Akathisia, Drug-induced

Pediatric Phagophobia: A Systematic Review and a Case Report of Pharmacological Interventions

Background: Phagophobia is characterized by conditioned excessive fear of swallowing or choking that is usually triggered by an incident. It usually leads to avoidance of certain types of food or, in severe forms, a complete refusal to eat solid food and/or liquids. The condition is commonly associated with physical and psychological symptoms impacting the health condition of the individual due to deprivation of essential nutrients.

Case Presentation: A 12-year-old boy developed acute onset fear of swallowing (Phagophobia) following a dream he had of someone choking. This was exacerbated by watching an online video of a person choking. This has led to an avoidance of solid food and dependence on soft food and liquids. Fear of swallowing along with food avoidance has led to malnutrition, weight loss, and several physical complaints for which the patient was admitted under pediatric care. A course of Cognitive Behavioral Therapy (CBT) resulted in limited response and was augmented with fluoxetine. Full remission was achieved within six weeks.

Methods: A systematic review of all peer-reviewed English literature was performed for articles related to the pharmacological treatment of pediatric phagophobia (0-18 years) following the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines.

Results: A total of 17 case reports were identified describing 17 children with phagophobia (females = 70%). The mean age was 9.3 and the average was between 2 and 15 years who were diagnosed with choking phobia/ phagophobia or different but equivalent diagnoses like Avoidant/Restrictive Food Intake Disorder or Post Traumatic Feeding Disorder. Different classes of medications were used in variable doses for different durations which were associated with significant improvement in eating patterns and reduction in fear and anxiety associated with eating.

Conclusion: Phagophobia is a serious and potentially life-threatening illness that can cause physical complications and functional impairment in the psychosocial aspect. Pharmacological treatment can be a beneficial and safe option either alone or in combination with therapeutic interventions for children presenting with phagophobia.

Molecular Pathways and Treatment Updates on Huntington’s Disease with Special Preference to Juvenile Phase: A Comprehensive Review

A degenerative brain ailment called Huntington's disease (HTD) causes irritable behavior, emotional distress, cognition, etc. It is also known as Huntington's chorea. Compared to men, women are more likely to get HTD. However, in India, if 3 to 5% of Europeans are affected, it is difficult to estimate the disease's prevalence. The full pathophysiological status, several molecular pathways, and pharmaceutical and non-pharmacological treatments for Huntington's disease are covered in this article. Google, PubMed, Scopus, Bentham, Elsevier, and other significant web resources were used to gather the scientific data. Moreover, this review article may serve as the foundation for future study, particularly on Huntington's illness.

Unravelling the Complex Interplay: Understanding Drug-induced Diseases and Teratogenicity from a Comprehensive Perspective

Iatrogenic diseases, also referred to as drug-induced diseases (DIDs), represent a recognized yet inadequately investigated phenomenon that may result in enduring afflictions, hospital admissions, pharmacological interventions, protracted pharmaceutical reliance, and health complications. In the contemporary era of personalized medicine, it is imperative for prescribers to remain abreast of the dynamic advancements in the field of toxicology. Iatrogenic disorders may manifest as a result of medical interventions, including diagnostic procedures, therapeutic interventions, or preventative measures. Key factors to be taken into consideration encompass the patient's chronological age, dietary patterns, genetic predisposition, pre-existing medical conditions, diminished host response mechanisms, and pharmacological tolerance. Teratogenicity pertains to the prevalence of congenital anomalies and disorders resulting from exposure to teratogenic agents, environmental influences, and pharmacological interventions. The primary objective of this review is to provide individuals with comprehensive knowledge regarding the potential risks associated with iatrogenic diseases, thereby facilitating the prevention of unforeseen adverse outcomes.

Considering New and Emerging Treatment Strategies for Depression: Beyond STAR*D and the Monoamines

While the number of treatment options for major depressive disorder (MDD) has grown in recent years, the lack of quality data to guide optimal modality selection has lessened the potential impact of having a more diverse set of mechanistic approaches to treatment. The last attempt to investigate treatment sequencing for MDD was the Sequenced Treatment Alternatives for Relief of Depression Study (STAR*D), which gave rise to the concept of treatment-resistant depression (TRD) as a failure to respond to two or more monoaminergic antidepressants. However, a recent reanalysis of the STAR*D data indicates that most patients do not remit even when treated with multiple traditional antidepressants. Given these new results, labeling the majority of patients as treatmentresistant is not appropriate or useful. If monoamine-based drugs are not that effective for the majority of MDD patients, then it is necessary to consider the mechanistically distinct pharmacological and non-pharmacological treatment options that have emerged recently, including brain stimulation, glutamate receptor modulators, and psychedelic medicines. While these new treatment modalities have the potential to enhance patient outcomes, clinicians and patients currently lack a framework to guide their choices other than cost, feasibility, personal preference, and certain medical contraindications. Here, we review alternative treatment modalities for monoamine non-responders and consider the possibility that there will be new first-line therapies for MDD. We will review how treatment decisions for these patients are currently being made and how developments in precision psychiatry may help guide rational treatment selection in the future.

Neurodegenerative Disorders and the Current State, Pathophysiology, and Management of Parkinson’s Disease

In the last few decades, major knowledge has been gained about pathophysiological aspects and molecular pathways behind Parkinson’s Disease (PD). Based on neurotoxicological studies and postmortem investigations, there is a general concept of how environmental toxicants (neurotoxins, pesticides, insecticides) and genetic factors (genetic mutations in PD-associated proteins) cause depletion of dopamine from substantia nigra pars compacta region of the midbrain and modulate cellular processes leading to the pathogenesis of PD. α-Synuclein, a neuronal protein accumulation in oligomeric form, called protofibrils, is associated with cellular dysfunction and neuronal death, thus possibly contributing to PD propagation. With advances made in identifying loci that contribute to PD, molecular pathways involved in disease pathogenesis are now clear, and introducing therapeutic strategy at the right time may delay the progression. Biomarkers for PD have helped monitor PD progression; therefore, personalized therapeutic strategies can be facilitated. In order to further improve PD diagnostic and prognostic accuracy, independent validation of biomarkers is required.

Beneficial Extracardiac Effects of Cardiovascular Medications

Cardiovascular diseases are the most common cause of death worldwide, with cardiovascular medications being amongst the most common medications prescribed. These medications have diverse effects on the heart, vascular system, as well as other tissues and organ systems. The extra cardiovascular effects have been found to be of use in the treatment of non-cardiovascular diseases and pathologies. Minoxidil is used to manage systemic hypertension with its well-known side effect of hirsutism used to treat alopecia and baldness. Sildenafil was originally investigated as a treatment option for systemic hypertension; however, its side effect of penile erection led to it being widely used for erectile dysfunction. Alpha-1 blockers such as terazosin are indicated to treat systemic hypertension but are more commonly used for benign prostatic hyperplasia and post-traumatic stress disorder. Beta blockers are the mainstay treatment for congestive heart failure and systemic hypertension but have been found useful to help in patients with intention tremors as well as prophylaxis of migraines. Similarly, calcium channel blockers are indicated in medical expulsion therapy for ureteric calculi in addition to their cardiovascular indications. Thiazides are commonly used for treating systemic hypertension and as diuretics. Thiazides can cause hypocalciuria and hypercalcemia. This side effect has led to thiazides being used to treat idiopathic hypercalciuria and associated nephrolithiasis. Spironolactone is commonly utilized in treating heart failure and as a diuretic for edema. It’s well described anti-androgen side effects have been used for acne vulgaris and hirsutism in polycystic ovarian syndrome. This review article discusses how the various extracardiovascular effects of commonly used cardiovascular medications are put to use in managing non-cardiovascular conditions.

