Showing papers in "CNS Drugs in 2009"

Getting into the brain: approaches to enhance brain drug delivery.

Abstract: Being the most delicate organ of the body, the brain is protected against potentially toxic substances by the blood-brain barrier (BBB), which restricts the entry of most pharmaceuticals into the brain. The developmental process for new drugs for the treatment of CNS disorders has not kept pace with progress in molecular neurosciences because most of the new drugs discovered are unable to cross the BBB. The clinical failure of CNS drug delivery may be attributed largely to a lack of appropriate drug delivery systems. Localized and controlled delivery of drugs at their desired site of action is preferred because it reduces toxicity and increases treatment efficiency. The present review provides an insight into some of the recent advances made in the field of brain drug delivery.The various strategies that have been explored to increase drug delivery into the brain include (i) chemical delivery systems, such as lipid-mediated transport, the prodrug approach and the lock-in system; (ii) biological delivery systems, in which pharmaceuticals are re-engineered to cross the BBB via specific endogenous transporters localized within the brain capillary endothelium; (iii) disruption of the BBB, for example by modification of tight junctions, which causes a controlled and transient increase in the permeability of brain capillaries; (iv) the use of molecular Trojan horses, such as peptidomimetic monoclonal antibodies to transport large molecules (e.g. antibodies, recombinant proteins, nonviral gene medicines or RNA interference drugs) across the BBB; and (v) particulate drug carrier systems. Receptor-mediated transport systems exist for certain endogenous peptides, such as insulin and transferrin, enabling these molecules to cross the BBB in vivo.The use of polymers for local drug delivery has greatly expanded the spectrum of drugs available for the treatment of brain diseases, such as malignant tumours and Alzheimer's disease. In addition, various drug delivery systems (e.g. liposomes, microspheres, nanoparticles, nanogels and bionanocapsules) have been used to enhance drug delivery to the brain. Recently, microchips and biodegradable polymers have become important in brain tumour therapy.The intense search for alternative routes of drug delivery (e.g. intranasal drug delivery, convection-enhanced diffusion and intrathecal/intraventricular drug delivery systems) has been driven by the need to overcome the physiological barriers of the brain and to achieve high drug concentrations within the brain. For more than 30 years, considerable efforts have been made to enhance the delivery of therapeutic molecules across the vascular barriers of the CNS. The current challenge is to develop drug delivery strategies that will allow the passage of drug molecules through the BBB in a safe and effective manner.

Toward a new understanding of attention-deficit hyperactivity disorder pathophysiology: an important role for prefrontal cortex dysfunction.

Abstract: Recent advances in neurobiology have aided our understanding of attention-deficit hyperactivity disorder (ADHD). The higher-order association cortices in the temporal and parietal lobes and prefrontal cortex (PFC) interconnect to mediate aspects of attention. The parietal association cortices are important for orienting attentional resources in time/space, while the temporal association cortices analyse visual features critical for identifying objects/places. These posterior cortices are engaged by the salience of a stimulus (its physical characteristics such as movement and colour). Conversely, the PFC is critical for regulating attention based on relevance (i.e. its meaning). The PFC is important for screening distractions, sustaining attention and shifting/dividing attention in a task-appropriate manner. The PFC is critical for regulating behaviour/emotion, especially for inhibiting inappropriate emotions, impulses and habits. The PFC is needed for allocating/planning to achieve goals and organizing behaviour/thought. These regulatory abilities are often referred to as executive functions. In humans, the right hemisphere of the PFC is important for regulating distractions, inappropriate behaviour and emotional responses. Imaging studies of patients with ADHD indicate that these regions are underactive with weakened connections to other parts of the brain. The PFC regulates attention and behaviour through networks of interconnected pyramidal cells. These networks excite each other to store goals/rules to guide actions and are highly dependent on their neurochemical environment, as small changes in the catecholamines noradrenaline (NA) or dopamine (DA) can have marked effects on PFC function. NA and DA are released in the PFC according to our arousal state; too little (during fatigue or boredom) or too much (during stress) impairs PFC function. Optimal amounts are released when we are alert/interested. The beneficial effects of NA occur at postsynaptic alpha(2A)-receptors on the dendritic spines of PFC pyramidal cells. Stimulation of these receptors initiates a series of chemical events inside the cell. These chemical signals lead to the closing of special ion channels, thus strengthening the connectivity of network inputs to the cell. Conversely, the beneficial effects of moderate amounts of DA occur at D(1) receptors, which act by weakening irrelevant inputs to the cells on another set of spines. Genetic linkage studies of ADHD suggest that these catecholamine pathways may be altered in some families with ADHD, e.g. alterations in the enzyme that synthesizes NA (DA beta-hydroxylase) are associated with weakened PFC abilities. Pharmacological studies in animals indicate catecholamine actions in the PFC are highly relevant to ADHD. Blocking NA alpha(2A)-receptors in the PFC with yohimbine produces a profile similar to ADHD: locomotor hyperactivity, impulsivity and poor working memory. Conversely, drugs that enhance alpha(2)-receptor stimulation improve PFC function. Guanfacine directly stimulates postsynaptic alpha(2A)-receptors in the PFC and improves functioning, while methylphenidate and atomoxetine increase endogenous NA and DA levels and indirectly improve PFC function via alpha(2A)- and D(1) receptor actions. Methylphenidate and atomoxetine have more potent actions in the PFC than in subcortical structures, which may explain why proper administration of stimulant medications does not lead to abuse. Further understanding of the neurobiology of attention and impulse control will allow us to better tailor treatments for specific patient needs.

Withdrawing Benzodiazepines in Primary Care

Abstract: The use of benzodiazepine anxiolytics and hypnotics continues to excite controversy. Views differ from expert to expert and from country to country as to the extent of the problem, or even whether long-term benzodiazepine use actually constitutes a problem. The adverse effects of these drugs have been extensively documented and their effectiveness is being increasingly questioned. Discontinuation is usually beneficial as it is followed by improved psychomotor and cognitive functioning, particularly in the elderly. The potential for dependence and addiction have also become more apparent. The licensing of SSRIs for anxiety disorders has widened the prescribers’ therapeutic choices (although this group of medications also have their own adverse effects). Melatonin agonists show promise in some forms of insomnia. Accordingly, it is now even more imperative that long-term benzodiazepine users be reviewed with respect to possible discontinuation. Strategies for discontinuation start with primary-care practitioners, who are still the main prescribers.

