcutaneous interferon-beta-1a 44 microg three times weekly had developed neutralising antibodies (NAbs). In the EVIDENCE trial, which served as an historical control, 24.4% of patients receiving the same dosage of the current formulation had developed NAbs at 48 weeks. The new formulation demonstrated similar pharmacokinetic activity to that of the current formulation in a phase I, double-blind, placebo-controlled study in healthy volunteers. About two-thirds of patients with MS who received the new formulation of subcutaneous interferon-beta-1a were relapse free in the interim, 48-week analysis of the single-arm trial; this is similar to results for the current formulation from historical data. A comparison of results from the interim, 48-week analysis with historical-control data from the EVIDENCE trial indicates that the new formulation of interferon-beta-1a may be associated with a lower incidence of injection-site reactions and a higher incidence of influenza-like symptoms than the current formulation. Adverse events associated with the new formulation were mostly mild to moderate in severity
Interferon-β-1b has been used as a disease-modifying therapy in multiple sclerosis (MS) for many years. Although its mechanism of action in MS has not been fully elucidated, it appears to involve immunomodulatory effects mediated by interactions with specific receptors.
Large, randomized, multicentre, clinical trials of 2–3.5 years’ duration have demonstrated the efficacy of interferon-β-1b 250 μg subcutaneously every other day in patients with a first clinical event suggestive of MS (i.e. those with clinically isolated syndrome [CIS]) and in those with relapsing-remitting MS (RRMS). In terms of its efficacy on primary (or co-primary) endpoints, interferon-β-1b significantly reduced the risk of developing clinically definite MS compared with placebo in patients with CIS in the BENEFIT study. In patients with RRMS, interferon-β-1b was associated with a significantly lower annualized relapse rate and a significantly higher proportion of relapse-free patients compared with placebo in a registration trial conducted by the Interferon-β MS Study Group. The INCOMIN trial in patients with RRMS showed a significant advantage of interferon-β-1b over intramuscular interferon-β-1a in terms of the percentage of relapse- and progression-free patients and the proportion of patients without new MRI-documented lesions. Other active-comparator trials in RRMS used a variety of primary (or co-primary) endpoints and showed no significant differences between interferon-β-1b and either subcutaneous glatiramer acetate (BECOME and BEYOND trials) or subcutaneous interferon-β-1a (Danish MS Group trial) for these outcomes.
In patients with secondary progressive MS (SPMS), the European Study Group showed that interferon-β-1b significantly increased the time to confirmed disease progression compared with placebo, although there was no significant between-group difference for this primary endpoint in a similar trial conducted by the North American Study Group. The studies allowed inclusion of patients with superimposed relapse, and both trials showed a significant reduction in annualized relapse rate with interferon-β-1b.
The most frequently reported adverse events with interferon-β-1b are flu-like symptoms and injection-site reactions, which can usually be managed. The incidence of these adverse events generally declines markedly after the first year of treatment. Lymphopenia is the most frequently reported laboratory abnormality and occurs in the majority of patients. Depression, suicidal ideation and injectionsite necrosis were the most serious adverse events reported with interferon-β-1b in clinical trials. Long-term safety data over a 16-year follow-up period showed no unexpected adverse events among patients treated with interferon-β-1b.
Thus, interferon-β-1b is a well established, first-line, disease-modifying therapy that has demonstrated efficacy in newly emerging MS, RRMS and SPMS with superimposed relapse in well designed clinical trials, and has a generally manageable tolerability profile, with no unexpected adverse events after many years of follow-up.
The mechanism of action of interferon-β-1b in multiple sclerosis (MS) is not clearly understood, but is thought to involve immunoregulatory activities, including enhancing the suppressor activity of peripheral blood mononuclear cells.
▴ In the planned 3-year analysis of the BENEFIT study in patients with a single clinical event suggestive of MS, the relative risk of clinically definite (CD) MS was reduced by 41% in those receiving interferon-β-1b 250 μg every other day for 3 years (early-treatment group) compared with patients who were initially randomized to placebo then switched to interferon-β-1b 250 μg every other day at the end of 2 years or at the onset of CDMS (delayed-treatment group) [p < 0.01].
▴ The relative risk of confirmed progression of the expanded disability status scale (EDSS) was reduced by 40% in the early-treatment group compared with the delayed-treatment group over 3 years (p < 0.05).
▴ At the end of the 2-year, randomized, placebo-controlled period of the BENEFIT study, the risk of developing CDMS (p < 0.0001) and McDonald-defined MS (p < 0.00001) was significantly lower in the interferon-β-1b group than in the placebo group, and in the magnetic resonance imaging analysis, fewer newly active lesions developed in the interferon-β-1b group (p < 0.001).