Restless Leg Syndrome in Patients with Liver Cirrhosis! Its Frequency, Severity, and Correlation

Background: Restless leg syndrome (RLS) has been recognized as a typical additional manifestation among patients with cirrhosis of the liver. RLS prevalence in liver cirrhosis further worsens the quality of life, which has already been compromised with the disease-related complications of cirrhosis itself.

Aims: The study aimed to determine the frequency and severity of Restless Leg Syndrome (RLS) among patients with cirrhosis of the liver and to correlate its severity with the severity of cirrhosis.

Methods: This prospective cross-sectional study was carried out at Ruth K.M. Pfau Civil Hospital (Karachi, Pakistan) from December 2019 to February 2020. Three hundred and fifteen cirrhotic patients with any etiology were included in the study after informed written consent. Restless leg syndrome with its severity was determined in all cirrhotic patients. For continuous variables, means and medians with standard deviations were calculated, while percentages and proportions were used for discrete variables. Spearman correlation was used to find significance between RLS Severity Score (RSS) and Model of End-stage Liver Disease MELD Score. A p value of < 0.05 was considered significant for all analyses.

Results: The frequency of RLS among cirrhotic patients was 38.4%. More than half (54.5%) of the patients had severe RLS. Viral related hepatitis C and hepatitis B were the most common cause of cirrhosis of the liver (57.8% and 30.8%). A significant difference was found between as patients both with or without RLS in terms of age (p=0.003), gender (p=0.005), hemoglobin (p=0.00), and serum albumin (p=0.01). No significant association was found between RLS severity score and MELD Score (p=0.693).

Conclusion: Prevalence of RLS is very high among cirrhotic patients, but no correlation was found between the severity of RLS and cirrhosis. Further studies should be carried out to assess the quality of life in cirrhotic patients having RLS.

The Novel Antipsychotic Drug Cariprazine and Cognition Enhancing Drugs: Indications for their Use as the Add-on Therapy in Schizophrenia

Background: Schizophrenia and schizoaffective disorder are treated with antipsychotic drugs. Some patients show treatment-resistant forms of psychotic disorders, and in this case, they can be treated with clozapine. Based on the previous reviews on novel antipsychotic drugs, it is important to know whether the add-on therapy with the new drugs can ameliorate the positive and negative schizophrenic scale (PANSS) total score.

Objectives: The aim of this review is to suggest an appropriate treatment for patients with treatment-resistant forms of psychotic disorders. A combination of the currently available antipsychotic drugs with novel antipsychotic or modulating drugs might improve negative schizophrenic symptoms and cognitive function and thereby social functioning and quality of life.

Results: The mechanisms of action, the therapeutic effects, and the pharmacokinetic profiles of novel antipsychotic drugs such as cariprazine, brexipiprazole, and lumateperone have been updated. Published case reports of patients with treatment-resistant psychoses have also been discussed in this study. These patients were treated only with clozapine, as a result of which a high PANSS total score was observed. Only the add-on therapy with cariprazine improved the score, and above all, the negative schizophrenic symptoms and cognitive functions were improved. For the ensurance of a constant antipsychotic drug concentration, long-acting injectable antipsychotic drugs might be a choice for the maintenance therapy in schizophrenia. New modulating drugs, such as receptor positive allosteric modulators (N-methyl-D-aspartate receptor; subtype 5 of the metabotropic glutamatergic receptor) and encenicline, an alpha7 nicotinic cholinergic receptor agonist, have been investigated in preclinical and clinical trials.

Conclusion: In clinical trials, patients with treatment-resistant forms of psychosis should be examined to know whether combination therapy with clozapine and a novel antipsychotic drug can ameliorate the PANSS total score. In schizophrenia, long-acting injectable antipsychotic drugs are safe and tolerable maintenance therapy. In further clinical studies, it should be investigated whether patients with treatment-resistant forms of psychoses can improve negative schizophrenic symptoms and cognitive functions by the add-on therapy with cognitionenhancing drugs.

Mitochondrial Dysfunction in Huntington’s Disease: Pathogenesis and Therapeutic Opportunities

Huntington’s disease (HD) is a prototypical neurodegenerative disease, preferentially disrupting the neurons of the striatum and cortex. Progressive motor dysfunctions, psychiatric disturbances, behavioral impairments, and cognitive decline are the clinical symptoms of HD progression. The disease occurs due to expanded CAG repeats in exon 1 of huntingtin protein (mHtt), causing its aggregation. Multiple cellular and molecular pathways are involved in HD pathology. Mitochondria, as vital organelles have an important role in most neurodegenerative diseases like HD. Over the years, the role of mitochondria in neurons has highly diverged; they not only contribute as a cell power source, but also as dynamic organelles that fragment and then fuse to attain a maximal bioenergetics performance, regulating intracellular calcium homeostasis, reactive oxygen species (ROS) generation, antioxidant activity and involved in apoptotic pathways. Indeed, these events are observed to be affected in HD, resulting in neuronal dysfunction in pre-symptomatic stages. MHtt causes critical transcriptional abnormality by altering the expression of a master co-regulator, peroxisome proliferator-activated receptor-gamma coactivator-1α (PGC-1α), leading to increased susceptibility to oxidative stress and neuronal degeneration. Moreover, mHtt influences multiple cellular signaling events, which end with mitochondrial biogenesis. Here, we resume recent findings that pose mitochondria as an important regulatory organelle in HD and how mHtt affects mitochondrial function, trafficking and homeostasis and makes neurons prone to degeneration. Besides, we also uncover the mitochondrial-based potential targets and therapeutic approaches with imminent or currently ongoing clinical trials.

One Pot Synthesis and Pharmacological Evaluation of Aryl Substituted Imidazoles as Potential Atypical Antipsychotics

Background: Second generation or “atypical” antipsychotics demonstrate an improved therapeutic profile over conventional neuroleptics. These are effective in both positive and negative symptoms of the disease and have a lower propensity to induce adverse symptoms.

Objective: The main objective of the research was in silico design and synthesis of potential atypical antipsychotics with combined antiserotonergic / antidopaminergic effect.

Methods: A one pot synthesis of aryl substituted imidazole derivatives was carried out in green solvent PEG-400 and the prepared compounds were evaluated for atypical antipsychotic activity in animal models for dopaminergic and serotonergic antagonism. The compounds were designed based on their 3D similarity studies to standard drugs and in silico (docking studies) with respect to 5-HT_2A and D₂ receptors.

Results: Results from the docking studies with respect to 5-HT_2A and D₂ receptors suggested a potential atypical antipsychotic profile for the test compounds. Theoretical ADME profiling of the compounds based on selected physicochemical parameters suggested an excellent compliance with Lipinski’s rules. The potential of these compounds to penetrate the blood brain barrier (log BB) was computed through an online software program and the values obtained for the compounds suggested a good potential for brain permeation. Reversal of apomorphine induced mesh climbing behaviour coupled with inactivity in the stereotypy assay indicates antidopaminergic effect and a potential atypical profile for the test compounds 1-5. Further, the activity of compounds in DOI assay indicated a 5-HT₂ antagonistic profile (5-HT₂ antagonism).

Conclusion: Compound 5 emerged as important lead compound showing combined antidopaminergic and antiserotonergic (5-HT_2A) activity with a potential atypical antipsychotic profile.

Antidepressants and Antipsychotic Agents as Repurposable Oncological Drug Candidates

Drug repurposing, also known as drug repositioning/reprofiling, is a relatively new strategy for the identification of alternative uses of well-known therapeutics that are outside the scope of their original medical indications. Such an approach might entail a number of advantages compared to standard de novo drug development, including less time needed to introduce the drug to the market, and lower costs. The group of compounds that could be considered as promising candidates for repurposing in oncology include the central nervous system drugs, especially selected antidepressant and antipsychotic agents. In this article, we provide an overview of some antidepressants (citalopram, fluoxetine, paroxetine, sertraline) and antipsychotics (chlorpromazine, pimozide, thioridazine, trifluoperazine) that have the potential to be repurposed as novel chemotherapeutics in cancer treatment, as they have been found to exhibit preventive and/or therapeutic action in cancer patients. Nevertheless, although drug repurposing seems to be an attractive strategy to search for oncological drugs, we would like to clearly indicate that it should not replace the search for new lead structures, but only complement de novo drug development.

