Showing papers in "CNS Drugs in 2013"

Intranasal insulin as a treatment for Alzheimer's disease: a review of basic research and clinical evidence.

Abstract: Research in animals and humans has associated Alzheimer’s disease (AD) with decreased cerebrospinal fluid levels of insulin in combination with decreased insulin sensitivity (insulin resistance) in the brain. This phenomenon is accompanied by attenuated receptor expression of insulin and insulin-like growth factor, enhanced serine phosphorylation of insulin receptor substrate-1, and impaired transport of insulin across the blood-brain barrier. Moreover, clinical trials have demonstrated that intranasal insulin improves both memory performance and metabolic integrity of the brain in patients suffering from AD or its prodrome, mild cognitive impairment. These results, in conjunction with the finding that insulin mitigates hippocampal synapse vulnerability to beta amyloid, a peptide thought to be causative in the development of AD, provide a strong rationale for hypothesizing that pharmacological strategies bolstering brain insulin signaling, such as intranasal administration of insulin, could have significant potential in the treatment and prevention of AD. With this view in mind, the review at hand will present molecular mechanisms potentially underlying the memory-enhancing and neuroprotective effects of intranasal insulin. Then, we will discuss the results of intranasal insulin studies that have demonstrated that enhancing brain insulin signaling improves memory and learning processes in both cognitively healthy and impaired humans. Finally, we will provide an overview of neuroimaging studies indicating that disturbances in insulin metabolism—such as insulin resistance in obesity, type 2 diabetes and AD—and altered brain responses to insulin are linked to decreased cerebral volume and especially to hippocampal atrophy.

Potential mechanisms of action of lithium in bipolar disorder : current understanding

Abstract: Lithium has been used for over half a century for the treatment of bipolar disorder as the archetypal mood stabilizer, and has a wealth of empirical evidence supporting its efficacy in this role. Despite this, the specific mechanisms by which lithium exerts its mood-stabilizing effects are not well understood. Given the inherently complex nature of the pathophysiology of bipolar disorder, this paper aims to capture what is known about the actions of lithium ranging from macroscopic changes in mood, cognition and brain structure, to its effects at the microscopic level on neurotransmission and intracellular and molecular pathways. A comprehensive literature search of databases including MEDLINE, EMBASE and PsycINFO was conducted using relevant keywords and the findings from the literature were then reviewed and synthesized. Numerous studies report that lithium is effective in the treatment of acute mania and for the long-term maintenance of mood and prophylaxis; in comparison, evidence for its efficacy in depression is modest. However, lithium possesses unique anti-suicidal properties that set it apart from other agents. With respect to cognition, studies suggest that lithium may reduce cognitive decline in patients; however, these findings require further investigation using both neuropsychological and functional neuroimaging probes. Interestingly, lithium appears to preserve or increase the volume of brain structures involved in emotional regulation such as the prefrontal cortex, hippocampus and amygdala, possibly reflecting its neuroprotective effects. At a neuronal level, lithium reduces excitatory (dopamine and glutamate) but increases inhibitory (GABA) neurotransmission; however, these broad effects are underpinned by complex neurotransmitter systems that strive to achieve homeostasis by way of compensatory changes. For example, at an intracellular and molecular level, lithium targets second-messenger systems that further modulate neurotransmission. For instance, the effects of lithium on the adenyl cyclase and phospho-inositide pathways, as well as protein kinase C, may serve to dampen excessive excitatory neurotransmission. In addition to these many putative mechanisms, it has also been proposed that the neuroprotective effects of lithium are key to its therapeutic actions. In this regard, lithium has been shown to reduce the oxidative stress that occurs with multiple episodes of mania and depression. Further, it increases protective proteins such as brain-derived neurotrophic factor and B-cell lymphoma 2, and reduces apoptotic processes through inhibition of glycogen synthase kinase 3 and autophagy. Overall, it is clear that the processes which underpin the therapeutic actions of lithium are sophisticated and most likely inter-related.

Serotonin 5-HT1A Receptors as Targets for Agents to Treat Psychiatric Disorders: Rationale and Current Status of Research

Abstract: Psychiatric disorders represent a large economic burden in modern societies. However, pharmacological treatments are still far from optimal. Drugs used in the treatment of major depressive disorder (MDD) and anxiety disorders (selective serotonin [5-HT] reuptake inhibitors [SSRIs] and serotonin-noradrenaline reuptake inhibitors [SNRIs]) are pharmacological refinements of first-generation tricyclic drugs, discovered by serendipity, and show low efficacy and slowness of onset. Moreover, antipsychotic drugs are partly effective in positive symptoms of schizophrenia, yet they poorly treat negative symptoms and cognitive deficits. The present article reviews the neurobiological basis of 5-HT1A receptor (5-HT1A-R) function and the role of pre- and postsynaptic 5-HT1A-Rs in the treatment of MDD, anxiety and psychotic disorders. The activation of postsynaptic 5-HT1A-Rs in corticolimbic areas appears beneficial for the therapeutic action of antidepressant drugs. However, presynaptic 5-HT1A-Rs play a detrimental role in MDD, since individuals with high density or function of presynaptic 5-HT1A-Rs are more susceptible to mood disorders and suicide, and respond poorly to antidepressant drugs. Moreover, the indirect activation of presynaptic 5-HT1A-Rs by SSRIs/SNRIs reduces 5-HT neuron activity and terminal 5-HT release, thus opposing the elevation of extracellular 5-HT produced by blockade of the serotonin transporter (SERT) in the forebrain. Chronic antidepressant treatment desensitizes presynaptic 5-HT1A-Rs, thus reducing the effectiveness of the 5-HT1A autoreceptor-mediated negative feedback. The prevention of this process by the non-selective partial agonist pindolol accelerates clinical antidepressant effects. Two new antidepressant drugs, vilazodone (marketed in the USA) and vortioxetine (in development) incorporate partial 5-HT1A-R agonist properties with SERT blockade. Several studies with transgenic mice have also established the respective role of pre- and postsynaptic 5-HT1A-Rs in MDD and anxiety. In agreement with pharmacological studies, presynaptic and postsynaptic 5-HT1A-R activation appears necessary for anxiolytic and antidepressant effects, respectively, yet, neurodevelopmental roles for 5-HT1A-Rs are also involved. Likewise, the use of small interference RNA has enabled the showing of robust antidepressant-like effects in mice after selective knock-down of 5-HT1A autoreceptors. Postsynaptic 5-HT1A-Rs in the prefrontal cortex (PFC) also appear important for the superior clinical effects of clozapine and other second-generation (atypical) antipsychotic drugs in the treatment of schizophrenia and related psychotic disorders. Despite showing a moderate in vitro affinity for 5-HT1A-Rs in binding assays, clozapine displays functional agonist properties at this receptor type in vivo. The stimulation of 5-HT1A-Rs in the PFC leads to the distal activation of the mesocortical pathway and to an increased dopamine release in PFC, an effect likely involved in the clinical actions of clozapine in negative symptoms and cognitive deficits in schizophrenia. The anxiolytic/antidepressant properties of 5-HT1A-R agonists in preclinical tests raised expectations enormously. However, these agents have achieved little clinical success, possibly due to their partial agonist character at postsynaptic 5-HT1A-Rs, together with full agonist properties at presynaptic 5-HT1A autoreceptors, as well as their gastrointestinal side effects. The partial 5-HT1A-R agonists buspirone, gepirone, and tandospirone are marketed as anxiolytic drugs, and buspirone is also used as an augmentation strategy in MDD. The development of new 5-HT1A-R agonists with selectivity for postsynaptic 5-HT1A-Rs may open new perspectives in the field.