STAR*D: Revising Conventional Wisdom

Abstract: The STAR * D (Sequenced Treatment Alternatives to Relieve Depression) study used a series of sequenced, randomized treatment trials following a first and, if needed, subsequent treatment steps to define the tolerability and effectiveness of various options in both acute and longer term treatment. Adult outpatients (n = 4041) with nonpsychotic major depressive disorder, substantial chronic and recurrent depression, and co-morbid psychiatric and general medical conditions were enrolled in 41 representative primary and specialty care settings. About one-third of participants remitted in first step treatment with citalopram, 50% of these within 6 weeks. Poorer outcomes were associated with minority status, socioeconomic disadvantage, more axis I and III co-morbid disorders, lower function and quality of life, and anxious and melancholic features. In step 2 medication switch, there were no significant differences in remission among within-class, out-of-class or dual-action agents: sertraline (27%), bupropion-sustained release (26%) and venlafaxine-extended release (25%). In step 2 medication augmentation of citalopram, there was no significant difference in remission between bupropion-sustained release (39%) and buspirone (33%), although participants using bupropion-sustained release had greater symptom reduction and better tolerability. There were no significant differences in remission in step 2 between cognitive therapy and medication treatment in either the switch (31% vs 27%) or augmentation (31% vs 33%) strategies, although participants in cognitive therapy augmentation had a longer time to remission than those in medication augmentation (55 vs 40 days). In step 3, there were no differences in remission between a switch to mirtazapine (8%) or nortriptyline (12%), or between augmentation with lithium (13%) or T 3 (triiodothyronine, liothyronine) [25%], although more participants discontinued lithium due to adverse effects than discontinued T 3 . In the fourth step, there was no difference in remission between tranylcypromine (14%) or venlafaxine-extended release plus mirtazapine (16%), although the combination treatment had fewer adverse effects and had the advantages of not requiring a washout period or diet restrictions. Participants requiring more than two well delivered treatments may be characterized as treatment resistant given the substantially lower remission rates after that point. Treatment resistance was associated with more concurrent axis I or III co-morbid conditions, socioeconomic disadvantage, chronicity and melancholic or anxious features. However, if participants remained in treatment for up to four steps, about 67% reached remission. Times to remission were not substantially longer for later treatment steps. The importance of reaching remission is highlighted by the lower relapse rates in naturalistic follow-up for participants entering in remission compared with those entering with response but not remission (step 1: 34% vs 59%; step 2: 47% vs 68%; step 3: 42% vs 76%; step 4: 50% vs 83%). Clinical decision making based on the itemized measurement of symptoms and adverse effects at each treatment visit was feasible in STAR * D's real world settings and resulted in adequate dosages and durations of treatment that generally exceeded those typically found in practice settings. Although switch and augmentation strategies could not be directly compared due to the equipoise stratified randomized design, the higher remission rates at step 2 with medication augmentation are intriguing and merit further study.

Dopamine dysregulation syndrome: an overview of its epidemiology, mechanisms and management.

Abstract: Dopamine dysregulation syndrome (DDS) is a relatively recently described iatrogenic disturbance that may complicate long-term symptomatic therapy of Parkinson’s disease. Patients with DDS develop an addictive pattern of dopamine replacement therapy (DRT) use, administering doses in excess of those required to control their motor symptoms. The prevalence of DDS in patients attending specialist Parkinson’s disease centres is 3–4%. Amongst the behavioural disturbances associated with DDS are punding, which is a complex stereotyped behaviour, and impulse control disorders (ICDs), such as pathological gambling, hypersexuality, compulsive shopping and compulsive eating.

Lithium: updated human knowledge using an evidence-based approach. Part II: Clinical pharmacology and therapeutic monitoring.

Abstract: After a single dose, lithium, usually given as carbonate, reaches a peak plasma concentration at 1.0-2.0 hours for standard-release dosage forms, and 4-5 hours for sustained-release forms. Its bioavailability is 80-100%, its total clearance 10-40 mL/min and its elimination half-life is 18-36 hours. Use of the sustained-release formulation results in 30-50% reductions in peak plasma concentrations without major changes in the area under the plasma concentration curve. Lithium distribution to the brain, evaluated using 7Li magnetic resonance spectroscopy, showed brain concentrations to be approximately half those in serum, occasionally increasing to 75-80%. Brain concentrations were weakly correlated with serum concentrations. Lithium is almost exclusively excreted via the kidney as a free ion and lithium clearance is considered to decrease with aging. No gender- or race-related differences in kinetics have been demonstrated. Renal insufficiency is associated with a considerable reduction in renal clearance of lithium and is considered a contraindication to its use, especially if a sodium-poor diet is required. During the last months of pregnancy, lithium clearance increases by 30-50% as a result of an increase in glomerular filtration rate. Lithium also passes freely from maternal plasma into breast milk. Numerous kinetic interactions have been described for lithium, usually involving a decrease in the drug's clearance and therefore increasing its potential toxicity. Clinical pharmacology studies performed in healthy volunteers have investigated a possible effect of lithium on cognitive functions. Most of these studies reported a slight, negative effect on vigilance, alertness, learning and short-term memory after long-term administration only. Because of the narrow therapeutic range of lithium, therapeutic monitoring is the basis for optimal use and administration of this drug. Lithium dosages should be adjusted on the basis of the serum concentration drawn (optimally) 12 hours after the last dose. In patients receiving once-daily administration, the serum concentration at 24 hours should serve as the control value. The efficacy of lithium is clearly dose-dependent and reliably correlates with serum concentrations. It is now generally accepted that concentrations should be maintained between 0.6 and 0.8 mmol/L, although some authors still favour 0.8-1.2 mmol/L. With sustained-release preparations, and because of the later peak of serum lithium concentration, it is advised to keep serum concentrations within the upper range (0.8-1 mmol/L), rather than 0.6-0.8 mmol/L for standard formulations. It is controversial whether a reduced concentration is required in elderly people. The usual maintenance daily dose is 25-35 mmol (lithium carbonate 925-1300 mg) for patients aged 60 years. The initial recommended dose is usually 12-24 mmol (450-900 mg) per day, depending on age and bodyweight. The classical administration schedule is two or three times daily, although there is no strong evidence in favour of a three-times-daily schedule, and compliance with the midday dose is questionable. With a modern sustained-release preparation, the twice-daily schedule is well established, although one single evening dose is being recommended by a number of expert panels.

Lithium: updated human knowledge using an evidence-based approach. Part III: clinical safety