▴ Interferon-β-1b was generally well tolerated. In the 3-year BENEFIT study, neutralizing activity, which was reported in about one-third of the early-treatment group, had no effect on outcome.
Interferon-beta-1b (Betaseron, Betaferon) is a non-glycosylated recombinant human interferon-beta approved for high-frequency, subcutaneous (SC) administration in the treatment of multiple sclerosis (MS). Its mechanism of action is unknown, but may involve modulation of the autoimmune pathogenic processes of MS. In a randomised, double-blind trial in patients with relapsing-remitting MS (RRMS), SC interferon-beta-1b 250 micro g (8 million International Units [MIU]) every other day reduced the annual relapse rate and increased the proportion of relapse-free patients compared with placebo. It also reduced relapse severity, hospitalisations, and disease activity assessed by magnetic resonance imaging (MRI), and increased the time to first relapse. Progression of disability showed a trend towards reduction relative to placebo and baseline, but did not reach statistical significance. SC interferon-beta-1b 250 micro g every other day was shown in a randomised trial to be superior to intramuscular (IM) interferon-beta-1a 30 micro g (6 MIU) once weekly with respect to reductions in relapse-related parameters, disability progression and MRI-assessed disease activity. In patients with secondary progressive MS (SPMS), SC interferon-beta-1b 250 micro g every other day slowed progression of the disease relative to placebo in one randomised, double-blind trial, but not in another. In both studies, interferon-beta-1b 250 micro g recipients had fewer relapses and less MRI-assessed disease activity than placebo recipients. The difference in primary outcome may reflect differences in patient entry criteria. Interferon-beta-1b is generally well tolerated and the common adverse events (e.g. injection site reactions, asthenia and an influenza-like symptom complex) are clinically manageable. In a randomised trial, the tolerability of SC interferon-beta-1b 250 micro g every other day was generally similar to that of IM interferon-beta-1a 30 micro g once weekly, except for higher incidences of injection site reactions and neutralising anti-interferon-beta antibodies with SC interferon-beta-1b. In conclusion, SC interferon-beta-1b 250 micro g every other day reduces the frequency and severity of relapses and MRI measures of disease activity and may delay the progression of disability in RRMS. The drug appeared to be more effective than, and as well tolerated as, IM interferon-beta-1a 30 micro g once weekly. Interferon-beta-1b also has positive effects on relapse rates and disease activity in patients with SPMS, although its effects on disease progression remain uncertain. The drug is generally well tolerated, and the common adverse events are clinically manageable. Thus, interferon-beta-1b is a valuable first-line therapy for patients with RRMS and a potentially useful option in those with SPMS.
Lithium has been the backbone of treatment for bipolar disorder for several decades, although recent advances have identified a number of other medications that have efficacy in treating various phases of the illness. These include the antiepileptic drugs valproate semisodium (divalproex sodium) and carbamazepine and some new antiepileptic drugs (e.g. lamotrigine and topiramate), and the atypical antipsychotics (e.g. olanzapine, clozapine and risperidone). Conventional antipsychotics continue to be used frequently in bipolar disorder, although they may be somewhat less effective than other treatments. Otherwise, to date, none of these treatments have been shown to be consistently more effective than any other, so that drug adverse effects and tolerability often dictate which agents are used in an individual patient. Drugs commonly used for the treatment of bipolar disorder are generally tolerated by most patients in large samples. However, the unique adverse effect signature of a drug will often suggest that it will be less tolerable in some patients than in others. Identifying a specific treatment for a specific patient requires a careful individualised assessment of the risk of adverse effects for that patient's unique circumstances.
Over the last two decades the Bech-Rafaelsen Mania Scale (MAS) has been used extensively in trials that have assessed the efficacy of treatments for bipolar disorder. The extent of its use makes it possible to evaluate the psychometric properties of the scale according to the principles of internal validity, reliability, and external validity.
Studies of the internal validity of the MAS have demonstrated that the simple sum of the 11 items of the scale is a sufficient statistic for the assessment of the severity of manic states. Both factor analysis and latent structure analysis (the Rasch analysis) have been used to demonstrate this. The total score of the MAS has been standardised such that scores below 15 indicate hypomania, scores around 20 indicate moderate mania, and scores around 28 indicate severe mania.
The inter-observer reliability has been found to be high in a number of studies conducted in various countries.
The MAS has shown an acceptable external validity, in terms of both sensitivity and responsiveness. Thus, the MAS was found to be superior to the Clinical Global Impression scale with regard to responsiveness, and sensitivity has been found to be adequate, with the MAS able to demonstrate large drug-placebo differences.