Postural instability in patients with Parkinson's disease : epidemiology, pathophysiology and management

Abstract: Postural instability is one of the cardinal signs in Parkinson's disease (PD). It can be present even at diagnosis, but becomes more prevalent and worsens with disease progression. It represents one of the most disabling symptoms in the advanced stages of the disease, as it is associated with increased falls and loss of independence. Clinical and posturographic studies have contributed to significant advances in unravelling the complex pathophysiology of postural instability in patients with PD, but it still remains yet to be fully clarified, partly due to the difficulty in distinguishing between the disease process and the compensatory mechanisms, but also due to the fact that non-standardized techniques are used to measure balance and postural instability. There is increasing evidence that physical therapy, especially highly challenging balance exercises, can improve postural stability and reduce the risk of falls, although the long-term effects of physical therapy interventions on postural stability need to be explored given the progressive nature of PD. Pharmacotherapy with dopaminergic medications can provide significant improvements in postural instability in early- to mid-stage PD but the effects tend to wane with time consistent with spread of the disease process to non-dopaminergic pathways in advanced PD. Donepezil has been associated with a reduced risk of falls and methylphenidate has shown potential benefit against freezing of gait, but the results are yet to be replicated in large randomized studies. Surgical treatments, including lesioning and deep brain stimulation surgery targeting the subthalamic nucleus and the globus pallidus internus, tend to only provide modest benefit for postural instability. New surgical targets such as the pedunculopontine nucleus have emerged as a potential specific therapy for postural instability and gait disorder but remain experimental.

Current Place of Monoamine Oxidase Inhibitors in the Treatment of Depression

Abstract: 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.

Sudden unexpected death in epilepsy. Potential role of antiepileptic drugs.

Abstract: Among people with epilepsy, there is a 20-fold higher risk of dying suddenly and unexpectedly compared with the general population. This phenomenon is called sudden unexpected death in epilepsy (SUDEP) and the term is used when sudden death occurs in an otherwise reasonably healthy person with epilepsy and the autopsy is unrevealing. In most cases, SUDEP occurs during sleep and is unwitnessed. Risk factors for SUDEP include the presence or number of generalized tonic–clonic seizures (GTCS), nocturnal seizures, young age at epilepsy onset, longer duration of epilepsy, dementia, absence of cerebrovascular disease, asthma, male gender, symptomatic aetiology of epilepsy and alcohol abuse. Suggested factors predisposing to SUDEP have included long-QT-related mutations, impaired serotonergic brain stem control of respiration, altered autonomic control and seizures with a pronounced postictal suppression and respiratory compromise. Final events that may lead up to SUDEP are a postictal CNS shutdown with pronounced EEG suppression, ictal or postictal apnoea, and ictal cardiac arrhythmia. It is unknown whether antiepileptic drugs (AEDs) modify the risk for SUDEP. Studies have consistently found that the presence or number of GTCS is associated with an increased risk for SUDEP. Since continued presence of GTCS clearly necessitates the use of AEDs, both factors must be taken into account to determine whether one or both increases the risk for SUDEP. Some studies suggest that AEDs, such as lamotrigine and carbamazepine, may increase the risk of SUDEP, but rarely adjust for GTCS. Other studies, which have found that AEDs are associated with a decreased SUDEP risk, either adjust for the number of GTCS or are meta-analyses of randomized clinical trials. Studies assessing the impact of AEDs on the risk for SUDEP are limited because SUDEP is a rare event, making randomized clinical trials impossible to conduct. Observational studies focus on whether or not an AED was prescribed. When postmortem AED concentrations are assessed they are usually low or absent, perhaps due to sampling in deceased individuals, making it difficult to fully resolve whether AEDs increase or decrease SUDEP risk. Despite these caveats, the evidence suggests that AEDs are not associated with an increased risk for SUDEP on a population level, although some individuals may be susceptible to effects of AEDs. Recent evidence from a meta-analysis of randomized clinical trials of adjunctive AEDs at efficacious doses provides strong support for AED treatment as mono- or polytherapy to increase seizure control and protect against SUDEP in patients with refractory epilepsy. For patients for whom seizure control is unattainable, supervision or monitoring may prevent SUDEP, though this has never been formally tested.

Blocking LINGO-1 as a therapy to promote CNS repair: from concept to the clinic.

Abstract: LINGO-1 is a leucine-rich repeat and Ig domain-containing, Nogo receptor interacting protein, selectively expressed in the CNS on both oligodendrocytes and neurons. Its expression is developmentally regulated, and is upregulated in CNS diseases and injury. In animal models, LINGO-1 expression is upregulated in rat spinal cord injury, experimental autoimmune encephalomyelitis, 6-hydroxydopamine neurotoxic lesions and glaucoma models. In humans, LINGO-1 expression is increased in oligodendrocyte progenitor cells from demyelinated white matter of multiple sclerosis post-mortem samples, and in dopaminergic neurons from Parkinson’s disease brains. LINGO-1 negatively regulates oligodendrocyte differentiation and myelination, neuronal survival and axonal regeneration by activating ras homolog gene family member A (RhoA) and inhibiting protein kinase B (Akt) phosphorylation signalling pathways. Across diverse animal CNS disease models, targeted LINGO-1 inhibition promotes neuron and oligodendrocyte survival, axon regeneration, oligodendrocyte differentiation, remyelination and functional recovery. The targeted inhibition of LINGO-1 function presents a novel therapeutic approach for the treatment of CNS diseases.

Plant-Based Medicines for Anxiety Disorders, Part 2: A Review of Clinical Studies with Supporting Preclinical Evidence