Abstract: Lithium use in mental diseases has changed over the years but remains a cornerstone of treatment in bipolar disorders. In two companion papers, we have reviewed existing (and especially recent) data on lithium efficacy and updated basic knowledge regarding the practical fundamentals of lithium therapy. The present paper reviews safety data on lithium available to date. Gastrointestinal pain or discomfort, diarrhoea, tremor, polyuria, nocturnal urination, weight gain, oedema, flattening of affect and exacerbation of psoriasis are typical complaints of patients receiving long-term lithium therapy. Renal involvement results in a reduced urinary concentrating capacity, expressed as obligate polyuria, with secondary thirst. With long-term therapy, this may result in nephrogenic diabetes insipidus. In addition, glomerular filtration rate falls slightly in about 20% of patients. The view that only a few patients receiving long-term lithium are at increased risk of glomerular impairment and progressive renal insufficiency should be regarded with caution. The risk is increased in case of concomitant diseases or medications. Lithium treatment may inhibit thyroid hormone release and induce goitre. Consequently, the prevalence of both overt and subclinical hypothyroidism is increased, with circulating thyroid auto-antibodies frequently being found. Much less commonly, thyrotoxicosis may also develop in association with lithium therapy. Long-term lithium treatment may also be associated with persistent hyperparathyroidism and hypercalcaemia, as well as with hypermagnesaemia. Overweight of up to 4-10 kg is found in approximately 30% of lithium-treated patients. Most neurological manifestations are benign, for example, the fine postural and/or action tremor present in 4-20% of patients. This is increased by high caffeine consumption and concomitant use of other psychotropic agents. A number of rare, potentially serious neurological adverse effects have been reported, including extrapyramidal symptoms, 'pseudotumour cerebri' or occasionally cerebellar symptoms. Severe neurological sequelae are exceptional. Cognitive disturbances are often mentioned as a lithium-related adverse effect. The few controlled studies do show a statistically significant negative effect of lithium on memory, vigilance, reaction time and tracking. There are frequent reports of mild effects of lithium on cognition at therapeutic serum concentrations. A number of deaths associated with lithium treatment have been reported. The most serious issue is that of non-accidental overdose, i.e. either long-term overdosage or acute overdose on long-term treatment. Progressive renal insufficiency, an exceptional complication of long-term lithium therapy, may also have a fatal outcome. In relation to pregnancy, lithium salts are rated as category D (positive evidence of risk). Therefore, prescription of lithium should be avoided during the first trimester of pregnancy unless the benefit to the mother exceeds the risk to the fetus. Although lithium transfer into breast milk is well established, the long-term fate of babies breast-fed by mothers receiving lithium therapy is unknown. Whether lithium therapy is safe in breast-feeding women is controversial. Although there is no absolute contraindication, it is known that the kidney is particularly sensitive to lithium just after birth. Intoxication in patients on long-term treatment with lithium in the absence of history of acute ingestion is not rare. Contributing factors include change in daily dose, long-term high dosage, kidney disease or drug interaction. In suspected cases, serum concentrations should be obtained early and repeatedly. In addition to supportive measures, haemodialysis is the treatment of choice for severe cases. Thorough knowledge of the limitations and drawbacks of lithium therapy is mandatory for its optimal use, especially at a time when its risk/benefit profile needs to be compared accurately with that of antiepileptic drugs and other mood stabilizing medications.

Antiepileptic drug-induced cognitive adverse effects: potential mechanisms and contributing factors.

Abstract: Cognitive dysfunction is frequently observed in patients with epilepsy and represents an important challenge in the management of patients with this disorder. In this respect, the relative contribution of antiepileptic drugs (AEDs) is of relevance. The fact that a considerable number of patients require AED therapy for many years, or perhaps even a lifetime, emphasizes the need to focus on the long-term adverse effects of these drugs on cognition. The most prevalent of the CNS adverse effects observed during AED therapy are sedation, somnolence, distractibility, insomnia and dizziness. Sedation, in particular, is associated with most of the commonly used AED therapies. Nevertheless, cognitive function in individuals with epilepsy may also be influenced by several factors, of which AEDs constitute only one of many putative causes. In general terms, most studies agree that some differences exist among the older AEDs with regard to the effects on cognition, and some newer generation molecules may have a better cognitive profile than older AEDs. The mechanisms of action are an obvious determinant; however, there is still a lack of evidence for differentiation between available drugs with regard to cognitive effects. Some authors have suggested that there may be different cognitive effects associated with individual drugs; however, the question as to whether there are more specific deficits related to the action of individual drugs remains unsolved. There seems to be agreement that polytherapy and high-dose treatment can produce cognitive adverse effects and when high dosages or adjunctive polytherapy is needed, the balance between benefits and disadvantages may be negatively biased against drug treatment. Thus, drug treatment requires careful balancing in the attempt to reach maximal seizure control while avoiding neurotoxic adverse effects. Finally, the mood status of the patient and clinical relevance of the information obtained by neuropsychological testing represent important variables that need to be taken into account when discussing cognitive adverse effects of AEDs.

Efficacy and safety limitations of attention-deficit hyperactivity disorder pharmacotherapy in children and adults.

Abstract: There have been major advances in the treatment and understanding of attention-deficit hyperactivity disorder (ADHD) in the last decade. Among these are the availability of newer stimulant formulations, an appreciation of the combined effects of medication and behavioural therapies, and a better understanding of the neurobiology of the disorder in children (aged 6-12 years), adolescents and adults. This article focuses on the evaluation of the efficacy and safety profiles of medications used for the management of ADHD. In assessing the various medical treatments for ADHD, certain issues and analyses have become important to address. The diagnosis, characterization and quantification of ADHD symptoms are crucial to assessing treatment effectiveness. A standardized setting for measuring the severity of ADHD symptoms is the laboratory school protocol, which simulates a school environment with tightly controlled timing of measurements. This method has been adapted successfully to the adult workplace environment to help with the evaluation of adult ADHD symptoms. Statistical analyses, such as effect size and number needed to treat, may aid in the comparison and interpretation of ADHD study results. Although an objective approach to evaluating the efficacy and safety profiles of the available medications provides necessary details about the medical options, typical clinical decisions are often based on trial and error and may be individualized based on a patient's daily routine, comorbidities and risk factors. Stimulants remain the US FDA-approved medical treatment of choice for patients with ADHD and are associated with an exceptional response rate. Findings of the Multimodal Treatment of Children With ADHD study suggest that the combination of behavioural and medical therapy may benefit most patients. Nonstimulant agents, such as atomoxetine (FDA-approved), and several non-approved agents, bupropion, guanfacine and clonidine, may offer necessary alternatives to the stimulants. This is especially important for patients who have comorbidities that are contraindicated for stimulant use based on medical issues and/or risk for stimulant abuse. Typical psychiatric comorbidities in patients with ADHD include oppositional defiant disorder, conduct disorder, major depressive disorder, bipolar disorder, anxiety, substance abuse disorder, tic disorder, and Tourette's syndrome. Although relatively safe, both stimulants and atomoxetine have class-related warnings and contraindications and are associated with adverse effects that require consideration when prescribing. Polypharmacy is a common psychiatric approach to address multiple symptoms or emergent adverse effects of necessary treatments. Future research may provide an improved understanding of polypharmacy and better characterization of the factors that influence the diagnosis and successful treatment of patients with ADHD.

Pharmacological manipulation of kynurenic acid: potential in the treatment of psychiatric disorders.

Abstract: The kynurenine pathway constitutes the main route of tryptophan degradation and generates the production of several neuroactive compounds; quinolinic acid is an excitotoxic NMDA receptor agonist, 3-hydroxykynurenine is a free-radical generator and kynurenic acid (KYNA) is an antagonist at glutamate and nicotinic receptors. In low micromolar concentrations, KYNA blocks the glycine site of the NMDA receptor and the nicotinic α7* acetylcholine receptor. Knowledge regarding kynurenine metabolites and their involvement in neurophysiological processes has increased dramatically in recent years. In particular, endogenous KYNA appears to tightly control firing of midbrain dopamine neurons and to be involved in cognitive functions. Thus, decreased endogenous levels of rat brain KYNA have been found to reduce firing of these neurons, and mice with a targeted deletion of kynurenine aminotransferase II display low endogenous brain KYNA levels concomitant with an increased performance in cognitive tests. It is also suggested that kynurenines participate in the pathophysiology of psychiatric disorders. Thus, elevated levels of KYNA have been found in the CSF as well as in the post-mortem brain of patients with schizophrenia. Advantages in understanding how kynurenines can be pharmacologically manipulated may provide new possibilities in the treatment of psychiatric disorders, such as schizophrenia.