Based on pretreatment scores, trials of antimanic therapies can be classified into: (i) ultrashort (1 week) therapy of severe mania; (ii) short-term therapy (3 to 8 weeks) of moderate mania; (iii) short-term therapy of hypomanic or mixed bipolar states; and (iv) long-term (12 months) therapy of bipolar states. The responsiveness of MAS is such that the scale has been able to demonstrated that typical antipsychotics are effective as an ultrashort therapy of severe mania; that lithium and anticonvulsants are effective in the short-term therapy of moderate mania; and that atypical antipsychotics, electroconvulsive therapy (ECT) and transcranial magnetic stimulation seem to have promising effects in the short-term therapy of moderate mania. In contrast, the scale has been used to demonstrate that calcium antagonists (e.g. verapamil) are ineffective in the treatment of mania. MAS has also been used to add to the literature on the evidence-based effect of lithium as a short-term therapy for hypomania or mixed bipolar states and as a long-term therapy of bipolar states.
Brain imaging and postmortem studies have reported a reduction in the volume of discrete brain regions, as well as cellular abnormalities in schizophrenic patients. In addition, basic research studies have demonstrated effects of antipsychotic drugs on cell morphology and number. Of particular interest is adult neurogenesis, which has been linked to cognitive and memory improvements, and is also associated with the behavioural actions of antidepressants. While the action of antidepressant treatment is restricted mainly to the hippocampus, long-term administration of antipsychotics is reported to increase neurogenesis in the subventricular zone (SVZ), as well as the subgranular zone (SGZ) of the hippocampus. In addition, antipsychotic drugs increase the proliferation of non-neuronal cell types in the prefrontal cortex and could thereby influence the function of this brain region. Typical and atypical antipsychotic drugs differentially regulate neurogenesis in the SVZ and SGZ.
Although the therapeutic relevance remains speculative, the results are consistent with the hypothesis that the actions of antipsychotic agents could be mediated, in part, by increased proliferation of neuronal as well as glial cells. Additional animal studies and postmortem analyses are required to further test this possibility and to investigate the relevance of this work in the pathophysiology and treatment of schizophrenia.
Parkinson's disease is a common condition, usually treated by dopaminergic agents, both ergot and non-ergot. Many behavioural abnormalities are associated with such usage, including impulse control disorders (ICDs), dopamine dysregulation syndrome and 'punding'. Pathological gambling, a form of ICD, comprises persistent and maladaptive gambling of various types that disrupts personal, family or occupational activity. Pathological gambling may be associated with other abnormal actions such as pathological shopping, hoarding and hypersexuality. The incidence varies widely from study to study but may be up to 7% of users of dopaminergic agents. Recognition of this problem has led drug regulatory agencies to add precautions concerning pathological gambling to official drug information for the entire class of antiparkinsonian medications. The literature is not entirely consistent and opinions differ greatly, but pramipexole (a dopamine D2 and D3 agonist), and perhaps ropinirole (also a D2/D3 agonist), may be especially likely to be associated with pathological gambling, although the precise nature of the relationship is unclear. Treatment involves reducing the dose of the medication or switching to another medication; unfortunately, the Parkinson's disease may worsen. The mechanism of this adverse effect is believed to be excessive dopaminergic stimulation but probably not specifically involving D3 receptors. A parallel to addictive behaviour with stimulant drugs has been noted.