Abstract: Research in the area of herbal psychopharmacology has revealed a variety of promising medicines that may provide benefit in the treatment of general anxiety and specific anxiety disorders. However, a comprehensive review of plant-based anxiolytics has been absent to date. Thus, our aim was to provide a comprehensive narrative review of plant-based medicines that have clinical and/or preclinical evidence of anxiolytic activity. We present the article in two parts. In part one, we reviewed herbal medicines for which only preclinical investigations for anxiolytic activity have been performed. In this current article (part two), we review herbal medicines for which there have been both preclinical and clinical investigations of anxiolytic activity. A search of MEDLINE (PubMed), CINAHL, Scopus and the Cochrane Library databases was conducted (up to 28 October 2012) for English language papers using the search terms 'anxiety' OR 'anxiety disorder' OR 'generalized anxiety disorder' OR 'social phobia' OR 'post-traumatic stress disorder' OR 'panic disorder' OR 'agoraphobia' OR 'obsessive compulsive disorder' in combination with the search terms 'Herb*' OR 'Medicinal Plants' OR 'Botanical Medicine' OR 'Chinese herb*', in addition to individual herbal medicines. This search of the literature revealed 1,525 papers, of which 53 plants were included in the review (having at least one study using the whole plant extract). Of these plants, 21 had human clinical trial evidence (reviewed here in part two), with the other 32 having solely preclinical evidence (reviewed in part one). Support for efficacy was found for chronic use (i.e. greater than one day) of the following herbs in treating a range of anxiety disorders in human clinical trials: Piper methysticum, Matricaria recutita, Ginkgo biloba, Scutellaria lateriflora, Silybum marianum, Passiflora incarnata, Withania somniferum, Galphimia glauca, Centella asiatica, Rhodiola rosea, Echinacea spp., Melissa officinalis and Echium amoenum. For several of the plants studied, conclusions need to be tempered due to methodological issues such as small sample sizes, brief intervention durations and non-replication. Current evidence does not support Hypericum perforatum or Valeriana spp. for any anxiety disorder. Acute anxiolytic activity was found for Centella asiatica, Salvia spp., Melissa officinalis, Passiflora incarnata and Citrus aurantium. Bacopa monnieri has shown anxiolytic effects in people with cognitive decline. The therapeutic application of psychotropic plant-based treatments for anxiety disorders is also discussed, specifically Psychotria viridis and Banisteriopsis caarti (ayahuasca), Psilocybe spp. and cannabidiol-enriched (low tetrahydrocannabinol (Δ(9)-THC)) Cannabis spp.

The safety, tolerability, and efficacy of once-daily memantine (28 mg): a multinational, randomized, double-blind, placebo-controlled trial in patients with moderate-to-severe Alzheimer's disease taking cholinesterase inhibitors.

Abstract: Immediate-release memantine (10 mg, twice daily) is approved in the USA for moderate-to-severe Alzheimer’s disease (AD). This study evaluated the efficacy, safety, and tolerability of a higher-dose, once-daily, extended-release formulation in patients with moderate-to-severe AD concurrently taking cholinesterase inhibitors. In this 24-week, double-blind, multinational study (NCT00322153), outpatients with AD (Mini-Mental State Examination scores of 3–14) were randomized to receive once-daily, 28-mg, extended-release memantine or placebo. Co-primary efficacy parameters were the baseline-to-endpoint score change on the Severe Impairment Battery (SIB) and the endpoint score on the Clinician’s Interview-Based Impression of Change Plus Caregiver Input (CIBIC-Plus). The secondary efficacy parameter was the baseline-to-endpoint score change on the 19-item Alzheimer’s Disease Cooperative Study–Activities of Daily Living (ADCS–ADL19); additional parameters included the baseline-to-endpoint score changes on the Neuropsychiatric Inventory (NPI) and verbal fluency test. Data were analyzed using a two-way analysis of covariance model, except for CIBIC-Plus (Cochran–Mantel–Haenszel test). Safety and tolerability were assessed through adverse events and physical and laboratory examinations. A total of 677 patients were randomized to receive extended-release memantine (n = 342) or placebo (n = 335); completion rates were 79.8 and 81.2 %, respectively. At endpoint (week 24, last observation carried forward), memantine-treated patients significantly outperformed placebo-treated patients on the SIB (least squares mean difference [95 % CI] 2.6 [1.0, 4.2]; p = 0.001), CIBIC-Plus (p = 0.008), NPI (p = 0.005), and verbal fluency test (p = 0.004); the effect did not achieve significance on ADCS–ADL19 (p = 0.177). Adverse events with a frequency of ≥5.0 % that were more prevalent in the memantine group were headache (5.6 vs. 5.1 %) and diarrhea (5.0 vs. 3.9 %). Extended-release memantine was efficacious, safe, and well tolerated in this population.

Quality of Life in Obsessive-Compulsive Disorder: Impact of the Disorder and of Treatment

Abstract: Obsessive-compulsive disorder (OCD) is a chronic debilitating anxiety disorder characterized by two distinct phenomena: obsessions which are recurrent, intrusive thoughts, images or impulses, and/or compulsions which are repetitive covert or overt actions that are carried out to decrease anxiety. OCD commonly affects young adults, is associated with other comorbid mental illnesses and often has a large treatment gap (the proportion of individuals who have OCD and require care but do not receive treatment). OCD thus runs a chronic and disabling course which compromises an individual’s functioning and well-being and ultimately has a rather detrimental impact on the lives of both patients and their families. Researchers and clinicians are increasingly paying attention to humanistic outcomes to encompass broader indicators of disease burden and outcome, one of which is quality of life (QoL). In this review, we provide a summary of the current knowledge of QoL in OCD, its socio-demographic and clinical correlates, and the effects of therapeutic interventions on QoL among those with OCD. Overall, studies indicate that those with OCD had diminished QoL across all domains relative to normative comparison subjects. Patients with OCD scored better on QoL domains than patients with major depressive disorder (MDD), whereas they showed no difference or scored worse than patients with schizophrenia. Although research on socio-demographic correlates of QoL in OCD is largely contradictory, most studies suggest that symptom severity and comorbid depression or depressive symptoms are predictors of decreased QoL in OCD, with numerous studies showing this association across multiple domains associated with QoL. Studies assessing QoL as an outcome of treatment have found an improvement in QoL in people with OCD after treatment with pharmacotherapy or cognitive behavioural therapy with some studies suggesting that this improvement in QoL is correlated with improvement in symptoms. A few studies have also evaluated other forms of treatment like partial hospitalisation programmes and deep brain stimulation for those with treatment-resistant OCD and found that QoL scores improve with treatment. A major gap in the field is the lack of instruments that measure QoL specifically in patients with OCD. It is evident that OCD affects specific domains and thus there is a pressing need for the development of multidimensional instruments that are reliable and valid. There is also a need for studies assessing QoL in individuals with OCD among both clinical and community samples with adequate sample size to examine socio-demographic and clinical correlates simultaneously. These populations ought to be followed longitudinally to examine QoL with the clinical course of the illness, and to help establish temporal relationships. Studies that examine improvements in QoL with treatment need to be designed carefully: sample size requirements should be met, raters must be blinded, and randomly assigning subjects to different arms would ensure that some of the inherent biases in open-label studies are avoided. QoL is an important component that measures the impact of OCD on an individual and QoL goals must be incorporated as an outcome measure of therapeutic interventions.

Risk of serious cardiovascular problems with medications for attention-deficit hyperactivity disorder.