Neuroleptic malignant syndrome associated with atypical antipsychotic drugs.

Abstract: Neuroleptic malignant syndrome (NMS) is a rare but potentially severe idiosyncratic adverse reaction usually seen in the context of treatment with antipsychotic drugs. Although NMS is historically associated with the classic or 'typical' antipsychotic drugs, it is also a potential adverse effect of atypical antipsychotic drugs. The widespread use of atypical antipsychotic drugs highlights the need to examine the data relating to the symptomatology, diagnosis, classification and management of NMS with these newer agents. We used MEDLINE and EMBASE to identify NMS case reports and systematic reviews published to June 2008 related to the atypical antipsychotic drugs clozapine, olanzapine, risperidone, paliperidone, aripiprazole, ziprasidone, amisulpride and quetiapine. Case reports and reviews were systematically examined. Our review suggests that, in general, NMS associated with atypical antipsychotic drugs manifests in a typical manner. One notable exception is clozapine-induced NMS, which appears less likely to manifest with extrapyramidal features, including rigidity and tremor. The available literature highlights the divergence of opinion relating to the core diagnostic features of NMS and its conceptualization as a categorical versus dimensional disorder. Both these issues have relevance for the identification of atypical or milder forms of NMS, which are sometimes seen with atypical antipsychotic drugs.

Lithium: updated human knowledge using an evidence-based approach: Part I: Clinical efficacy in bipolar disorder

Abstract: Although there has been a decrease in lithium use over several years, it is still recommended as a first-line mood stabilizer in all recent guidelines. It has been argued that many studies of lithium were conducted at a time when study design, assessment standards and the diagnostic criteria for patient selection were not as established as they presently are. However, recent placebo-controlled data from three-arm trials have demonstrated a definite efficacy of lithium in bipolar disorder. Regarding mania, recent trials of novel antimanic treatments (such as second-generation antipsychotics) that have included both placebo and lithium control groups have confirmed that lithium is effective in the treatment of moderate to severe manic episodes. The efficacy of lithium as monotherapy for acute bipolar depression is still controversial, but this therapy is recognized as a therapeutic option. For maintenance therapy, lithium is superior to placebo for the prevention of relapse or recurrence of mood episodes in bipolar I disorder patients with recent manic or hypomanic episodes. Lithium is more effective in preventing episodes of the manic/hypomanic type, including mixed episodes, than preventing depressive episodes. In rapid cycling patients, lithium improves clinical symptoms as efficiently as in nonrapid cycling persons, but is not likely to prevent recurrences. Finally, data from a number of studies suggest that lithium reduces the high suicide rates associated with mood disorders. A well designed cohort study and two independent meta-analyses are in agreement with this finding. In conclusion, most experts, and the most recent guidelines, continue to consider lithium as a keystone therapy of bipolar disorders.

Mirtazapine: a review of its use in major depression and other psychiatric disorders.

Abstract: Mirtazapine (Remeron ® , Zispin ® ) is a noradrenergic and specific serotonergic antidepressant (NaSSA) that is approved in many counties for use in the treatment of major depression. Monotherapy with mirtazapine 15―45 mg/day leads to rapid and sustained improvements in depressive symptoms in patients with major depression, including the elderly. It is as effective as other antidepressants and may have a more rapid onset of action than selective serotonin reuptake inhibitors (SSRIs). Furthermore, it may also have a higher sustained remission rate than amitriptyline. Preliminary data suggest that mirtazapine may also be effective in the treatment of anxiety disorders (including post-traumatic stress disorder, panic disorder and social anxiety disorder), obsessive-compulsive disorder, undifferentiated somatoform disorder and, as add-on therapy, in schizophrenia, although large, well designed trials are needed to confirm these findings. Mirtazapine is generally well tolerated in patients with depression. In conclusion, mirtazapine is an effective antidepressant for the treatment of major depression and also has the potential to be of use in other psychiatric indications. The antidepressant activity of mirtazapine, an NaSSA agent, is thought to result from a combination of noradrenergic and serotonergic effects, with the latter specifically involving enhancement of serotonin 5-HT 1 receptor-mediated effects. It acts as an antagonist at central α 2 -adrenergic autoreceptors and heteroreceptors, and postsynaptic 5-HT 2 and 5-HT 3 receptors. Mirtazapine has low affinity for central and peripheral dopaminergic receptors, but is a potent antagonist of histamine H 1 receptors and a moderate antagonist at muscarinic receptors. Mirtazapine improves sleep efficiency and continuity, and does not suppress rapid eye movement sleep. Mirtazapine is absorbed rapidly after oral administration, with peak plasma concentrations achieved within 2 hours. Food has no clinically relevant effect on absorption. Mirtazapine displays linear pharmacokinetics over the therapeutic dosage range, and steady state is reached after =5 days. Mirtazapine is extensively metabolized, principally via cytochrome P450 (CYP) isoenzymes CYP3A4, CYP2D6 and CYP1A2. The elimination half-life of mirtazapine is 20―40 hours. Mirtazapine is a racemate and the enantiomers display differing pharmacokinetic and pharmacodynamic properties; both enantiomers contribute to the pharmacodynamic effects of mirtazapine. A number of well designed trials have demonstrated the efficacy of mirtazapine in the treatment of patients with moderate to severe major depression. Mirtazapine was more effective than placebo at relieving the symptoms of depression in short-term studies and effectively prevented relapse for up to 1 year. In short-term comparisons with tricyclic antidepressants (TCAs) and related drugs, mirtazapine showed antidepressant efficacy similar to that of comparator agents such as amitriptyline and trazodone. The proportion of patients classified as Hamilton Depression Rating Scale (HAM-D) responders in comparisons with amitriptyline ranged from 53% to 72% with mirtazapine and from 48% to 72% with amitriptyline. Mirtazapine also had a higher sustained remission rate than amitriptyline in a long-term, double-blind continuation study. In comparisons with trazodone, HAM-D response rates were 51-61% with mirtazapine and 41―51% with trazodone. In comparisons with SSRIs over 6-24 weeks, mirtazapine showed similar antidepressant efficacy to citalopram (single study), fluoxetine, paroxetine and sertraline (single study). Overall, the proportion of patients classified as HAM-D responders at endpoint in these trials was 50-73% for mirtazapine, 45―71% for fluoxetine, 50-56% for paroxetine and 52% for sertraline (HAM-D response data not available for citalopram). Mirtazapine was as effective as venlafaxine in the treatment of hospitalized patients with severe depression with melancholic features. In a meta-analysis comparing 12 newer-generation antidepressants, mirtazapine emerged as one of four agents deemed to have superior efficacy in the acute-phase treatment of major depression. Other meta-analyses of trials comparing mirtazapine with SSRIs found that mirtazapine was associated with an earlier onset of action than SSRIs. The efficacy of mirtazapine has been demonstrated in patients treated in hospital, outpatient and primary care settings. Efficacy has been shown in elderly patients, patients who have not responded to SSRIs and in those with symptoms of anxiety or insomnia. A number of smaller trials (n < 100) have also shown promising results with mirtazapine in other psychiatric disorders, including post-stroke depression, post-traumatic stress disorder, panic disorder, social anxiety disorder, obsessive-compulsive disorder, undifferentiated somatoform disorder and (as add-on therapy) in schizophrenia. Other small studies showed promising results with mirtazapine in patients with major depression and concomitant conditions such as Parkinson's disease, cancer or fibromyalgia syndrome. Mirtazapine was generally well tolerated in clinical trials in patients with major depression. Events occurring at a significantly higher incidence with mirtazapine than with placebo included drowsiness, excessive sedation, increased appetite, weight gain and dry mouth. The pattern of adverse events in elderly patients was similar to that in the overall population. At therapeutic doses, mirtazapine had no significant effect on blood pressure or heart rate and had a low potential for inducing seizures. Mirtazapine generally had no adverse effects on sexual function, and switching patients with SSRI-induced sexual dysfunction to mirtazapine improved sexual function. Compared with TCAs and trazodone, mirtazapine was generally associated with a lower incidence of dizziness, tremor and anticholinergic adverse events. Compared with SSRIs, mirtazapine was associated with less insomnia and nausea, but with more weight gain, dry mouth, fatigue and excessive somnolence.