Duloxetine (Cymbalta(R)) is a potent serotonin and noradrenaline (norepinephrine) reuptake inhibitor (SNRI) in the CNS. It is indicated for the treatment of generalized anxiety disorder (GAD) as well as other indications. In patients with GAD of at least moderate severity, oral duloxetine 60-120 mg once daily was effective with regard to improvement from baseline in assessments of anxiety and functional impairment, and numerous other clinical endpoints. Longer-term duloxetine 60-120 mg once daily also demonstrated efficacy in preventing or delaying relapse in responders among patients with GAD. In addition, duloxetine was generally well tolerated, with most adverse events being of mild to moderate severity in patients with GAD in short- and longer-term trials. Additional comparative and pharmacoeconomic studies are required to position duloxetine among other selective serotonin reuptake inhibitors and SNRIs. However, available clinical data, and current treatment guidelines, indicate that duloxetine is an effective first-line treatment option for the management of GAD. Duloxetine is a potent and selective inhibitor of serotonin and noradrenaline transporters, and a weak inhibitor of dopamine transporters. It has a low affinity for neuronal receptors, such as alpha(1)- and alpha(2)-adrenergic, dopamine D(2), histamine H(1), muscarinic, opioid and serotonin receptors, as well as ion channel binding sites and other neurotransmitter transporters, such as choline and GABA transporters. It does not inhibit monoamine oxidase types A or B. The pharmacokinetics of duloxetine in healthy volunteers were dose proportional over the range of 40-120 mg once daily. Steady state was typically reached by day 3 of administration. Duloxetine may be administered without regard to food or time of day. Duloxetine is highly protein bound and is widely distributed throughout tissues. It is rapidly and extensively metabolized in the liver by cytochrome P450 (CYP) 1A2 and 2D6, and its numerous metabolites, which are inactive, are mainly excreted in the urine. The mean elimination half-life of duloxetine is approximately 12 hours. Duloxetine is a substrate for CYP1A2 and CYP2D6 and a moderate inhibitor of CYP2D6. Concomitant use of duloxetine and potent CYP1A2 inhibitors should be avoided and duloxetine should be used with caution in patients receiving drugs that are extensively metabolized by CYP2D6, particularly those with a narrow therapeutic index. Duloxetine was effective in the short-term treatment of patients with primary GAD of at least moderate severity. In four randomized, double-blind, placebo-controlled, multicentre, phase III trials, duloxetine 60-120 mg once daily for 9 or 10 weeks was significantly more effective than placebo with regard to the primary endpoint of mean change in Hamilton Anxiety Rating Scale (HAM-A) total score from baseline to study endpoint. In addition, all other endpoints were generally improved from baseline to a greater extent with duloxetine 60-120 mg once daily than with placebo. Duloxetine also improved patient role functioning (assessed using Sheehan Disability Scale global impairment functioning scores), health-related quality of life and patient well-being compared with placebo. Duloxetine was effective in patients with GAD who were aged >/=65 years. Pooled results of data from the two short-term efficacy trials that also included an active comparator arm showed that the mean change in HAM-A scores with duloxetine relative to placebo were of the same magnitude as those with venlafaxine extended release versus placebo. Duloxetine 60-120 mg once daily was also more effective than placebo in preventing or delaying relapse in responders to duloxetine in a longer-term study. In this study, patients with GAD received duloxetine during a 26-week, open-label, acute treatment phase and responders were then randomized to continue on duloxetine or receive placebo during a 26-week, double-blind, continuation phase. Time to relapse was significantly longer in duloxetine recipients than in placebo recipients. In addition, significantly fewer duloxetine recipients than placebo recipients relapsed during the double-blind phase of the trial and more duloxetine recipients achieved remission. Short- (9-10 weeks) and longer-term (52 weeks) treatment with duloxetine 60-120 mg once daily was generally well tolerated in patients with GAD, with the majority of adverse events being of mild to moderate severity. Nausea, dry mouth, headache, constipation, dizziness and fatigue were among the most common treatment-emergent adverse events. The adverse event profile of duloxetine did not differ with dose or treatment duration. Significantly more patients receiving short-term duloxetine than placebo discontinued treatment because of an adverse event, with nausea being the only event that resulted in significantly more treatment discontinuations in duloxetine recipients than in placebo recipients. Serious adverse events were uncommon with both short- and longer-term duloxetine treatment. Two episodes of attempted suicide and one episode of completed suicide occurred in duloxetine recipients during the 24-week open-label phase of a longer-term trial. No deaths or suicides were reported in any of the short-term trials. Discontinuation-emergent adverse events, most commonly nausea and dizziness, occurred in up to one-third of duloxetine recipients in the short-term trials.
Among the most prevalent of mental illnesses, depression is increasing in incidence in the Western world. It presents with a wide variety of symptoms that involve both the CNS and the periphery. Multiple pharmacological observations led to the development of the monoamine theory as a biological basis for depression, according to which diminished neurotransmission within the CNS, including that of the dopamine, noradrenaline (norepinephrine) and serotonin systems, is the leading cause of the disorder. Current conventional pharmacological antidepressant therapies, using selective monoamine reuptake inhibitors, tricyclic antidepressants and monoamine oxidase inhibitors, aim to enhance monoaminergic neurotransmission. However, the use of these agents presents severe disadvantages, including a delay in the alleviation of depressive symptoms, significant adverse effects and high frequencies of non-responding patients.