Abstract: Attention-deficit hyperactivity disorder (ADHD) is a chronic neurodevelopmental disorder characterized by persistent symptoms of inattention, hyperactivity and/or impulsivity. The proportion of patients diagnosed with ADHD receiving pharmacological treatments has increased enormously in recent years. Despite the well established efficacy and the good safety and tolerability profile, there is concern about the potential for rare but serious cardiovascular adverse events, as well as sudden cardiac death, with pharmacotherapies used for treating ADHD in children, adolescents and adults. The present paper aims to comprehensively and critically review the published evidence on the controversial association between medications approved for treating patients with ADHD and the risk of serious cardiovascular problems, specifically the risk of corrected QT interval (QTc) prolongation, and the risk of sudden cardiac death. A comprehensive search of relevant databases (PubMed, EMBASE and PsychINFO) was conducted to identify studies published in peer-reviewed journals until 21 July 2012. Clinical reports, as well as retrospective or prospective population-based studies with children, adolescents or adults as participants, of pharmacotherapies for ADHD reporting cardiovascular adverse events were included. Stimulant medications for ADHD, including methylphenidate and amphetamine derivatives, are generally safe and well tolerated. Small but statistically significant increases in blood pressure (BP) and heart rate (HR) are among the adverse events of stimulant treatment in all age groups. Similarly, the non-stimulant medication atomoxetine has also been associated with increased HR and BP, although as is the case with stimulants, these are generally minor, time limited and of minor clinical significance in children, adolescents or adults. Growing evidence suggests that these medications do not cause sudden and unexpected cardiac death or serious cardiovascular problems including statistically or clinically significant increases in QTc, at therapeutic doses in ADHD patients across the lifespan. Small decreases in mean systolic BP, diastolic BP and HR have been observed in studies with guanfacine-extended release (-XR) or clonidine-XR, two α2-adrenergic receptor agonists, administered alone or in combination with psychostimulants to children and adolescents with ADHD. There are also no statistically or clinically significant increases in QTc associated with clonidine or guanfacine. There are no reports of torsades de pointes clearly and directly related to medications used for treating ADHD in patients of all age groups. The risk for serious cardiovascular adverse events, including statistically or clinically significant increases in QTc, and sudden cardiac death associated with stimulants, atomoxetine or α2-adrenergic agonists prescribed for ADHD is extremely low and the benefits of treating individual patients with ADHD, after an adequate assessment, outweigh the risks. However, great caution is advised when considering stimulant and non-stimulant medications for patients of any age with a diagnosis of ADHD and a personal or family history or other known risk factors for cardiovascular disease.

Overdose of Drugs for Attention-Deficit Hyperactivity Disorder: Clinical Presentation, Mechanisms of Toxicity, and Management

Abstract: The prevalence of attention-deficit hyperactivity disorder (ADHD) in the USA is estimated at approximately 4–9 % in children and 4 % in adults. It is estimated that prescriptions for ADHD medications are written for more than 2.7 million children per year. In 2010, US poison centers reported 17,000 human exposures to ADHD medications, with 80 % occurring in children <19 years old and 20 % in adults. The drugs used for the treatment of ADHD are diverse but can be roughly separated into two groups: the stimulants such as amphetamine, methylphenidate, and modafinil; and the non-stimulants such as atomoxetine, guanfacine, and clonidine. This review focuses on mechanisms of toxicity after overdose with ADHD medications, clinical effects from overdose, and management. Amphetamine, dextroamphetamine, and methylphenidate act as substrates for the cellular monoamine transporter, especially the dopamine transporter (DAT) and less so the norepinephrine (NET) and serotonin transporter. The mechanism of toxicity is primarily related to excessive extracellular dopamine, norepinephrine, and serotonin. The primary clinical syndrome involves prominent neurological and cardiovascular effects, but secondary complications can involve renal, muscle, pulmonary, and gastrointestinal (GI) effects. In overdose, the patient may present with mydriasis, tremor, agitation, hyperreflexia, combative behavior, confusion, hallucinations, delirium, anxiety, paranoia, movement disorders, and seizures. The management of amphetamine, dextroamphetamine, and methylphenidate overdose is largely supportive, with a focus on interruption of the sympathomimetic syndrome with judicious use of benzodiazepines. In cases where agitation, delirium, and movement disorders are unresponsive to benzodiazepines, second-line therapies include antipsychotics such as ziprasidone or haloperidol, central alpha-adrenoreceptor agonists such as dexmedetomidine, or propofol. Modafinil is not US FDA approved for treatment of ADHD; however, it has been shown to improve ADHD signs and symptoms and has been used as an off-label pharmaceutical for this diagnosis in both adults and children. The mechanism of action of modafinil is complex and not fully understood. It is known to cause an increase in extracellular concentrations of dopamine, norepinephrine, and serotonin in the neocortex. Overdose with modafinil is generally of moderate severity, with reported ingestions of doses up to 8 g. The most common neurological effects include increased anxiety, agitation, headache, dizziness, insomnia, tremors, and dystonia. The management of modafinil overdose is largely supportive, with a focus on sedation, and control of dyskinesias and blood pressure. Atomoxetine is a selective presynaptic norepinephrine transporter inhibitor. The clinical presentation after overdose with atomoxetine has generally been mild. The primary effects have been drowsiness, agitation, hyperactivity, GI upset, tremor, hyperreflexia, tachycardia hypertension, and seizure. The management of atomoxetine overdose is largely supportive, with a focus on sedation, and control of dyskinesias and seizures. Clonidine is a synthetic imidazole derivative with both central and peripheral alpha-adrenergic agonist actions. The primary clinical syndrome involves prominent neurological and cardiovascular effects, with the most commonly reported features of depressed sensorium, bradycardia, and hypotension. While clonidine is an anti-hypertensive medication, a paradoxical hypertension may occur early with overdose. The clinical syndrome after overdose of guanfacine may be mixed depending on central or peripheral alpha-adrenoreceptor effects. Initial clinical effects may be drowsiness, lethargy, dry mouth, and diaphoresis. Cardiovascular effects may depend on time post-ingestion and may present as hypotension or hypertension. The management of guanfacine overdose is largely supportive, with a focus on support of blood pressure. Overdose with ADHD medications can produce major morbidity, with many cases requiring intensive care medicine and prolonged hospital stays. However, fatalities are rare with appropriate care.

Intranasal oxytocin as an adjunct to risperidone in patients with schizophrenia : an 8-week, randomized, double-blind, placebo-controlled study.

Abstract: Background Impairment of oxytocinergic function and/or oxytocin receptor genetic abnormalities has been demonstrated in patients with schizophrenia. Oxytocin reverses emotional recognition deficit and might restore sense of trust in patients with schizophrenia. Some short-term studies have shown efficacy and tolerability of oxytocin in patients with schizophrenia. However, there is a lack of evidence on the efficacy and tolerability of oxytocin in patients with schizophrenia beyond 3 weeks.

The Role of Hypothalamic H1 Receptor Antagonism in Antipsychotic-Induced Weight Gain

Abstract: Treatment with second generation antipsychotics (SGAs), notably olanzapine and clozapine, causes severe obesity side effects. Antagonism of histamine H1 receptors has been identified as a main cause of SGA-induced obesity, but the molecular mechanisms associated with this antagonism in different stages of SGA-induced weight gain remain unclear. This review aims to explore the potential role of hypothalamic histamine H1 receptors in different stages of SGA-induced weight gain/obesity and the molecular pathways related to SGA-induced antagonism of these receptors. Initial data have demonstrated the importance of hypothalamic H1 receptors in both short- and long-term SGA-induced obesity. Blocking hypothalamic H1 receptors by SGAs activates AMP-activated protein kinase (AMPK), a well-known feeding regulator. During short-term treatment, hypothalamic H1 receptor antagonism by SGAs may activate the AMPK—carnitine palmitoyltransferase 1 signaling to rapidly increase caloric intake and result in weight gain. During long-term SGA treatment, hypothalamic H1 receptor antagonism can reduce thermogenesis, possibly by inhibiting the sympathetic outflows to the brainstem rostral raphe pallidus and rostral ventrolateral medulla, therefore decreasing brown adipose tissue thermogenesis. Additionally, blocking of hypothalamic H1 receptors by SGAs may also contribute to fat accumulation by decreasing lipolysis but increasing lipogenesis in white adipose tissue. In summary, antagonism of hypothalamic H1 receptors by SGAs may time-dependently affect the hypothalamus-brainstem circuits to cause weight gain by stimulating appetite and fat accumulation but reducing energy expenditure. The H1 receptor and its downstream signaling molecules could be valuable targets for the design of new compounds for treating SGA-induced weight gain/obesity.