Of Mice and Men: Bridging the Translational Disconnect in CNS Drug Discovery

Abstract: The tremendous advances in transgene animal technology, especially in the area of Alzheimer's disease, have not resulted in a significantly better success rate for drugs entering clinical development Despite substantial increases in research and development budgets, the number of approved drugs in general has not increased, leading to the so-called innovation gap While animal models have been very useful in documenting the possible pathological mechanisms in many CNS diseases, they are not very predictive in the area of drug development This paper reports on a number of under-appreciated fundamental differences between animal models and human patients in the context of drug discovery with special emphasis on Alzheimer's disease and schizophrenia, such as different affinities of the same drug for human versus rodent target subtypes and the absence of many functional genotypes in animal models I also offer a number of possible solutions to bridge the translational disconnect and improve the predictability of preclinical models, such as more emphasis on good-quality translational studies, more pre-competitive information sharing and the embracing of multi-target pharmacology strategies Re-engineering the process for drug discovery and development, in a similar way to other more successful industries, is another possible but disrupting solution to the growing innovation gap This includes the development of hybrid computational models, based upon documented preclinical physiology and pharmacology, but populated and validated with clinical data from actual patients

Disruption of the circadian timing systems: molecular mechanisms in mood disorders.

Abstract: Depression is one of the leading causes of morbidity worldwide and represents a huge burden to society. As with many other psychiatric disorders, a genetic basis for depression has been identified. Evidence for the role of circadian genes in depression is particularly compelling. Circadian gene mutations are also associated with circadian rhythm disorders such as familial advanced sleep phase syndrome, delayed sleep phase syndrome, and non-24-hour sleep-wake syndrome. Such disorders, plus the other manifestations of a disrupted circadian system such as hormone dysregulation, are often observed among those with depression. This suggests a shared aetiology between circadian disruption and depression, although the exact mechanisms underlying the association are unclear. This paper reviews the molecular mechanisms involved in depression, with an emphasis on circadian genes. Twin studies in depression have reported probandwise concordance rates of 40% and 70% using narrow and broad diagnostic criteria, respectively, and heritability of over 85% for bipolar disorder. In association studies, increased susceptibility to depression has been noted in those with polymorphisms in the following: D-amino-acid-oxidase activator/G30 gene complex, glucocorticoid receptor gene, serotonin transporter gene, tryptophan hydroxylase 2 gene, dopamine transporter gene and G protein-coupled receptor 50 gene. Polymorphisms in these genes have also been linked to a better or worse response to antidepressant therapy, an increased likelihood of responding poorly to adversity and increased suicide ideation. Polymorphisms in the CLOCK, BMAL1, Per3 and TIMELESS genes have been associated with susceptibility to mood disorder, and single nucleotide polymorphisms and haplotypes in several circadian genes have been observed among those displaying certain circadian phenotypes, including worse mood in the evening, insomnia in mania and early, middle or late insomnia in depression. Manipulation of the circadian timing system via sleep deprivation, bright light or pharmacological therapy has also been shown to alleviate depressive symptoms, providing further evidence for the role of circadian dysfunction in depression pathophysiology. The new antidepressant agomelatine is the first melatonergic antidepressant with an innovative mode of action: it is a melatonergic MT(1), MT(2) receptor agonist and 5-HT(2c) antagonist, and is able to restore the internal clock, which is profoundly disturbed in depression, thus being efficacious in major depressive disorders. In conclusion, a wealth of evidence is now available supporting a genetic basis for depression. The apparent importance of mutations in the circadian genes in determining disease susceptibility, disease recurrence and response to treatment suggests that the circadian pathway represents an attractive target for pharmacological manipulation to improve management of this debilitating disorder.

Neurobiology of Circadian Systems

Abstract: Time is a dimension tightly associated with the biology of living species. There are cycles of varied lengths in biological activities, from very short (ultradian) rhythms to rhythms with a period of approximately one day (circadian) and rhythms with longer cycles, of a week, a month, a season, or even longer. These rhythms are generated by endogenous biological clocks, i.e. time-keeping structures, rather than being passive reactions to external fluctuations. In mammals, the suprachiasmatic nucleus (SCN) is the major pacemaker. The pineal gland, which secretes melatonin, is the major pacemaker in other phyla. There also exist biological clocks generating circadian rhythms in peripheral tissues, for example the liver. A series of clock genes generates the rhythm through positive and negative feedback effect of proteins on their own synthesis, and this system oscillates with a circadian period. External factors serve as indicators of the astronomical (solar) time and are called zeitgebers, literally time-givers. Light is the major zeitgeber, which resets daily the SCN circadian clock. In the absence of zeitgebers, the circadian rhythm is said to be free running; it has a period that differs from 24 hours. The SCN, together with peripheral clocks, enables a time-related homeostasis, which can become disorganized in its regulation by external factors (light, social activities, food intake), in the coordination and relative phase position of rhythms, or in other ways. Disturbances of rhythms are found in everyday life (jet lag, shift work), in sleep disorders, and in several psychiatric disorders including affective disorders. As almost all physiological and behavioural functions in humans occur on a rhythmic basis, the possibility that advances, delays or desynchronization of circadian rhythms might participate in neurological and psychiatric disorders has been a theme of research. In affective disorders, a decreased circadian amplitude of several rhythms as well as a phase advance or delay have been described, leading to hypotheses about changes in biological clocks themselves or in their sensitivity to environmental factors, such as light or social cues. Molecular genetics studies have suggested the involvement of circadian clock genes, but no tight association has yet been found. Agomelatine is an antidepressant, agonist at melatonergic MT(1), MT(2) receptors and antagonist at 5-HT(2C) receptors, and is able to phase advance circadian rhythms in humans. The fact that non-pharmacological (light therapy, sleep deprivation, rhythm therapy) and pharmacological (lithium, antidepressants, agomelatine) therapies of affective disorders influence circadian rhythms indicates that biological clocks play a role in the pathophysiology of these disorders.