Pharmacologic Treatment of Restless Legs Syndrome

Restless legs syndrome (RLS)/Willis-Ekbom disease is a neurologic disorder characterized by a strong desire to move when at rest (usually in the evening) and paraesthesia in their lower legs. The most widely used therapies for first-line treatment of RLS are dopaminergic drugs; however, their long-term use can lead to augmentation. α2δ Ligands, opioids, iron, glutamatergic drugs, adenosine, and sleep aids have been investigated as alternatives. The pathogenesis of RLS is not well understood. Despite the efficacy of dopaminergic drugs in the treatment of this disorder, unlike in Parkinson’s disease dopaminergic cell loss in the substantia nigra has not been observed in RLS. The etiology of RLS is likely complex, involving multiple neural pathways. RLS-related genes identified in genome-wide association studies can provide insight into the mechanistic basis and pathophysiology of RLS. Here we review the current treatments and knowledge of the mechanisms underlying RLS.

The Potential of Hydrogen for Improving Mental Disorders

In 2007, Ohsawa and colleagues reported that molecular hydrogen (H₂) gas significantly reduced the infarct volume size in a rat model of cerebral infarction, which was, at least, partially due to scavenging hydroxyl radicals. Since then, multiple studies have shown that H₂ has not only anti-oxidative but also anti-inflammatory and anti-apoptotic properties, which has ignited interest in the clinical use of H₂ in diverse diseases. A growing body of studies has indicated that H₂ affects both mental and physical conditions. Mental disorders are characterized by disordered mood, thoughts, and behaviors that affect the ability to function in daily life. However, there is no sure way to prevent mental disorders. Although antidepressant and antianxiety drugs relieve symptoms of depression and anxiety, they have efficacy limitations and are accompanied by a wide range of side effects. While mental disorders are generally thought to be caused by a variety of genetic and/or environmental factors, recent progress has shown that these disorders are strongly associated with increased oxidative and inflammatory stress. Thus, H₂ has received much attention as a novel therapy for the prevention and treatment of mental disorders. This review summarizes the recent progress in the use of H₂ for the treatment of mental disorders and other related diseases. We also discuss the potential mechanisms of the biomedical effects of H₂ and conclude that H₂ could offer relief to people suffering from mental disorders.

Phosphodiesterase as a Target for Cognition Enhancement in Schizophrenia

Schizophrenia is a severe mental disorder that affects more than 1% of the population worldwide. Dopamine system dysfunction and alterations in glutamatergic neurotransmission are strongly implicated in the aetiology of schizophrenia. To date, antipsychotic drugs are the only available treatment for the symptoms of schizophrenia. These medications, which act as D2-receptor antagonist, adequately address the positive symptoms of the disease, but they fail to improve the negative symptoms and cognitive impairment. In schizophrenia, cognitive impairment is a core feature of the disorder. Therefore, the treatment of cognitive impairment and the other symptoms related to schizophrenia remains a significant unmet medical need. Currently, phosphodiesterases (PDEs) are considered the best drug target for the treatment of schizophrenia since many PDE subfamilies are abundant in the brain regions that are relevant to cognition. Thus, this review aims to illustrate the mechanism of PDEs in treating the symptoms of schizophrenia and summarises the encouraging results of PDE inhibitors as anti-schizophrenic drugs in preclinical and clinical studies.

Discovery and Development of Non-Dopaminergic Agents for the Treatment of Schizophrenia: Overview of the Preclinical and Early Clinical Studies

Schizophrenia is a chronic psychiatric disorder that affects about 1 in 100 people around the world and results in persistent emotional and cognitive impairments. Untreated schizophrenia leads to deterioration in quality of life and premature death. Although the clinical efficacy of dopamine D2 receptor antagonists against positive symptoms of schizophrenia supports the dopamine hypothesis of the disease, the resistance of negative and cognitive symptoms to these drugs implicates other systems in its pathophysiology. Many studies suggest that abnormalities in glutamate homeostasis may contribute to all three groups of schizophrenia symptoms. Scientific considerations also include disorders of gamma-aminobutyric acid-ergic and serotonergic neurotransmissions as well as the role of the immune system. The purpose of this review is to update the most recent reports on the discovery and development of non-dopaminergic agents that may reduce positive, negative, and cognitive symptoms of schizophrenia, and may be alternative to currently used antipsychotics. This review collects the chemical structures of representative compounds targeting metabotropic glutamate receptor, gamma-aminobutyric acid type A receptor, alpha 7 nicotinic acetylcholine receptor, glycine transporter type 1 and glycogen synthase kinase 3 as well as results of in vitro and in vivo studies indicating their efficacy in schizophrenia. Results of clinical trials assessing the safety and efficacy of the tested compounds have also been presented. Finally, attention has been paid to multifunctional ligands with serotonin receptor affinity or phosphodiesterase inhibitory activity as novel strategies in the search for dedicated medicines for patients with schizophrenia.

Cariprazine in Bipolar Depression and Mania: State of the Art

Background & Objective: Cariprazine is a piprazine derivative approved by the FDA in 2015 for the treatment of schizophrenia and bipolar manic or mixed episodes in adults. High affinity for D3 dopamine receptors and observed actions on 5HT1A, 5HT2A and alpha 1B receptors differentiate it pharmacologically from other antipsychotics. This review is a comprehensive and thorough summary of the most important findings on cariprazine use in bipolar mania and depression. Pharmacokinetics, pharmacogenetics, tolerability and safety adverse effects are discussed in this paper.

Results & Conclusion: Moreover, the results from pivotal clinical trials are presented. Cariprazine represents an additional option for clinicians to treat patients with bipolar disorder. It shows a unique pharmacological profile and has demonstrated in randomized clinical trials efficacy and general tolerability compared to placebo in bipolar mania and seem to be a promising therapeutic option for bipolar depression.

The Use of Antidepressants for Physical and Psychological Symptoms in Cancer

Cancer patients are commonly associated with various physical and psychological symptoms. In palliative setting, the aims are to relieve those symptoms, improve quality of life, and increase medication adherence among cancer patients. Antidepressants are generally accepted for the treatment of depression among patients with or without cancer. Some other potential benefits of the antidepressants have been reported in cancer patients.

Objective: This study aims to review the use of antidepressants for physical and psychological symptoms in cancer patients.

Results: Our findings showed the mixed result of positive and negative findings in various symptoms associated with cancer patients. These studies are categorised according to the hierarchy of evidence from high to low level, namely randomised controlled trials, cohort studies, case-control studies, case series, case reports, as well as other type of publications. The majority of antidepressants used in cancer patients seem to be beneficial for the treatment of depression, anxiety, hot flashes and other symptoms such as sexual dysfunction, fatigue, nicotine dependence, vasomotor symptoms, executive functions, sleep problems, pruritus, as well as for hypochondriasis. While fluoxetine was found to be associated with the reduction of antiemetic property in ondansetron, mirtazapine was identified to be a good alternative in treating nausea and cachexia among cancer patients.

Conclusion: More research studies with adequate statistical power are warranted to validate the use of antidepressants among cancer patients in treating these physical and psychological symptoms.

Unmet Needs in Schizophrenia

Background: Schizophrenia is a complex psychiatric disorder that represents a challenge for all clinicians. Although treatment must address both positive and negative symptoms, several authors have reported the importance of managing unmet needs among patients with schizophrenia. Unmet needs in schizophrenia include difficulties at various clinical, psychosocial, relational, economic, and occupational levels. An important unmet need is represented by insight into the illness that is associated with treatment adherence and compliance with medical prescriptions.