Can antipsychotics improve social cognition in patients with schizophrenia

Abstract: Social cognition is described as the higher mental processes that are engaged while people store, process, and use social information to make sense of themselves and others. Aspects of social cognition include emotion perception, social cue interpretation, attribution style, and theory of mind, all of which appear disordered in schizophrenia. Such social cognitive deficits are believed to be important predictors of functional outcome in schizophrenia, therefore they may represent a crucial treatment target. Few studies have evaluated the influence of antipsychotic treatment on these deficits. The purpose of this review is to examine the relationship between antipsychotic treatment and social cognition, whether antipsychotics improve social cognitive function, and if so to explore differential medication effects. Comprehensive searches of PsycINFO and MEDLINE/PUBMED were conducted to identify relevant published manuscripts. Fifteen relevant papers published in English were found, describing original studies. On the basis of this review, we have drawn the following conclusions: first, the results do not engender optimism for the possibility that antipsychotic drugs can specifically facilitate social recovery. Second, the actions of antipsychotics on social cognition are inconclusive, due to lack of standardization across research groups, leading to inconsistencies between study designs, methods used, and medication dosages. Third, large-scale longitudinal investigations are needed to explore the unclear relationships between social cognition, symptoms, and functional outcome. Other non-pharmacological treatments focusing on training patients in the social cognitive areas may hold more promise.

Management of alcohol dependence in patients with liver disease

Abstract: Alcohol dependence represents a chronic and relapsing disease affecting nearly 10 % of the general population both in the USA and in Europe, with a widespread burden of morbidity and mortality. Alcohol dependence represents the most common cause of liver damage in the Western world. Although alcoholic liver disease is associated primarily with heavy drinking, continued alcohol consumption, even in low doses after the onset of liver disease, increases the risk of severe consequences, including mortality. Consequently, the ideal treatment of patients affected by alcohol dependence and alcoholic liver disease should aim at achieving long-term total alcohol abstinence and preventing relapse. The aim of the present review is to provide an update on the management of alcohol dependence in patients with alcoholic liver disease. Increasing evidence suggests the usefulness of psychosocial interventions and medications combined in order to reduce alcohol intake, promote abstinence and prevent relapse in alcohol-dependent patients. Disulfiram, naltrexone and acamprosate have been approved for this indication; gamma-hydroxybutyric acid (GHB) is approved in Italy and Austria. However, these drugs have not been tested in patients with advanced liver disease. Amongst other emerging pharmacotherapies for alcoholism, topiramate, ondansetron, and baclofen seem the most promising ones. Both topiramate and ondansetron have a safe profile in alcoholic patients; however, none of them has been tested in alcoholic patients with advanced liver disease. To date, baclofen represents the only anti-craving medication formally tested in a randomized clinical trial in alcoholic patients affected by liver cirrhosis, although additional confirmatory studies are warranted.

Second generation antipsychotic-induced type 2 diabetes: a role for the muscarinic M3 receptor.

Abstract: Second generation antipsychotics (SGAs) are widely prescribed to treat various disorders, most notably schizophrenia and bipolar disorder; however, SGAs can cause abnormal glucose metabolism that can lead to insulin-resistance and type 2 diabetes mellitus side-effects by largely unknown mechanisms. This review explores the potential candidature of the acetylcholine (ACh) muscarinic M3 receptor (M3R) as a prime mechanistic and possible therapeutic target of interest in SGA-induced insulin dysregulation. Studies have identified that SGA binding affinity to the M3R is a predictor of diabetes risk; indeed, olanzapine and clozapine, SGAs with the highest clinical incidence of diabetes side-effects, are potent M3R antagonists. Pancreatic M3Rs regulate the glucose-stimulated cholinergic pathway of insulin secretion; their activation on β-cells stimulates insulin secretion, while M3R blockade decreases insulin secretion. Genetic modification of M3Rs causes robust alterations in insulin levels and glucose tolerance in mice. Olanzapine alters M3R density in discrete nuclei of the hypothalamus and caudal brainstem, regions that regulate glucose homeostasis and insulin secretion through vagal innervation of the pancreas. Furthermore, studies have demonstrated a dynamic sensitivity of hypothalamic and brainstem M3Rs to altered glucometabolic status of the body. Therefore, the M3R is in a prime position to influence glucose homeostasis through direct effects on pancreatic β-cells and by potentially altering signalling in the hypothalamus and brainstem. SGA-induced insulin dysregulation may be partly due to blockade of central and peripheral M3Rs, causing an initial disruption to insulin secretion and glucose homeostasis that can progressively lead to insulin resistance and diabetes during chronic treatment.

Orexin (hypocretin) receptor agonists and antagonists for treatment of sleep disorders. Rationale for development and current status.

Abstract: Orexin A and orexin B are hypothalamic neuropeptides initially identified as endogenous ligands for two orphan G-protein coupled receptors (GPCRs). They play critical roles in the maintenance of wakefulness by regulating function of monoaminergic and cholinergic neurons that are implicated in the regulation of wakefulness. Loss of orexin neurons in humans is associated with narcolepsy, a sleep disorder characterized by excessive daytime sleepiness and cataplexy, further suggesting the particular importance of orexin in the maintenance of the wakefulness state. These findings have encouraged pharmaceutical companies to develop drugs targeting orexin receptors as novel medications of sleep disorders, such as narcolepsy and insomnia. Indeed, phase III clinical trials were completed last year of suvorexant, a non-selective (dual) antagonist for orexin receptors, for the treatment of primary insomnia, and demonstrate promising results. The New Drug Application (NDA) for suvorexant has been submitted to the US FDA. Thus, the discovery of a critical role played by the orexin system in the regulation of sleep/wakefulness has opened the door of a new era for sleep medicine.

Withdrawal symptoms and rebound syndromes associated with switching and discontinuing atypical antipsychotics: theoretical background and practical recommendations.