The CATIE and CUtLASS Studies in Schizophrenia: Results and Implications for Clinicians

Abstract: Numerous double-blind studies have compared second-generation antipsychotics (SGAs) with first-generation antipsychotics (FGAs), with most finding better efficacy and tolerability for SGAs. However, these 'efficacy trials' were generally short term and included only highly selected patients. Mostly because of weight gain and other metabolic effects of the SGAs, as well as their high acquisition price, the debate on the (cost) effectiveness of the SGAs led to two pragmatic clinical trials with no sponsorship by industry. Both trials had broad inclusion criteria and long follow-up, and tried to mimic clinical routine: CATIE (Clinical Antipsychotic Trials of Intervention Effectiveness) and CUtLASS (Cost Utility of the Latest Antipsychotic drugs in Schizophrenia Study). 1493 patients participated in CATIE, an 18-month, double-blind trial comparing the SGAs olanzapine, quetiapine, risperidone and ziprasidone with the FGA perphenazine. If efficacy or tolerability was insufficient, patients were re-randomized to a medication other than the one they previously received. Improvement of psychopathology and of quality of life was only moderate. Overall, 74% of patients discontinued study medication before 18 months, and the median time to discontinuation was 4.6 months. Aside from olanzapine (time to discontinuation 9.2 months), the other SGAs did not differ from each other or from perphenazine. Except for adverse effects as a reason for discontinuation, differences between the SGAs and the FGA were minimal. In CUtLASS, a 12-month open-label trial, 277 patients were randomized to receive an FGA or a SGA. Again, efficacy was rather similar between the two groups, with only limited improvement of psychopathology and quality of life. The authors of both trials concluded that SGAs do not markedly differ from FGAs regarding compliance, quality of life and effectiveness. The methodological problems of both trials have been discussed extensively. Patients had psychotic symptoms that were moderate in severity and were at least partially treatment resistant. The marginal improvement observed indicated that this population might not be appropriate to detect differences between FGAs and SGAs. Specific issues of CATIE include the exclusion of patients with tardive dyskinesia in the perphenazine arm and the high discontinuation rate. In CUtLASS, the concept of including 13 different FGAs and four SGAs in the respective classes was problematic. It is of interest that the most widely prescribed drug was sulpiride--of the FGAs, this is probably the 'most atypical' drug. Aside from the finding that the advantages of the SGAs are not as strong as early trials and marketing suggested or promised, the trials do not provide much helpful information regarding everyday practice. For tardive dyskinesia, no conclusions at all can be drawn. Similarly, methodological problems inhibited the detection of the other major advantage of the SGAs, i.e. the improved subjective well-being/quality of life while receiving these agents. It is well known that patients' and doctors' perspectives differ markedly, and the Quality of Life Scale (QLS), an expert-rated scale used in both trials, might not be sensitive enough to detect the subjective advantages reported by the majority of patients in other trials. CATIE and CUtLASS suggest that SGAs do not live up to all the previous expectations. However, even if most of these advantages are debatable, the lower risk of tardive dyskinesia and the better subjective effects should be strong enough reasons to favour these drugs. There is no single antipsychotic that is best for every schizophrenia patient, as individual responses differ markedly. For successfully individualized treatment, a multitude of antipsychotic options are needed.

Protein Kinase C Inhibitors Rationale for Use and Potential in the Treatment of Bipolar Disorder

Abstract: Bipolar disorder is one of the most severely debilitating of all medical illnesses. For a large number of patients, outcomes are quite poor. The illness results in tremendous suffering for patients and their families and commonly impairs functioning and workplace productivity. Risks of increased morbidity and mortality, unfortunately, are frequent occurrences as well. Until recently, little has been known about the specific molecular and cellular underpinnings of bipolar disorder. Such knowledge is crucial for the prospect of developing specific targeted therapies that are more effective and that have a more rapid onset of action than currently available treatments. Exciting recent data suggest that regulation of certain signalling pathways may be involved in the aetiology of bipolar disorder and that these pathways may be profitably targeted to treat the disorder. In particular, mania is associated with overactive protein kinase C (PKC) intracellular signalling, and recent genome-wide association studies of bipolar disorder have implicated an enzyme that reduces the activation of PKC. Importantly, the current mainstays in the treatment of mania, lithium (a monovalent cation) and valproate (a small fatty acid) indirectly inhibit PKC. In addition, recent clinical studies with the relatively selective PKC inhibitor tamoxifen add support to the relevance of the PKC target in bipolar disorder. Overall, a growing body of work both on a preclinical and clinical level indicates that PKC signalling may play an important role in the pathophysiology and treatment of bipolar disorder. The development of CNS-penetrant PKC inhibitors may have considerable benefit for this devastating illness.

Tumour Necrosis Factor Modulation for Treatment of Alzheimer’s Disease

Abstract: Tumour necrosis factor (TNF), a key regulator of varied physiological mechanisms in multiple organ systems, is an immune signalling molecule produced by glia, neurons, macrophages and other immune cells In the brain, among other functions, TNF serves as a gliotransmitter, secreted by glial cells that envelope and surround synapses, which regulates synaptic communication between neurons The role of TNF as a gliotransmitter may help explain the profound synaptic effects of TNF that have been demonstrated in the hippocampus, in the spinal cord and in a variety of experimental models Excess TNF is present in the CSF of individuals with Alzheimer’s disease (AD), and has been implicated as a mediator of the synaptic dysfunction that is hypothesized to play a central role in the pathogenesis of AD TNF may also play a role in endothelial and microvascular dysfunction in AD, and in amyloidogenesis and amyloid-induced memory dysfunction in AD Genetic and epidemiological evidence has implicated increased TNF production as a risk factor for AD Perispinal administration of etanercept, a potent anti-TNF fusion protein, produced sustained clinical improvement in a 6-month, open-label pilot study in patients with AD ranging from mild to severe Subsequent case studies have documented rapid clinical improvement following perispinal etanercept in both AD and primary progressive aphasia, providing evidence of rapidly reversible, TNF-dependent, pathophysiological mechanisms in AD and related disorders Perispinal etanercept for AD merits further study in randomized clinical trials

Current considerations in the treatment of generalized anxiety disorder.