Conclusion: In order to improve our understanding and management of schizophrenia, it is critically important to address the complexity of needs among patients with schizophrenia.

Older and Newer Strategies for the Pharmacological Management of Agitation in Patients with Bipolar Disorder or Schizophrenia

Background: The management of acute agitation in patients with bipolar disorder or schizophrenia is a multifaceted and dynamic task, which presents unique and complex challenges to healthcare providers.

Objective: To ascertain and describe which medications are best to use in patients with agitation, affected by bipolar disorder or schizophrenia.

Method: Selective review of current literature and guidelines referred to the treatment of agitation in individuals affected with bipolar disorder or schizophrenia

Results: When possible, the pharmacologic management of agitation should be preceded by a in-depth evaluation of the possible causes of the agitation. The use for of first and second-generation antipsychotic medications, of benzodiazepines and of the newer inhaled antipsychotic loxapine, is reviewed and commented.

Conclusion: The mainstay of medication treatment of acute agitation should be based on a thotough assessment cause. If agitation is due to delirium or to another physial condition, an attempt to address the underlying causes should be always considered. When agitation is primarily due to schizophrenia or bipolar disorder, antipsychotics and/or benzodiazepines are usually the mainstay of treatment. Newer inhaled formulation of loxapine has shown ability to rapidly reduce the agitation in mild to moderate patients with schizophrenia or bipolar disorder, with a decrease in agitation that was evident since the first assessment, 10 minutes after the first dose.

A Comparative Study of Short Term Efficacy of Aripiprazole and Risperidone in Schizophrenia

Objective: To compare the short term anti-schizophrenic efficacy and side effect profile of aripiprazole with risperidone.

Methodology: The study was a non-randomized, naturalistic, rater blinded, prospective, 8-12 weeks, comparative trial between the risperidone and aripiprazole in patients with schizophrenia. Patients already getting treatment with aripiprazole (10 to 30 mg/day) or risperidone (3 to 8mg/day) were recruited. Mini International Neuropsychiatric Interview (MINI) Plus, Positive and Negative Syndrome Scale (PANSS), Abnormal Involuntary Movement Scale (AIMS), Simpson Angus Scale (SAS), Udvalg for Klinske Undersogelser (UKU) Scale, Clinical Global Impression-severity scales were administered by principal investigator on the day of recruitment. Anthropometric measurements (height, weight, BMI, waist, hip, waist circumference) blood pressure and pulse rate were measured on day 1 and during follow up. All tests except MINI plus were administered again after 8-12weeks.

Results: Both aripiprazole and risperidone treated patients have shown significant improvement on positive and negative symptoms but there was no statistically significant difference between the two groups. Mean improvement in patient rated improvement scale score showed a trend towards significance favoring aripiprazole. Common adverse events (seen in ≥ 5% of patients) as assessed by the UKU Scale occurred more frequently in the risperidone group than in the aripiprazole group. Drug induced extra pyramidal symptoms were more common in risperidone treated patients. Aripiprazole showed less treatment emerged weight gain.

Conclusion: Aripiprazole is equally efficacious and better tolerated than risperidone in patients with schizophrenia over a short-term period of eight weeks. Aripiprazole showed better patient satisfaction and side effect profile.

Aripiprazole, A Drug that Displays Partial Agonism and Functional Selectivity

Background: The treatment of schizophrenia is challenging due to the wide range of symptoms (positive, negative, cognitive) associated with the disease. Typical antipsychotics that antagonize D2 receptors are effective in treating positive symptoms, but extrapyramidal side-effects (EPS) are a common occurrence. Atypical antipsychotics targeting 5-HT2A and D2 receptors are more effective at treating cognitive and negative symptoms compared to typical antipsychotics, but these drugs also result in side-effects such as metabolic syndromes.

Objective: To identify evidence in the literature that elucidates the pharmacological profile of aripiprazole.s.

Methods: We searched PubMed for peer reviewed articles on aripiprazole and its clinical efficacy, side-effects, pharmacology, and effects in animal models of schizophrenia symptoms.

Results: Aripiprazole is a newer atypical antipsychotic that displays a unique pharmacological profile, including partial D2 agonism and functionally selective properties. Aripiprazole is effective at treating the positive symptoms of schizophrenia and has the potential to treat negative and cognitive symptoms at least as well as other atypical antipsychotics. The drug has a favorable side-effect profile and has a low propensity to result in EPS or metabolic syndromes. Animal models of schizophrenia have been used to determine the efficacy of aripiprazole in symptom management. In these instances, aripiprazole resulted in the reversal of deficits in extinction, pre-pulse inhibition, and social withdrawal. Because aripiprazole requires a greater than 90% occupancy rate at D2 receptors to be clinically active and does not produce EPS, this suggests a functionally selective effect on intracellular signaling pathways.

Conclusion: A combination of factors such as dopamine system stabilization via partial agonism, functional selectivity at D2 receptors, and serotonin-dopamine system interaction may contribute to the ability of aripiprazole to successfully manage schizophrenia symptoms. This review examines these mechanisms of action to further clarify the pharmacological actions of aripiprazole.

Clinically Relevant Drug Interactions with Anti-Alzheimer's Drugs

Background: The aging world population had led to an increase in the prevalence of Alzheimer’s disease (AD). The drugs used to slow down the onset of AD, galantamine, donepezil, rivastigmine and memantine, are generally well-tolerated. However, drug interactions between these drugs and other drugs are an important aspect of patient safety that should be borne in mind, particularly given the high burden of polypharmacy in the elderly. The aim of this review is to provide an updated review of clinically significant drug-drug interactions concerning drugs approved for AD.

Method: PubMed was searched for relevant keywords. No time limit was imposed but only articles in English published in peer-reviewed journals were selected. Relevant literature was also identified from the references of identified articles. Further information was obtained from drug summary of product characteristics.

Results: The major pharmacokinetic interactions identified concerned fluoxetine, paroxetine and ketoconazole when used with galantamine or donepezil. On the other hand, the major potential pharmacodynamic interactions concerned anti-dementia drugs and general anesthesia agents, anti-cholinergic drugs, conventional antipsychotics and bradycardia-inducing drugs. In clinical practice memantine shows a lower potential for pharmacodynamic drug-drug interactions (DDIs) compared to other drug classes.

Conclusion: The concomitant use of anti-dementia drugs with other drugs can have variable clinical effects, making appropriate prescribing of these drugs very challenging. A simple and coherent way of presenting evidence on complex drug interaction information from heterogenous sources to clinicians is needed in order for the voluminous data available to have an impact on clinical practice.

Revisiting Antipsychotic-induced Akathisia: Current Issues and Prospective Challenges

Background: Akathisia continues to be a significant challenge in current neurological and psychiatric practice. Prompt and accurate detection is often difficult and there is a lack of consensus concerning the neurobiological basis of akathisia. No definitive treatment has been established for akathisia despite numerous preclinical and clinical studies.]

Method: We reviewed antipsychotic-induced akathisia including its clinical presentation, proposed underlying pathophysiology, current and under investigation therapeutic strategies.

Conclusion: Despite the initial promise that second generation antipsychotics would be devoid of akathisia effects, this has not been confirmed. Currently, there are limited therapeutic options for the clinical practice and the evidence supporting the most widely used treatments (beta blockers, anticholinergic drugs) is still absent or inconsistent.

Overview of Short-Term and Long-Term Safety of Brexpiprazole in Patients with Major Depressive Disorder and Inadequate Response to Antidepressant Treatment

Background: Many patients with major depressive disorder (MDD) do not respond adequately to first-line antidepressant treatment (ADT). Adjunctive treatment with second-generation antipsychotics has demonstrated efficacy for patients with MDD, but is limited by tolerability and safety issues. The recently introduced serotonin-dopamine activity modulator, brexpiprazole, has demonstrated efficacy as an adjunctive treatment for MDD.