Abstract: With the widespread use of atypical or second-generation antipsychotics, switching treatment has become current practice and more complicated, as the pharmacological profiles of these agents differ substantially despite their similarity in being ‘atypical’. All share the ability to block dopamine D2 receptors, and most of them also block serotonin 5-HT2A receptors. Apart from these common features, some atypical antipsychotics are also able to block or stimulate other dopamine or serotonin receptors, as well as histaminergic, muscarinergic or adrenergic receptors. As a result of the varying receptor affinities, in switching or discontinuing compounds several possible pitfalls have to be considered, including the occurrence of withdrawal and rebound syndromes. This article reviews the pharmacological background of functional blockade or stimulation of receptors of interest in regard to atypical antipsychotics and the implicated potential withdrawal and rebound phenomena. A MEDLINE search was carried out to identify information on withdrawal or rebound syndromes occurring after discontinuation of atypical antipsychotics. Using the resulting literature, we first discuss the theoretical background to the functional consequences of atypical antipsychotic-induced blockade or stimulation of neurotransmitter receptors and, secondly, we highlight the clinical consequences of this. We then review the available clinical literature on switching between atypical antipsychotics, with respect to the occurrence of withdrawal or rebound symptoms. Finally, we offer practical recommendations based on the reviewed findings. The systematic evaluation of withdrawal or rebound phenomena using randomized controlled trials is still understudied. Knowledge of pharmacological receptor-binding profiles may help clinicians in choosing adequate switching or discontinuation strategies for each agent. Results from large switching trials indicate that switching atypical antipsychotics can be performed in a safe manner. Treatment-emergent adverse events during or after switching are not always considered to be, at least in part, associated with the pre-switch antipsychotic. Further studies are needed to substantiate the evidence gained so far on different switching strategies. The use of concomitant medication, e.g., benzodiazepines or anticholinergic drugs, may help to minimize symptoms arising from the discontinuation or switching of antipsychotic treatment.

The Long-Term Safety of Antiepileptic Drugs

Abstract: Antiepileptic drugs (AEDs) are used by millions of people worldwide for the treatment of epilepsy, as well as in many other neurological and psychiatric conditions. They are frequently associated with adverse effects (AEs), which have an impact on the tolerability and success of treatment. Half the people who develop intolerable AEs discontinue treatment early on after initiation, while the majority of people will continue to be exposed to their effects for long periods of time. The long-term safety of AEDs reflects their potential for chronic, cumulative dose effects; rare, but potentially serious late idiosyncratic effects; late, dose-related effects; and delayed, teratogenic or neurodevelopmental effects. These AEs can affect every body system and are usually insidious. With the exception of delayed effects, most other late or chronic AEs are reversible. To date, there is no clear evidence of a carcinogenic effect of AEDs in humans. While physicians are aware of the long-term AEs of old AEDs (the traditional liver enzyme-inducing AEDs and valproate), information about AEs of new AEDs (such as lamotrigine, levetiracetam, oxcarbazepine, topiramate or zonisamide), particularly of their teratogenic effects, has emerged over the years. Sporadic publications have raised issues about AEs of the newer AEDs eslicarbazepine, retigabine, rufinamide, lacosamide and perampanel but their long-term safety profiles may take years to be fully appreciated. Physicians should not only be aware of the late and chronic AEs of AEDs but should systematically enquire and screen for these according to the individual AED AE profile. Care should be taken for individuals with comorbid conditions that may render them more susceptible to specific AEs. Prevention and appropriate management of long-term AED AEs is expected to improve adherence to treatment, quality of life and control of epilepsy.

Pharmacological Management of Bipolar Depression: Acute Treatment, Maintenance, and Prophylaxis

Abstract: Although the most distinctive clinical feature of bipolar disorder is the pathologically elevated mood, it does not usually constitute the prevalent mood state of bipolar illness. The majority of patients with bipolar disorder spend much more time in depressive episodes, including subsyndromal depressive symptoms, and bipolar depression accounts for the largest part of the morbidity and mortality of the illness. The pharmacological treatment of bipolar depression mostly consists of combinations of at least two drugs, including mood stabilizers (lithium and anticonvulsants), atypical antipsychotics, and antidepressants. Antidepressants are the most frequently prescribed drugs, but recommendations from evidence-based guidelines are not conclusive and do not overtly support their use. Among antidepressants, best evidence exists for fluoxetine, but in combination with olanzapine. Although some guidelines recommend the use of selective serotonin reuptake inhibitors or bupropion in combination with antimanic agents as first-choice treatment, others do not, based on the available evidence. Among anticonvulsants, the use of lamotrigine is overall recommended as a first-line choice, but acute monotherapy studies have failed. Valproate is generally mentioned as a second-line treatment. Lithium monotherapy is also suggested by most guidelines as a first-line treatment, but its efficacy in acute use is not totally clear. Amongst atypical antipsychotics, quetiapine, in monotherapy or as adjunctive treatment, is recommended by most guidelines as a first-line choice. Olanzapine monotherapy is also suggested by some guidelines and is approved in Japan. Armodafinil, pramipexole, ketamine, and lurasidone are recent proposals. Long-term treatment in bipolar disorder is strongly recommended, but guidelines do not recommend the use of antidepressants as a maintenance treatment. Lithium, lamotrigine, valproate, olanzapine, quetiapine, and aripiprazole are the recommended first-line maintenance options.

Management of Motor and Non-Motor Symptoms in Parkinson’s Disease

Abstract: Parkinson's disease (PD) is the second most common neurodegenerative disorder that affects approximately 1 % of people over the age of 60 years. Accurate diagnosis and individualized assessment of the risks and benefits of available antiparkinsonian medications as well as specific clinical features and the phase of disease should guide treatment for patients with PD. Levodopa still remains the gold standard for the treatment of motor symptoms of PD but dopamine agonists (DAs), catechol-O-methyltransferase (COMT) inhibitors and monoamine oxidase B (MAO-B) inhibitors have also been developed to provide more continuous oral delivery of dopaminergic stimulation in order to improve motor outcomes and decrease the risk of levodopa-induced motor complications. Deep-brain stimulation as well as other invasive therapies can be used for the treatment of drug-refractory levodopa-induced motor complications. Despite all of the therapeutic advances achieved within the last 20 years, PD continues to be a progressive disorder leading to severe disability caused by motor and non-motor symptoms. To date, neuroprotective interventions able to modify PD progression are not available. This review focuses on medical and invasive treatment strategies for early and advanced stages of PD as well as on the treatment of PD non-motor symptoms such as mood and behavioural disorders, cognitive and autonomic dysfunction, and sleep disorders, which can antedate PD motor symptoms for years.