Abstract: Generalized anxiety disorder (GAD) is a chronic disorder that frequently co-occurs with a variety of co-morbidities in patients with somatic conditions and other mental disorders. GAD is highly prevalent and is one of the most common anxiety disorders seen by primary care physicians. The individual and societal cost associated with GAD is high and the marked level of impairment experienced by patients with this disorder is equivalent in magnitude to that reported in patients with major depressive disorder. Furthermore, patients with GAD are at risk of suicide or suicide attempts, and are frequent users of healthcare services. Thus, GAD is a serious and chronic condition that requires appropriate long-term treatment. The focus of acute treatment for patients with GAD is the improvement of symptoms, while the primary goal of long-term clinical management is remission, i.e. the complete resolution of both symptoms and functional impairment. The consensus across current treatment guidelines is that first-line treatment for patients with GAD should consist of an antidepressant, either a selective serotonin reuptake inhibitor (SSRI) such as sertraline, paroxetine or escitalopram, or a selective serotonin noradrenaline (norepinephrine) reuptake inhibitor (SNRI) such as venlafaxine or duloxetine. However, the SSRIs and SNRIs have efficacy limitations, such as lack of response in many patients, a 2- to 4-week delay before the onset of symptom relief, lack of full remission, and risk of relapse. In addition, there are troublesome adverse effects associated with both the SSRIs and SNRIs. Evidence from early clinical studies of the atypical antipsychotics in the treatment of anxiety and GAD indicate that they may have a potential role in the treatment of GAD, either as monotherapy or as augmentation to standard treatment.

Cardiovascular abnormalities in patients with major depressive disorder: autonomic mechanisms and implications for treatment.

Abstract: This article provides a detailed review of the association of major depression with coronary heart disease (CHD), examines the biological variables underpinning the linkage and discusses the clinical implications for treatment. When considering the co-morbidity between major depressive disorder (MDD) and CHD it is important to differentiate between (i) the prevalence and impact of MDD in those with existing CHD and (ii) MDD as a risk factor for the development of CHD. Whether the same biological mechanisms are at play in these two instances remains unknown. Depression is common in patients with CHD. Importantly, depression in these patients increases mortality. There is also consistent evidence that MDD is a risk factor for the development of CHD. The relative risk of developing CHD is proportional to the severity of depression and is independent of smoking, obesity, hypercholesterolaemia, diabetes mellitus and hypertension. There is a clear need to identify the underlying neurochemical mechanisms responsible for MDD and their linkage to the heart and vascular system. Of particular interest are activation of stress pathways, including both the sympathetic nervous system and hypothalamic-pituitary-adrenal axis, and inflammatory-mediated atherogenesis. Elevated sympathetic activity, reduced heart rate variability and increased plasma cortisol levels have been documented in patients with MDD. In addition to direct effects on the heart and vasculature, activation of stress pathways may also be associated with increased release of inflammatory cytokines such as interleukin-6 and tumour necrosis factor-α. Elevated levels of C-reactive protein are commonly observed in patients with MDD. The majority of investigations examining treatment of depression following myocardial infarction have focused on safety and efficacy; there is little evidence to indicate that treating depression in these patients improves survival. Given that strategies for preventive therapy remain incompletely formulated, future research should focus on generating a better understanding of the neurobiology of MDD and heart disease as a basis for rational and effective therapy.

Seizures in patients with multiple sclerosis: Epidemiology, pathophysiology and management

Abstract: Seizures have been recognized to occur in multiple sclerosis (MS) since early descriptions of the disease. Various studies have attempted to determine the incidence and prevalence of seizures in MS; although they differ in the reported prevalence, seizures do appear to be more common in MS cohorts than in the general population. The pathological underpinning of seizures in MS remains indeterminate. Cortical and subcortical demyelination and inflammation may explain the increased frequency of seizures in MS, although this hypothetical correlation remains to be proven. Management of seizures in MS is similar to the management of seizures in other patients. Consideration of the underlying neurological deficits related to MS may be necessary, and dosages of antiepileptic drugs should be adjusted if increased sensitivity to the adverse effects of these agents or interaction with other centrally acting medications is suspected. The prognosis of epilepsy in patients with MS remains uncertain, with some studies suggesting a more favourable prognosis than others.

Cholinergic functioning in stimulant addiction: implications for medications development.

Abstract: Acetylcholine, the first neurotransmitter discovered, participates in many CNS functions, including sensory and motor processing, sleep, nociception, mood, stress response, attention, arousal, memory, motivation and reward. These diverse cholinergic effects are mediated by nicotinic- and muscarinic-type cholinergic receptors (nAChR and mAChR, respectively). The goal of this review is to synthesize a growing literature that supports the potential role of acetylcholine as a treatment target for stimulant addiction. Acetylcholine interacts with the dopaminergic reward system in the ventral tegmental area, nucleus accumbens and prefrontal cortex. In the ventral tegmental area, both nAChR and mAChR stimulate the dopaminergic system. In the nucleus accumbens, cholinergic interneurons integrate cortical and subcortical information related to reward. In the prefrontal cortex, the cholinergic system contributes to the cognitive aspects of addiction. Preclinical studies support a facilitative role of nicotinic receptor agonists in the development of stimulant addiction. In contrast, nonselective muscarinic receptor agonists seem to have an inhibitory role. In human studies, acetylcholinesterase inhibitors, which increase synaptic acetylcholine levels, have shown promise for the treatment of stimulant addiction. Further studies testing the efficacy of cholinergic medications for stimulant addiction are warranted.

Pharmacotherapy for cannabis dependence: how close are we?

Abstract: Cannabis is the most widely used illicit drug in the world. Treatment admissions for cannabis use disorders have risen considerably in recent years, and the identification of medications that can be used to improve treatment outcomes among this population is a priority for researchers and clinicians. To date, several medications have been investigated for indications of clinically desirable effects among cannabis users (e.g. reduced withdrawal, attenuation of subjective or reinforcing effects, reduced relapse). Medications studied have included those: (i) known to be effective in the treatment of other drug use disorders; (ii) known to alleviate symptoms of cannabis withdrawal (e.g. dysphoric mood, irritability); or (iii) that directly affect endogenous cannabinoid receptor function. Results from controlled laboratory studies and small open-label clinical studies indicate that buspirone, dronabinol, fluoxetine, lithium and lofexidine may have therapeutic benefit for those seeking treatment for cannabis-related problems. However, controlled clinical trials have not been conducted and are needed to both confirm the potential clinical efficacy of these medications and to validate the laboratory models being used to study candidate medications. Although the recent increase in research towards the development of pharmacotherapy for cannabis use disorders has yielded promising leads, well controlled clinical trials are needed to support broad clinical use of these medications to treat cannabis use disorders.

Safety of selective serotonin reuptake inhibitors in pregnancy.

Abstract: Selective serotonin reuptake inhibitors (SSRIs) are among the most commonly used medications, with a prescription frequency of 2.3% in pregnant women. Although most babies born to women who take SSRIs during pregnancy are normal, there is accumulating evidence that maternal SSRI treatment during pregnancy may cause adverse reproductive outcomes. Maternal SSRI treatment during the first trimester has been implicated in increased risks of birth defects, specifically cardiac abnormalities, in the infant, whereas third-trimester treatment has been linked to various neonatal complications, including symptoms of neonatal withdrawal and toxicity, prematurity, low birth weight and persistent pulmonary hypertension of the newborn. Although data on neurobehavioural and long-term cognitive problems among children of women who were treated with SSRIs during pregnancy remain limited, the possibility of such functional abnormalities is an additional concern. On the other hand, untreated maternal depression also carries serious risks for both the mother and the baby, and SSRIs are one of the best available treatments. Thus, pregnant women who require treatment for depression and their physicians often face a difficult choice regarding the use of SSRIs.