Objective/Method: We report tolerability and safety results for adjunctive brexpiprazole from four 6-week short-term (ST; pooled phase 2 and 3, placebo-controlled) and two 52-week long-term (LT; pooled, openlabel) studies.

Results: Approximately 90% of patients completed the ST studies, and 48.8% of patients completed the LT studies. In the ST studies, 2.9% of patients discontinued because of an adverse event (AE); in the LT studies, 14.1% of patients discontinued because of an AE. In the ST and LT studies, the most frequently reported treatment-emergent AEs (TEAEs) were akathisia (8.6% and 10.0%, respectively) and weight gain (7.3% and 25.5%, respectively). Rates of sedation and somnolence were low (ST and LT: sedation, 0.8% and 3.7%, respectively; somnolence, 3.4% and 9.4%, respectively). In the ST and LT studies, brexpiprazole was associated with small changes in metabolic parameters and moderate weight increase.

Conclusions: Collectively, these data suggest brexpiprazole is well tolerated as an adjunctive treatment for MDD.

The Novel Antipsychotic Cariprazine (RGH-188): State-of-the-Art in the Treatment of Psychiatric Disorders

Cariprazine (RGH-188) is a novel antipsychotic drug that exerts partial agonism of dopamine D2/D3 receptors with preferential binding to D3 receptor, antagonism of 5HT2B receptors and partial agonism of 5HT1A. Currently, cariprazine is in late-stage clinical development (phase III clinical trials) in patients with schizophrenia (S) and in patients with bipolar disorder (BD), as well as an adjunctive treatment in patients with Major Depressive Disorder (MDD) and drug-resistant MDD. Cariprazine has completed phase III trials for the acute treatment of schizophrenia and bipolar mania, phase II trials for the bipolar depression and MDD whilst it is undergoing phase III trials as an adjunct to antidepressants. The present review aims at proving a comprehensive summary of the current evidence on the safety, tolerability and efficacy of cariprazine in the treatment of schizophrenia, BD (manic/mixed/ depressive episode) and MDD. A systematic search was conducted on PubMed/Medline/ Scopus and the database on Clinical Trials from inception until April 2015 by typing a set of specified keywords. Available evidence seems to support cariprazine efficacy in the treatment of cognitive and negative symptoms of schizophrenia. Preliminary findings suggest its antimanic activity whilst it is still under investigation its efficacy in the treatment of bipolar depression and MDD. Furthermore, the available data seems not to allow judgements about its antipsychotic potential in comparison with currently prescribed antipsychotics. Further studies should be carried out to better investigate its pharmacodynamic and clinical potential, particularly as alternative to current antipsychotic drugs.

Dopamine Targeting Drugs for the Treatment of Schizophrenia: Past, Present and Future

Schizophrenia is a chronic and debilitating neuropsychiatric disorder affecting approximately 1% of the world’s population. This disease is associated with considerable morbidity placing a major financial burden on society. Antipsychotics have been the mainstay of the pharmacological treatment of schizophrenia for decades. The traditional typical and atypical antipsychotics demonstrate clinical efficacy in treating positive symptoms, such as hallucinations and delusions, while are largely ineffective and may worsen negative symptoms, such as blunted affect and social withdrawal, as well as cognitive function. The inability to treat these latter symptoms may contribute to social function impairment associated with schizophrenia. The dysfunction of multiple neurotransmitter systems in schizophrenia suggests that drugs selectively targeting one neurotransmission pathway are unlikely to meet all the therapeutic needs of this heterogeneous disorder. Often, however, the unintentional engagement of multiple pharmacological targets or even the excessive engagement of intended pharmacological targets can lead to undesired consequences and poor tolerability. In this article, we will review marketed typical and atypical antipsychotics and new therapeutic agents targeting dopamine receptors and other neurotransmitters for the treatment of schizophrenia. Representative typical and atypical antipsychotic drugs and new investigational drug candidates will be systematically reviewed and compared by reviewing structure-activity relationships, pharmacokinetic properties, drug metabolism and safety, pharmacological properties, preclinical data in animal models, clinical outcomes and associated side effects.

Current Trends on Antipsychotics: Focus on Asenapine

Over the years, both first- (FGAs) and second-generation antipsychotics (SGAs), continue to gain increasing evidence of being effective in the treatment of psychotic symptoms. Currently, they represent the first-line treatment of schizophrenia and bipolar disorder, although they are widely used in psychotic depression and other clinical conditions, such as agitation and/or behavioural disturbances. Despite representing an indispensable tool for the treatment of severe psychotic disorders, they are widely known to have a number of unwanted side effects that the clinician must be aware of, and handle carefully to provide the patient the best available treatment in the short and long-term. However, even with respect to the long-term use of some of the most effective SGAs, it is imperative for clinicians not to overlook the risk linked to the onset of potentially severe metabolic side effects such as weight gain, dyslipidaemia, insulinresistance and type II diabetes.

Asenapine is one of the newest SGAs licenced in Europe for the treatment of manic episodes and in the US for schizophrenia. It belongs to the same class of clozapine, olanzapine and quetiapine, sharing with them a rather complex pharmacological binding profile. In fact, asenapine shows a high affinity for the serotonin (5HT) receptor of the type 2A (5HT2A) and to a lesser extent for the dopamine receptor of the type 2 (D2), similar to other SGAs. Asenapine behaves also as an antagonist at the level of 5HT2C, H1 and α2-receptors. Asenapine has been reported to be effective either in monotherapy or in combination with mood stabilers (lithium and valproate) in the treatment of manic or mixed episodes, with a lower propensity to induce, or being followed by, depressive symptoms, when compared to other SGAs. These unique properties may explain the increasing interest towards the use of this drug in mixed states, besides schizophrenia and acute mania.

The aim of this paper was at reviewing current data on pharmacological properties and clinical use of asenapine, as well as on possible future indication of this SGA.

The Role of Therapeutic Drugs on Acquired Mitochondrial Toxicity

Background: Certain therapeutic drugs used in medical practice may trigger mitochondrial toxicity leading to a wide range of clinical symptoms including deafness, neuropathy, myopathy, hyperlactatemia, lactic acidosis, pancreatitis and lipodystrophy, among others, which could even compromise the life of the patient.

Objectives: The aim of this work is to review the potential mitochondrial toxicity derived from drugs used in health care, including anesthetics, antiepileptics, neuroleptics, antidepressants, antivirals, antibiotics, antifungals, antimalarics, antineoplastics, antidiabetics, hypolipemiants, antiarrhythmics, anti-inflammatories and nitric oxide.

Methods: We herein have reviewed data from experimental and clinical studies to document the molecular mitochondrial basis, potential biomarkers and putative clinical symptoms associated to secondary effects of drugs.

Results: One hundred and forty-five articles were selected and the information was organized by means of the primary target to which pharmacologic drugs were directed. Adverse toxic events were classified depending on the mitochondrial offtarget effect and whether they had been demonstrated in the experimental or clinical setting. Conclusions: Since treatment of acquired mitochondriopathies remains supportive and therapeutic interventions cannot be avoided, information of molecular and clinical consequences of toxic exposure becomes fundamental to assess riskbenefit imbalance of treatment prescription. Additionally, there is a crucial need to develop less mitochondrial toxic compounds, novel biomarkers to follow up mitochondrial toxicity (or implement those already proposed) and new approaches to prevent or revert unintended mitochondrial damage.