The Impact of Newer Atypical Antipsychotics on Patient-Reported Outcomes in Schizophrenia

Abstract: Over the past two decades there has been increasing interest in including patients’ self-reports in the management of their illness. Among the many reasons for such recent interest has been a rising consumer movement over the past few decades, which has led patients, their caregivers and their families to press for more meaningful sharing with physicians in the clinical decision-making process, with the clear expectations of better therapies and improved outcomes. Patients as consumers of services, their views, attitudes towards healthcare, as well as their level of satisfaction with care, have become increasingly recognized. The recent interest by the US Food and Drug Administration (FDA), as well as other regulatory agencies, in patient-reported outcomes (PROs) in the process of developing and testing new antipsychotics, has also added more impetus. It is clear that including patients in the decision-making process about the management of their psychiatric conditions also broadens the concept of ‘recovery’, by empowering patients to be active participants and gives a clear message that successful treatment in schizophrenia is more than a symptomatic improvement, but also includes improved functional status. Additionally, the recent interest in personalized medicine puts the patient in the centre of such development. Since 2004, when we published our review about the impact of new antipsychotics on quality of life in CNS Drugs, a number of newer antipsychotics have been introduced and include ziprasidone, aripiprazole, paliperidone, asenapine, iloperidone and lurasidone. The current review is based on 31 selected publications that cover the years 2004–2012, and deals with the impact of such newer antipsychotics on specific domains of PROs, such as subjective tolerability, quality of life, medication preference, satisfaction and social functioning. Most of the available data deal with ziprasidone, aripiprazole and paliperidone. Though the great majority of the studies indicate the newer antipsychotics have favourably impacted on aspects of PROs, such a conclusion can only be considered a trend due to the many design and methodological limitations of many of these studies. It is interesting to note, as the field awaits more rigorous studies, that there seems to be a unifying core that exists among the various subjective outcomes and that tends to generalize from one subjective outcome to other subjective outcomes. The patient who experiences good subjective tolerability to medications tends generally to be more satisfied and has a strong medication preference. The identification of such a unifying core can prove helpful, not only in the development of appropriate scales, but also in informing and guiding the process of development of new antipsychotics.

A review of the pharmacology, efficacy and tolerability of recently approved and upcoming oral antipsychotics: an evidence-based medicine approach.

Abstract: Evidence-based medicine (EBM) is a broad concept, but the key elements include the incorporation of clinical judgment (which requires clinical experience) together with relevant scientific evidence while remaining mindful of the individual patient’s values and preferences. Using the framework and philosophy of EBM, this systematic review summarizes the pharmacology, efficacy, and tolerability of newly approved oral antipsychotics, including iloperidone, asenapine, and lurasidone, and outlines what is known about agents that are in late-stage clinical development, such as cariprazine, brexpiprazole, zicronapine, bitopertin, and EVP-6124. Potential advantages and disadvantages of these agents over existing antipsychotics are outlined, centered on clinically relevant issues such as the potential for weight gain and metabolic abnormalities, potential association with somnolence/sedation, extra-pyramidal side effects, akathisia, and prolongation of the electrocardiogram (ECG) QT interval, as well as practical issues regarding dosing instructions, titration requirements, and drug–drug interactions. Lurasidone appears to be best in class in terms of minimizing untoward alterations in body weight and metabolic variables. However, iloperidone, asenapine, lurasidone, and cariprazine differ among themselves in terms of on-label dosing frequency (once daily for lurasidone and, presumably, cariprazine versus twice daily for iloperidone and asenapine), the need for initial titration to a therapeutic dose for iloperidone and possibly cariprazine, requirement to be taken sublingually for asenapine, requirement for administration with food for lurasidone, lengthening of the ECG QT interval (greater for iloperidone than for asenapine and no effect observed with lurasidone), and adverse effects such as akathisia (seen with cariprazine, lurasidone, and asenapine but not with iloperidone) and sedation (most notable with asenapine).

Recent progress in understanding the pathophysiology of post-traumatic stress disorder: implications for targeted pharmacological treatment.

Abstract: Post-traumatic stress disorder (PTSD) is a common and chronic anxiety disorder that can result after exposure to a traumatic event. Though our understanding of the aetiology of PTSD is incomplete, several neurobiological systems have been implicated in the pathophysiology and vulnerability towards developing PTSD after trauma exposure. We aimed to provide a concise review of benchmark findings in important neurobiological systems related to the aetiology and maintenance of PTSD symptomology. Specifically, we discuss functional aetiologies in the noradrenergic, serotonergic, endogenous cannabinoid and opioid systems as well as the hypothalamic-pituitary adrenal (HPA) axis. This article provides a succinct framework to appreciate the current understanding of neurobiological mechanisms related to the pathophysiology of PTSD and how these findings may impact the development of future, targeted pharmacological treatments for this debilitating disorder.

Clinically Significant Drug Interactions with Atypical Antipsychotics

Abstract: Atypical antipsychotics [also known as second-generation antipsychotics (SGAs)] have become a mainstay therapeutic treatment intervention for patients with schizophrenia, bipolar disorders and other psychotic conditions. These agents are commonly used with other medications--most notably, antidepressants and antiepileptic drugs. Drug interactions can take place by various pharmacokinetic, pharmacodynamic and pharmaceutical mechanisms. The pharmacokinetic profile of each SGA, especially with phase I and phase II metabolism, can allow for potentially significant drug interactions. Pharmacodynamic interactions arise when agents have comparable receptor site activity, which can lead to additive or competitive effects without alterations in measured plasma drug concentrations. Additionally, the role of drug transporters in drug interactions continues to evolve and may effect both pharmacokinetic and pharmacodynamic interactions. Pharmaceutical interactions occur when physical incompatibilities take place between agents prior to drug absorption. Approximate therapeutic plasma concentration ranges have been suggested for a number of SGAs. Drug interactions that markedly increase or decrease the concentrations of these agents beyond their ranges can lead to adverse events or diminished clinical efficacy. Most clinically significant drug interactions with SGAs occur via the cytochrome P450 (CYP) system. Many but not all drug interactions with SGAs are identified during drug discovery and pre-clinical development by employing a series of standardized in vitro and in vivo studies with known CYP inducers and inhibitors. Later therapeutic drug monitoring programmes, clinical studies and case reports offer methods to identify additional clinically significant drug interactions. Some commonly co-administered drugs with a significant potential for drug-drug interactions with selected SGAs include some SSRIs. Antiepileptic mood stabilizers such as carbamazepine and valproate, as well as other antiepileptic drugs such as phenobarbital and phenytoin, may decrease plasma SGA concentrations. Some anti-infective agents such as protease inhibitors and fluoroquinolones are of concern as well. Two additional important factors that influence drug interactions with SGAs are dose and time dependence. Smoking is very common among psychiatric patients and can induce CYP1A2 enzymes, thereby lowering expected plasma levels of certain SGAs. It is recommended that ziprasidone and lurasidone are taken with food to promote drug absorption, otherwise their bioavailability can be reduced. Clinicians must be aware of the variety of factors that can increase the likelihood of clinically significant drug interactions with SGAs, and must carefully monitor patients to maximize treatment efficacy while minimizing adverse events.

Newly initiated opioid treatment and the risk of fall-related injuries. A nationwide, register-based, case-crossover study in Sweden.