Neuroendocrinological data of recent decades reveal that depression and anxiety disorders may occur simultaneously due to hypothalamus-pituitary-adrenal (HPA) axis hyperactivity. As a result, the stress-diathesis model was developed, which attempts to associate genetic and environmental influences in the aetiology of depression. The amygdala and the hippocampus control the activity of the HPA axis in a counter-balancing way, and a plethora of regulatory neuropeptide signalling pathways are involved. Intervention at these molecular targets may lead to alternative antidepressant therapeutic solutions that are expected to overcome the limitations of existing antidepressants. This prospect is based on preclinical evidence from pharmacological and genetic modifications of the action of neuropeptides such as corticotropin-releasing factor, substance P, galanin, vasopressin and neuropeptide Y. The recent synthesis of orally potent non-peptide micromolecules that can selectively bind to various neuropeptide receptors permits the onset of clinical trials to evaluate their efficacy against depression.
Blonanserin is a novel atypical antipsychotic agent with potent dopamine D(2) and serotonin 5-HT(2) antagonist properties. It may potentially have a lower incidence of adverse events than other antipsychotic agents.
To determine the efficacy and safety of three doses of blonanserin compared with placebo and haloperidol in patients with acute-phase schizophrenia.
This was a 6-week, randomized, double-blind, placebo- and haloperidol-controlled, international, multicentre study. Patients with an acute exacerbation of their schizophrenia, with a Positive and Negative Syndrome Scale (PANSS) score >/=70 and a Clinical Global Impression - Severity of Illness (CGI-S) score >/=4 ('moderately ill') [with no decrease >/=20% or >/=1 point, respectively, during the wash-out period] were randomized into one of five treatment groups (blonanserin 2.5, 5 or 10 mg, haloperidol 10 mg or placebo once daily). Patients were assessed weekly for clinical efficacy, adverse events, extrapyramidal symptoms (EPS) and drug compliance, and were assessed biweekly for other safety variables.
All 307 randomized patients received at least one dose of study medication and 228 (74.3%) completed the study. The mean reduction in PANSS total score at week 6 was significantly greater with all active treatments compared with placebo (-12.58; p < 0.001); blonanserin 10 mg was significantly superior to blonanserin 2.5 mg (-30.18 vs -20.6; p < 0.001), but blonanserin 5 mg (-27.19) and haloperidol 10 mg (-28.16) were not. All active treatments showed greater efficacy against the positive symptoms of schizophrenia, and blonanserin (5 and 10 mg) was more effective against the negative symptoms than haloperidol. Blonanserin was well tolerated at all doses and there was no evidence of clinically important weight gain, orthostatic hypotension, corrected QT interval prolongation or clinically relevant changes in laboratory test results. Haloperidol caused persistent elevation in prolactin levels, but this was not seen with any dose of blonanserin throughout the study period. There was a lower incidence of EPS with blonanserin 10 mg (26.6%) than with haloperidol 10 mg (53.3%).
Blonanserin was effective in the treatment of acute schizophrenia and showed greater efficacy in negative symptoms compared with placebo and haloperidol. Blonanserin was well tolerated and its safety profile compared favourably with haloperidol, particularly with respect to prolactin elevation and EPS frequency.
This paper reviews the discovery and history of the use of irreversible monoamine oxidase (MAO) inhibitors (MAOIs) such as phenelzine, tranylcypromine and isocarboxazid, as well as the second generation selective and reversible MAOIs such as the MAO-A inhibitor, moclobemide and the MAO-B inhibitor, selegiline. Data for review were identified from a literature search of OvidSP Medline and PsycInfo performed in July 2012, using the subject terms and keywords of ‘monoamine oxidase inhibitors’, ‘major depression’, ‘depressive disorder’ and ‘depression (emotion)’. The search was limited to papers published in the English language and from 2007 onward only.
Irreversible MAOIs have the potential to treat the most challenging mood disorder patients including those with treatment-resistant depression, atypical depression and bipolar depression. Unfortunately, the use of irreversible MAOIs has been declining sharply due to lack of marketing and the excessive fears of clinicians. Moreover, few clinicians now have any experience, let alone comfort, in prescribing this class of antidepressants. The newer MAOIs are available as another option for the treatment of major depression but have not replaced the irreversible MAOIs for the specific sub-types of depression for which they are now recommended in most consensus guidelines and treatment algorithms.
The pharmacology, drug interactions and dietary recommendations associated with the use of MAOIs are reviewed. With the appropriate dietary restrictions and attention to potential drug interactions with serotonin and noradrenaline agents this class of drugs can be used effectively and safely. The MAOIs still represent an important element in our therapeutic armamentarium. Despite recommendations by opinion leaders and consensus guidelines for the use of MAOIs in specific sub-types of depression, the prescription rate of MAOIs is far less than expected and is decreasing. The “bad reputation” and the lack of industry support for this class of agents (especially the irreversible MAOIs) must be overcome in order to continue to provide a potentially useful treatment for a very vulnerable yet substantial sub-population of mood disorder patients.