Data-driven Approach to Detect and Predict Adverse Drug Reactions

Background: Many factors that directly or indirectly cause adverse drug reaction (ADRs) varying from pharmacological, immunological and genetic factors to ethnic, age, gender, social factors as well as drug and disease related ones. On the other hand, advanced methods of statistics, machine learning and data mining allow the users to more effectively analyze the data for descriptive and predictive purposes. The fast changes in this field make it difficult to follow the research progress and context on ADR detection and prediction. Methods: A large amount of articles on ADRs in the last twenty years is collected. These articles are grouped by recent data types used to study ADRs: omics, social media and electronic medical records (EMRs), and reviewed in terms of the problem addressed, the datasets used and methods. Results: Corresponding three tables are established providing brief information on the research for ADRs detection and prediction. Conclusion: The data-driven approach has shown to be powerful in ADRs detection and prediction. The review helps researchers and pharmacists to have a quick overview on the current status of ADRs detection and prediction.

Restless Legs Syndrome/Willis-Ekbom Disease and Periodic Limb Movements: A Comprehensive Review of Epidemiology, Pathophysiology, Diagnosis and Treatment Considerations

Restless legs syndrome (RLS) or Willis-Ekbom Disease is a common, but frequently under- recognized and misdiagnosed condition seen in many subspecialty practices including neurology, sleep medicine, primary care and rheumatology. Periodic limb movements are a frequent co-morbid diagnosis in RLS. Despite prior beliefs that the condition was “benign”, it has been demonstrated to have a considerable impact on sufferers quality of life, physically and psychologically, as well as socially. This chapter is meant as a comprehensive review of RLS encompassing epidemiology, pathophysiology, diagnosis, and treatment considerations.

A Comparison Between Quetiapine and Aripiprazole for Treatment of Schizophrenia: A Double Blind Contrast

Objective: Schizophrenia is usually characterized by abnormal social behavior, lack of insight, and positive and negative symptoms. While there is increasing evidence that atypical antipsychotics have advantages over conventional ones, few long-term studies have directly compared the atypical antipsychotics with each other. Therefore, in the present assessment, the efficacy and safety of aripiprazole had been compared with quetiapine.

Method: 50 schizophrenic patients entered into two comparable groups for participation in a twelve-week, double-blind study, for random assignment to quetiapine or aripiprazole. The main outcome scales included the Scale for Assessment of Negative Symptoms (SANS) and the Scale for Assessment of Positive Symptoms (SAPS). Also, the Clinical Global Impressions-Severity Scale (CGI-S), the Simpson Angus Scale (SAS), and finally the schedule for Assessment of Insight (SAI) had been used as the auxiliary ones.

Results: While both of aripiprazole and quetiapine demonstrated important efficacy in alleviation of positive symptoms (p<0. 04 & p<0. 01, respectively), their efficacy was not so with respect to negative cluster of symptoms (p<0. 07 & p<0.06, respectively). CGI-S and SAI, as well, revealed significant improvement with aripiprazole (p<0.05 & p<0.05, respectively) and quetiapine (p<0.05 & p<0. 04, respectively) at the end of the assessment. In contrast, in neither of groups any significant increase in SAS was detectible.

Conclusion: Based on the outcomes of the current study, no significant difference was evident between aripiprazole and quetiapine regarding improvement of positive and negative symptoms of schizophrenia.

Restless Legs Syndrome After Single Low Dose Quetiapine Administration

Restless legs syndrome is an underdiagnosed sensori-motor disorder and psychotropic drugs are one of the main secondary causes of the illness. The most common psychotropic agents that cause restless legs syndrome are antidepressants; however, antipsychotics have also been reported to induce restless legs syndrome. The prevalence, vulnerability factors and the underlying mechanism of antipsychotic-induced restless legs syndrome are unclear. A possible explanation is that dopaminergic blockade is the main precipitator of the syndrome. Quetiapine-induced restless legs syndrome is another point of interest because of its low binding to D2 receptors. We herein report the case of a restless legs syndrome that emerged after a single low dose quetiapine administration.

The Cholinergic System: An Emerging Drug Target for Schizophrenia

Background: Cognitive deficits are amongst the most socially debilitating and least effectively treated symptoms of schizophrenia. The cholinergic system is a promising target for the design of novel drugs that can more effectively treat these symptoms. Methods: We review the literature supporting the dysfunction of the cholinergic system in schizophrenia, discuss the preclinical and clinical data showing that modulating the cholinergic system could improve the symptoms of schizophrenia and review the main pharmacological strategies being investigated to treat cholinergic dysfunction in schizophrenia. Results: Post-mortem and neuroimaging studies suggest there are widespread reductions in cholinergic receptor signalling in the cortex as well as subcortical regions, such as the hippocampus and striatum, in individuals with schizophrenia. Potential cholinergic drug targets are being pursued to increase receptor function. These include inhibiting the activity of the enzyme acetylcholinesterase to increase synaptic acetylcholine levels, and increasing the nicotinic receptor and muscarinic receptor activity with agonists or positive allosteric modulators. Conclusion: Amongst the most promising drug targets for treating schizophrenia are the α₇ nicotinic receptor and the CHRM1 and CHRM4 muscarinic receptors. The recent development of allosteric modulators that selectively target these receptors offers the potential to more effectively treat the symptoms of schizophrenia.

Tardive Dyskinesia and Covert Dyskinesia with Aripiprazole: A Case Series

Aripiprazole, a dopamine stabilizing atypical antipsychotic is used in treatment of tardive dyskinesia caused by other neuroleptics. Tardive dyskinesia is rarely caused by Aripiprazole and has only been documented in high risk patients i.e., female gender, advanced age, affective illness, coexisting neurological disorders. Here the author describes two atypical cases of tardive dyskinesia associated with Aripiprazole. First case of tardive dyskinesia was observed in a neuroleptic naïve young adult male with paranoid illness after six months of treatment with Aripiprazole upon addition of Fluoxetine and the second case was a middle aged female with affective illness where dyskinetic movements appeared after stopping Aripiprazole. The role of Fluoxetine in causing tardive dyskinesia with Aripiprazole and covert dyskinesia due to Aripiprazole with appropriate management is discussed.

EDITORIAL (Thematic Issue: New Targets of Medical Treatment in Psychiatric Disorders)

Beta-Blockers: Current State of Knowledge and Perspectives

It has been over half a century since propranolol, the first beta-blocker, was developed for medical treatment. Since that time a large number of compounds from this group have been synthesised and many are now in clinical use. The structure, function, pharmacokinetics, and mechanism of beta-blockers have been established. The possibilities for their use in treating different conditions continue to evolve. Since the discovery of later generation beta-blockers, such as carvedilol and nebivolol, the search for new compounds continues, and may include known substances with betablocking properties which could extend their therapeutic potential.

The Incidence of Akathisia in the Treatment of Schizophrenia with Aripiprazole, Asenapine and Lurasidone: A Meta-Analysis

Akathisia is a troubling side effect that leads to non-adherence with antipsychotic regimens. Second generation antipsychotics (SGAs) tend to cause less akathisia than older agents but the risk still exists and rates vary between agents. Little is known about the incidence of akathisia among the newer SGAs. The purpose of this study was to conduct a meta-analysis of akathisia incidence rates for three of the newer SGAs: aripiprazole, asenapine, and lurasidone. Data were drawn from published and unpublished clinical trials comparing the drug of interest to either placebo or another SGA in adults with schizophrenia. Twenty-four studies (11 aripiprazole, 5 asenapine, and 8 lurasidone) provided incidence rates for akathisia and related nervous system events. Data showed that the relative risk (RR) of akathisia was double that of controls, with lurasidone having the highest individual RR at 2.7 [CI: 2-3.6]. Sensitivity analysis changed the RR of akathisia to less than 10%. The RR of akathisia was still elevated (1.75 [1.4-2.1]) when these drugs were compared only to actives (older SGAs). Agitation and anxiety RRs were also higher with the newer SGAs as compared to the older SGAs. Previous theory suggests antagonism of serotonin (5-HT)_2A receptors may decrease akathisia risk. Expectations were that aripiprazole, asenapine and lurasidone would have a low incidence of akathisia, as all display strong antagonism at 5-HT_2A. However, in this study all three had a significantly higher risk of akathisia compared to placebo or other SGAs. This suggests the pathophysiology of akathisia involves other receptors and is multifactorial.