Abstract: There is growing epidemiological evidence that opioids may increase the risk of unintentional injuries and it is plausible that the time of initiation is most critical in that respect. Studies on fall-related injuries remain few, limited and mostly focused on specific groups of elderly patients. The objective of this study was to assess the short-term effects of newly prescribed opioids on the risk of fall-related injuries in the general adult population. A case-crossover design was applied on national register data linking, at the individual level, fall-injury information involving adults aged 18 years and above identified in the Swedish National Inpatient Register (during the period 1 May 2006 to 31 December 2009) and dispensed drugs from the Swedish Prescribed Drug Register (n = 167,257 cases with a first fall-related injury). All types of opioid substances were considered, classified according to the Anatomical Therapeutic Chemical (ATC) classification system. We investigated newly dispensed opioids 28 days preceding the injury, compared with an earlier, and equally long, control period following a 3-month washout period. Conditional logistic regression was used to estimate odds ratio (OR) and 95 % confidence interval (CI). The analyses were also conducted stratified by age group, by type of fall and for each period of 1 week during the 28-day period. From among the fall-injured patients, 7,450 patients (4.5 %) had a new opioid dispensation within 28 days prior to the injury, of which the most frequent types were tramadol (2.0 %) and codeine (1.1 %). Consistently increased risks of fall-related injuries associated with a new prescription of any opioid were found and they were most pronounced among young adults, 18–29 years of age (OR, 7.17; 95 % CI 5.04–10.2). The closer the dispensation date to the injury, the higher the odds: an OR of 5.14 (95 % CI 4.76–5.55) during the first week of opioid treatment and 1.23 (95 % CI 1.10–1.38) for the fourth week. Of the documented falls, the risk was most pronounced for falls from ‘another, high level’ (OR, 5.33; 95 % CI 3.99–7.10). Newly prescribed opioids may trigger injurious falls. The effect lowers over time and is less pronounced with increasing age. The risk is also higher for fall from height.

Role of orexin in the pathophysiology of depression: potential for pharmacological intervention.

Abstract: Depression is a devastating mental disorder with an increasing impact throughout the world, whereas the efficacy of currently available pharmacological treatment is still limited. Growing evidence from preclinical and clinical studies suggests that orexins (neuropeptides that are also known as hypocretins) and their receptors are involved in the physiopathology of depression. Indeed, the orexinergic system regulates functions that are disturbed in depressive states such as sleep, reward system, feeding behavior, the stress response and monoaminergic neurotransmission. Nevertheless, the precise role of orexins in behavioral and neurophysiological impairments observed in depression is still unclear. Both hypoactivity and hyperactivity of orexin signaling pathways have been found to be associated with depression. These discrepancies in the literature prompted the necessity for additional investigations, as the orexinergic system appears to be a promising target to treat the symptoms of depression. This assumption is underlined by recent data suggesting that pharmacological blockade of orexin receptors induces a robust antidepressant-like effect in an animal model of depression. Further preclinical and clinical studies are needed to progress the overall understanding of the orexinergic alterations in depression, which will eventually translate preliminary observations into real therapeutic potential. The aim of this paper is to provide an overview of human and animal research dedicated to the study of the specific involvement of orexins in depression, and to propose a framework in which disturbances of the orexinergic system are regarded as an integral component of the etiology of depression.

Genetic influences on response to mood stabilizers in bipolar disorder: current status of knowledge.

Abstract: Mood stabilizers form a cornerstone in the long-term treatment of bipolar disorder. The first representative of their family was lithium, still considered a prototype drug for the prevention of manic and depressive recurrences in bipolar disorder. Along with carbamazepine and valproates, lithium belongs to the first generation of mood stabilizers, which appeared in psychiatric treatment in the 1960s. Atypical antipsychotics with mood-stabilizing properties and lamotrigine, which were introduced in the mid-1990s, form the second generation of such drugs. The response of patients with bipolar disorder to mood stabilizers has different levels of magnitude. About one-third of lithium-treated patients are excellent responders, showing total prevention of the episodes, and these patients are clinically characterized by an episodic clinical course, complete remission, a bipolar family history, low psychiatric co-morbidity and a hyperthymic temperament. It has been suggested that responders to carbamazepine or lamotrigine may differ clinically from responders to lithium. The main phenotype of the response to mood stabilizers is a degree of prevention against recurrences of manic and depressive episodes during long-term treatment. The most specific scale in this respect is the so-called Alda scale, where retrospective assessment of lithium response is scored on a 0–10 scale. The vast majority of data on genetic influences on the response to mood stabilizers has been gathered in relation to lithium. The studies on the mechanisms of action of lithium and on the neurobiology of bipolar disorder have led to the identification of a number of candidate genes. The genes studied for their association with lithium response have been those connected with neurotransmitters (serotonin, dopamine and glutamate), second messengers (phosphatidyl inositol [PI], cyclic adenosine-monophosphate [cAMP] and protein kinase C [PKC] pathways), substances involved in neuroprotection (brain-derived neurotrophic factor [BDNF] and glycogen synthase kinase 3-β [GSK-3β]) and a number of other miscellaneous genes. There are no published pharmacogenomic studies of mood stabilizers other than lithium, except for one study of the X-box binding protein 1 (XBP1) gene in relation to the efficacy of valproate. In recent years, a number of genome-wide association studies (GWAS) in bipolar disorders have been performed and some of those have also focused on lithium response. They suggest roles for the glutamatergic receptor AMPA (GRIA2) gene and the amiloride-sensitive cation channel 1 neuronal (ACCN1) gene in long-term lithium response. A promise for better elucidating the genetics of lithium response has been created by the formation of the Consortium on Lithium Genetics (ConLiGen) to establish the largest sample, to date, for the GWAS of lithium response in bipolar disorder. The sample currently comprises more than 1,200 patients, characterized by their response to lithium treatment according to the Alda scale. Preliminary results from this international study suggest a possible involvement of the sodium bicarbonate transporter (SLC4A10) gene in lithium response. It is concluded that the pharmacogenetics of response to mood stabilizers has recently become a growing field of research, especially so far as the pharmacogenetics of the response to lithium is concerned. Clearly, the ConLiGen project is a highly significant step in this research. Although the results of pharmacogenetic studies are of significant scientific value, their possible practical implications are yet to be seen.

Intrathecal Ziconotide: A Review of Its Use in Patients with Chronic Pain Refractory to Other Systemic or Intrathecal Analgesics

Abstract: Ziconotide (Prialt®) is a synthetic conopeptide analgesic that acts by selectively antagonizing N-type voltage-gated calcium channels. Intrathecal ziconotide is the only non-opioid intrathecal analgesic that is FDA-approved for use in patients with treatment-refractory, chronic pain. The efficacy of intrathecal ziconotide was demonstrated in randomized, double-blind, placebo-controlled trials in patients with treatment-refractory noncancer-related pain or cancer- or AIDS-related pain. Across trials, ziconotide recipients had significantly greater reductions in pain intensity during ziconotide treatment than those receiving placebo (primary endpoint). At the end of the titration period, approximately one-sixth to one-third of patients with noncancer chronic pain and one-half with cancer- or AIDS-related pain who received ziconotide reached a pain response threshold (≥30 % reduction in the pain intensity score). In ziconotide responders, analgesic effects were enduring, with some patients continuing treatment over extended periods. Across trials, the chief tolerability concerns in ziconotide recipients during the titration phase and during extended treatment were related to CNS adverse events. These were mostly of mild to moderate intensity, although serious adverse events were commonly attributed to ziconotide treatment, especially in trials with rapid ziconotide titration and that permitted higher dosages. In general, clinically important non-CNS adverse events were infrequent, and during the ziconotide titration phase, relatively few patients discontinued treatment because of adverse events. Ongoing research will assess various strategies for selecting patients for ziconotide treatment and for enhancing its efficacy and tolerability. At the present time, intrathecal ziconotide provides a treatment option for patients with severe, unremitting pain who have failed to respond to other intensive analgesic regimens.