Adjustment disorder: epidemiology, diagnosis and treatment.

Abstract: Adjustment disorder was introduced into the psychiatric classification systems almost 30 years ago, although the concept was recognized for many years before that. In DSM-IV, six subtypes are described based on the predominant symptoms, but no further diagnostic criteria are offered to assist the clinician. These are common conditions, especially in primary care and in consultation liaison psychiatry, where the prevalence ranges from 11% to 18% and from 10% to 35%, respectively. Yet they are under-researched, possibly due to the failure of some of the common diagnostic tools to allow for the diagnosis of adjustment disorder. Among the tools that incorporate adjustment disorder, the concordance between the clinical and interview diagnosis is very poor, with the diagnosis being made more commonly in clinical practice than the diagnostic tools allow for. Adjustment disorder is found in all cultures and in all age groups. The presence of a causal stressor is essential before a diagnosis of adjustment disorder can be made, while the symptoms vary and include those that are found in other common psychiatric disorders. It is also important to distinguish adjustment disorder from normal reactions to stressful events. Adjustment disorders are difficult to distinguish from normal responses to life's stressors, while the distinction from major depression also poses a classificatory conundrum since both are conceptually different. Adjustment disorder is a diagnosis based on the longitudinal course of symptoms in the context of a stressor, while a diagnosis of major depression is a cross-sectional one based on symptom numbers. Treatments consist mainly of brief interventions, while pharmacotherapy is limited to the symptomatic management of anxiety or insomnia. There are no robust studies demonstrating benefits from antidepressants. However, the number of studies of either type of intervention is very limited.

The efficacy and safety of blonanserin compared with haloperidol in acute-phase schizophrenia: a randomized, double-blind, placebo-controlled, multicentre study.

Abstract: Background: Blonanserin is a novel atypical antipsychotic agent with potent dopamine D2 and serotonin 5-HT2 antagonist properties. It may potentially have a lower incidence of adverse events than other antipsychotic agents. Objective: To determine the efficacy and safety of three doses of blonanserin compared with placebo and haloperidol in patients with acute-phase schizophrenia. Methods: 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. Results: 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 10mg 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%). Conclusion: 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.

Role of antiepileptic drugs in the management of eating disorders.

Abstract: Growing evidence suggests that antiepileptic drugs (AEDs) may be useful in managing some eating disorders. In the present paper, we provide a brief overview of eating disorders, the rationale for using AEDs in the treatment of these disorders and review the data supporting the effectiveness of specific AEDs in the treatment of patients with eating disorders. In addition, the potential mechanisms of action of AEDs in these conditions are discussed. Of the available AEDs, topiramate appears to have the broadest spectrum of action as an anti-binge eating, anti-purging and weight loss agent, as demonstrated in two placebo-controlled studies in bulimia nervosa and three placebo-controlled studies in binge-eating disorder (BED) with obesity. Topiramate may also have beneficial effects in night-eating syndrome and sleep-related eating disorder, but controlled trials in these conditions are needed. The results of one small controlled study suggest that zonisamide may have efficacy in BED with obesity. However, both topiramate and zonisamide are associated with adverse effect profiles that may limit their use in patients with eating disorders. Phenytoin may be effective in some patients with compulsive binge eating, particularly if co-morbid EEG abnormalities are present, but available data are too varied to allow definitive conclusions to be made. Carbamazepine and valproate may be effective in treating patients with bulimia nervosa or anorexia nervosa when they are used to treat an associated psychiatric (e.g. mood) or neurological (e.g. seizure) disorder; otherwise, both agents, particularly valproate, are associated with weight gain. In conclusion, AEDs have an emerging role in the management of some eating disorders.

Adverse endocrine and metabolic effects of psychotropic drugs: selective clinical review.

Abstract: The article critically reviews selected, clinically significant, adverse endocrine and metabolic effects associated with psychotropic drug treatments, including hyperprolactinaemia, hyponatraemia, diabetes insipidus, hypothyroidism, hyperparathyroidism, sexual dysfunction and virilization, weight loss, weight gain and metabolic syndrome (type 2 diabetes mellitus, dyslipidaemia and hypertension). Such effects are prevalent and complex, but can be managed clinically when recognized. They encourage continued critical assessment of benefits versus risks of psychotropic drugs and underscore the importance of close coordination of psychiatric and general medical care to improve long-term health of psychiatric patients. Options for management of hyperprolactinaemia include lowering doses, switching to agents such as aripiprazole, clozapine or quetiapine, managing associated osteoporosis, carefully considering the use of dopamine receptor agonists and ruling out stress, oral contraceptive use and hypothyroidism as contributing factors. Disorders of water homeostasis may include syndrome of inappropriate antidiuretic hormone (SIADH), managed by water restriction or slow replacement by hypertonic saline along with drug discontinuation. Safe management of diabetes insipidus, commonly associated with lithium, involves switching mood stabilizer and consideration of potassium-sparing diuretics. Clinical hypothyroidism may be a more useful marker than absolute cut-offs of hormone values, and may be associated with quetiapine, antidepressant and lithium use, and managed by thyroxine replacement. Hyper-parathyroidism requires comprehensive medical evaluation for occult tumours. Hypocalcaemia, along with multiple other psychiatric and medical causes, may result in decreased bone density and require evaluation and management. Strategies for reducing sexual dysfunction with psychotropics remain largely unsatisfactory. Finally, management strategies for obesity and metabolic syndrome are reviewed in light of the recent expert guidelines, including risk assessment and treatments, such as monoamine transport inhibitors, anticonvulsants and cannabinoid receptor antagonists, as well as lifestyle changes.

Memantine: a review of its use in moderate to severe Alzheimer's disease.

Abstract: Memantine is an uncompetitive, moderate-affinity NMDA receptor antagonist that is indicated for the treatment of moderate to severe Alzheimer's disease. In well designed trials in patients with moderate to severe Alzheimer's disease, oral memantine monotherapy improved outcomes in the area of functional ability more than placebo in one trial, but in a second trial, treatment differences did not reach significance. Memantine has a distinct mode of action compared with that of acetylcholinesterase (AChE) inhibitors, and in a well designed study, combination therapy with memantine plus donepezil improved outcomes more than donepezil plus placebo in all four domains (function, cognition, behaviour and global change). Memantine is generally well tolerated, with adverse events occurring with a similar incidence to that reported with placebo. In modelled cost-effectiveness analyses, memantine was dominant to no therapy in regard to cost per quality-adjusted life-year (QALY) gained, and the combination of memantine plus donepezil was dominant to donepezil therapy alone in regard to QALYs gained when treatment periods exceeded 1 year in patients with moderate to severe disease. Thus, in the management of patients with moderate to severe Alzheimer's disease, memantine provides an effective treatment option. To date, clinical trial support is greater for memantine use in combination with an AChE inhibitor, while more data are needed to confirm its efficacy as monotherapy.