Pharmacological Approaches for Treatment-resistant Bipolar Disorder

Bipolar disorder is prevalent, with high risks of disability, substance abuse and premature mortality. Treatment responses typically are incomplete, especially for depressive components, so that many cases can be considered “treatment resistant.” We reviewed reports on experimental treatments for such patients: there is a striking paucity of such research, mainly involving small incompletely controlled trials of add-on treatment, and findings remain preliminary. Encouraging results have been reported by adding aripiprazole, bupropion, clozapine, ketamine, memantine, pramipexole, pregabalin, and perhaps tri-iodothyronine in resistant manic or depressive phases. The urgency of incomplete responses in such a severe illness underscores the need for more systematic, simpler, and better controlled studies in more homogeneous samples of patients.

Challenging Treatment-Resistant Major Depressive Disorder: A Roadmap for Improved Therapeutics

Major depressive disorder (MDD) is associated with a significant burden and costs to the society. As remission of depressive symptoms is achieved in only one-third of the MDD patients after the first antidepressant trial, unsuccessful treatments contribute largely to the observed suffering and social costs of MDD. The present article provides a summary of the therapeutic strategies that have been tested for treatment-resistant depression (TRD). A computerized search on MedLine/PubMed database from 1975 to September 2014 was performed, using the keywords “treatment-resistant depression”, “major depressive disorder”, “adjunctive”, “refractory” and “augmentation”. From the 581 articles retrieved, two authors selected 79 papers. A manual searching further considered relevant articles of the reference lists. The evidence found supports that adding or switching to another antidepressant from a different class is an effective strategy in more severe MDD after failure to an initial antidepressant trial. Also, in subjects resistant to two or more classes of antidepressants, some augmentation strategies and antidepressant combinations should be considered, although the overall response and remission rates are relatively low, except for fast acting glutamatergic modulators. The wide range of available treatments for TRD reflects the complexity of MDD, which does not underlie diverse key features of the disorder. Larger and well-designed studies applying dimensional approaches to measure efficacy and effectiveness are warranted.

Cannabidiol and Sodium Nitroprusside: Two Novel Neuromodulatory Pharmacological Interventions to Treat and Prevent Psychosis

Since most patients with schizophrenia do not respond properly to treatment, scientific effort has been driven to the development of new compounds acting on pharmacological targets beyond the dopaminergic system. Therefore, the aim is to review basic and clinical research findings from studies evaluating the effects of cannabidiol (CBD), an inhibitor of the reuptake and metabolism of anandamide and several other effects on nervous system, and sodium nitroprusside, a nitric oxide donor, on the prevention and treatment of psychosis. Animal and human research supports that CBD and sodium nitroprusside might be effective in the prevention and treatment of psychosis in general and especially in schizophrenia. The evidence available to date shows that CBD and sodium nitroprusside act in pathways associated with psychotic symptoms and that they may be important agents in the management of prodromal psychotic states and psychosis. This underscores the relevance of further research on the effects of these agents and others that mediate the activity of the cannabinoid system and of nitric oxide, as well as comparative studies of their antipsychotic effects and those of other antipsychotic drugs currently used to treat schizophrenia.

Atypical antipsychotics and inverse agonism at 5-HT₂ receptors

It is now well accepted that receptors can regulate cellular signaling pathways in the absence of a stimulating ligand, and inverse agonists can reduce this ligand-independent or “constitutive” receptor activity. Both the serotonin 5-HT_2A and 5-HT_2C receptors have demonstrated constitutive receptor activity in vitro and in vivo. Each has been identified as a target for treatment of schizophrenia. Further, most, if not all, atypical antipsychotic drugs have inverse agonist properties at both 5-HT_2A and 5-HT_2C receptors. This paper describes our current knowledge of inverse agonism of atypical antipsychotics at 5-HT_2A/2C receptor subtypes in vitro and in vivo. Exploiting inverse agonist properties of APDs may provide new avenues for drug development.

Non-Antidepressant Pharmacological Treatment of Obsessive Compulsive Disorder: A Comprehensive Review

Introduction: Obsessive-compulsive disorder (OCD) is associated with significant morbidity and dysfunction. First-line OCD treatments - serotonin reuptake inhibitors (SRIs), cognitive behavioral therapy (CBT) and their combination - though widely used, are not sufficient in treating resistant cases. This eventually raises the need for finding novel strategies, whether by adding-on drugs or switching to a different psychopharmacological class. The aim of this paper is to present a comprehensive review of non-antidepressant pharmacological treatment that has been evaluated for the management of OCD.

Materials and methods: A research has been conducted using MedLine and the following Medical Subject Headings (MeSH) terms were used: Obsessive compulsive disorder AND drug therapy. Articles that conformed to specific inclusion criteria were stratified per drug and per quality of evidence. For each drug, articles having the best level of evidence were retained.

Results: Sixty-eight articles were reviewed and presented by drug class as follows: antipsychotics, mood stabilizers, gamma-amino-butyric acid (GABA) analogues and GABA reuptake inhibitors, benzodiazepines, glutamatergic agents and other miscellaneous drugs.

Discussion: There is substantial collective evidence supporting the use of antipsychotics as an augmentation treatment of resistant OCD patients. Although not always consistent, the following drugs showed some efficacy upon randomized controlled trials: risperidone, olanzapine, quetiapine, aripiprazole, haloperidol, topiramate, pindolol, morphine, ondansetron and celecoxib. The efficacy of glutamatergic agents is promising. Numerous other pharmacological agents have been studied yet the results are inconclusive due to several limitations mainly of methodological nature.

Off-Label Trazodone Prescription: Evidence, Benefits and Risks

Although trazodone is approved and marketed in most countries worldwide for the sole treatment of Major Depressive Disorder, the use for this medication is very common for many other conditions, such as primary or secondary insomnia, Generalised Anxiety Disorder, Panic Disorder, Post-Traumatic Stress Disorder and Obsessive- Compulsive Disorder. Other, not officially approved, uses of trazodone include: the treatment of bulimia, benzodiazepine and/or alcohol dependence or abuse, fibromyalgia, degenerative diseases of the central nervous system such as dementia and other organic disorders, schizophrenia, chronic pain, and diabetic neuropathy. In addition, due to its 5HT2A receptor antagonistic action, trazodone may be used to prevent the occurrence of initial and long-term side effects of SSRI, such as anxiety, insomnia and sexual dysfunction.

Despite the favorable clinical experience and the encouraging results from the studies that have tested the efficacy of trazodone for some of its off-label indications, it is paramount that large, randomized and controlled clinical trials be conducted in the near future to evaluate which of the many off-label indications are supported by a strong scientific evidence.

Restless Leg Syndrome Associated with Atypical Antipsychotics: Current Status, Pathophysiology, and Clinical Implications

Restless leg syndrome (RLS) is a common disorder, frequently of unclear origin, which is often associated with significant distress. There are a few case reports of atypical antipsychotic agents (AAP) causing RLS. The pathophysiological mechanisms resulting in emergence of these movements suggest central dopaminergic dysfunction. Dopamine agonists and L-dopa reduce the symptoms of RLS, and some agents that block the dopaminergic system aggravate RLS. Genetic influences are implicated in RLS and an association between gene polymorphisms and antipyschotic-associated onset of RLS has been postulated. Greater awareness of potential causes of RLS, and its differentiation from akathisia and illness related agitation might help in reducing the distress associated with it and improving patient compliance in patients using atypical antipsychotic agents.

Antidepressant Related Movement Disorders in the Elderly

Background: Antidepressant related movement disorders have been reported in individuals who are ≤ 65 years in age, but a review of such cases in individuals who are ≥ 65 years from medical literature has not yet been conducted.

Objectives: To review case reports of antidepressant related movement disorders in individuals who are ≥ 65 years in age from medical literature.

Methods: A systematic search of PubMed, Medline, PsychINFO, Embase and Cochrane Library was conducted through January, 31, 2014 for case reports of antidepressant related movement disorders in the elderly.

Results: A total of 40 reports (43 individual cases) of movement disorders related to antidepressant use in the elderly were identified. The most common movement disorders noted in these cases were dyskinesias, myoclonus and Parkinsonism. Approximately 80% of the cases occurred in women. About 40% of the cases involved Selective Serotonin Reuptake Inhibitors (SSRIs), with paroxetine being the most commonly noted drug in this class with a total of six cases. Discontinuation of the antidepressant resulted in a resolution of the abnormal movements in a majority of the cases.

Conclusions: Antidepressant related movement disorders are uncommon among older adults.

Safety Profile of the Use of Second Generation Antipsychotics in the Child and Adolescent Population

The search for novel, effective, and safe psychotropic medications for use in children and adolescents is an ongoing journey. Specifically, several atypical antipsychotics have received FDA indications for use in children and adolescents, although carry the risk of potentially serious side effects such as extrapyramidal symptoms, tardive dyskinesia, weight gain, metabolic syndrome, and symptoms of hyperprolactinemia. Three newer antipsychotics – asenapine, iloperidone, and lurasidone – have been considered by some as alternatives to use in children and adolescents with various psychiatric conditions. However, the data on the use of these medications in this population is limited. We review the current literature regarding the use of these agents in children and adolescents. Although these medications may have similar properties to current agents with approved indications, there is not sufficient evidence at this time to recommend their use in children and adolescents. More research is needed regarding the efficacy, safety, and tolerability of these medications in the pediatric population.

Polyphenols and Depression: from Chemistry to Medicine

Polyphenols are an extensive group of substances present in plants. Animals and humans achieve them through the diet. Polyphenols have been related to several processes, such as oxidative stress and signaling pathways modulating gene expression that promote an anti-inflammatory environment. Moreover, polyphenols also have a possible role in the protection of several diseases, including major depression. Depression is an important public-health problem with a multifactorial etiology and lots of pathways that can be altered in affected subjects. Moreover, this disease can be affected by exercise, sleep and diet. There are animal works studying polyphenols and depression, but human studies are scarce. This review summarizes recent evidences in relation to the effects of polyphenols as antidepressant agents in the depression.

Pain in Patients with Parkinson’s Disease; A Pain-related Evoked Potential Study

Pain is a well-known non-motor symptom of Parkinson’s disease (PD) and might be related to not only peripheral factors but also abnormal processing in the central nervous system (CNS). The aim of this study is to investigate dysfunction of the central processing of pain, and examine the relationships between abnormal processing of pain and motor or non-motor symptoms of PD. To induce pain-related evoked potentials in 23 PD patients and 12 healthy controls, we activated Aδ fibers using a push-pin type needle electrode inserted in the epidermis. Evoked potentials were recorded from the Cz electrode at the index finger and second toe. The Hoehn-Yahr stage, Unified Parkinson’s Disease Rating Scale (UPDRS), Self-rating Depression Scale (SDS), and Mini Mental State Examination (MMSE) were evaluated. In addition, MIBG myocardial scintigraphy was performed and early and delayed heart-to-mediastinum (H/M) ratios were examined. The N1-P1 peak-to-peak amplitudes, which are thought to originate from the anterior cingulate cortex and insula, were significantly lower in PD patients than in the controls for both the upper and lower limbs (both P<0.01). The N1-P1 amplitudes for the upper limbs were significantly correlated with the H/M ratio (P<0.05). The N1-P1 amplitudes did not correlate with the severity of clinical parameters such as the Hoehn-Yahr stage or UPDRS and SDS or MMSE. These results may reflect abnormal central processing of pain in PD patients, which appears to be independent of the clinical features and severity of motor and nonmotor symptoms except for degeneration of the myocardial sympathetic nerve.

N-Acetylcysteine for the Treatment of Obsessive-Compulsive Disorder

Many children and adults with Obsessive-Compulsive Disorder experience incomplete symptom relief despite treatment with several evidence-based interventions for OCD. Converging lines of evidence from genetic, neuroimaging, biochemical and pharmacological studies implicate the importance of abnormalities in the glutamate symptoms in the pathogenesis of OCD. Strong evidence suggests that oxidative stress may be important in the progression of several psychiatric disorders, especially psychotic and affective disorders. N-acetylcysteine (NAC) is a cheap, relatively safe over-the-counter supplement that crosses the blood-brain barrier and acts potentially as a glutamate modulating agent and antioxidant. NAC has demonstrated efficacy in the treatment of a wide variety of psychiatric conditions in individual randomized, controlled trials including psychosis, autism, bipolar depression, trichotillomania. A recent double-blind placebo-controlled in adults with SRI-refractory OCD demonstrated the efficacy of NAC compared to placebo. In this review we summarize the preclinical and clinical data demonstrating NAC is a potentially promising new pharmacological agent in the treatment of OCD.

Implication of Circadian Rhythms and Melatonin in Major Depressive Disorder: The Evidence Base for New Antidepressant Treatment

Major depressive disorder (MDD) is a highly prevalent and disabling disease. Recent studies have highlighted the interactions between the circadian system and depression and indicate a probable bidirectional relationship between MDD and the circadian system. In clinical practice MDD leads to circadian disturbances, and circadian disorders increase the risk of depression. Recent interest has focused on the use of melatonin and melatonin agonists in the treatment and relapse prevention of MDD. This review summarises the mechanisms of the biological clock and its links with MDD. It looks at the effects of melatonin and melatonin agonists on sleep and on symptoms of depression and focuses on agomelatine, a MT1/MT2 agonist and a 5-HT2_C antagonist which combines a chronobiotic and antidepressant action with similar efficacy to fluoxetine, venlafaxine and sertraline. Relapse rates are reduced on agomelatine compared to placebo. Agomelatine is well tolerated and rapid improvements in disturbed sleep are reported by patients. In the light of these studies, the potential role of melatonin agonists in treating MDD and subtypes of MDD is discussed.

Use of Benzodiazepines and Haloperidol Among Orthopedic Patients in Postoperative Delirium. A Systematic Review

Postoperative delirium may occur as a serious complication after orthopedic surgery. In addition, risk factors such as age, mental and organic illnesses may increase the incidence of the aforementioned complication. Delirium has a negative impact on postoperative mobilization and recovery. Furthermore, it may result in longer hospital treatment. This study is a systematic literature review of articles that was conducted through a key word search of PubMed. The review includes: 1) pathogenesis, 2) risk factors in the development of postoperative delirium, and 3) the effective methods and strategies of treatment, especially in relation to patients hospitalized in orthopedics.

This systematic review will discuss benzodiazepines and haloperidol, which are used to treat delirium in the prevention and treatment of postoperative delirium. The findings suggest that prevention of postoperative delirium with drugs can be an effective strategy.

Prevalence, Severity and Characteristics of Tardive Dyskinesia Among Schizophrenia Patients in an Israeli Psychiatric Center

Tardive dyskinesia (TD) is a debilitating side-effect of antipsychotic treatment associated with reduced compliance and quality of life. TD prevalence is difficult to estimate accurately and is influenced by the increased use of antipsychotic drugs and the aging of the population. We assessed the prevalence, severity and characteristics of TD among schizophrenia patients at a university-affiliated psychiatric center in Israel. One hundred and twenty eight patients with schizophrenia were recruited and underwent demographic and clinical assessments. Subjects who met Schooler-Kane criteria for probable TD were compared to those without TD. Forty five subjects met probable TD criteria (prevalence: 35.2%; 95% CI 26.9% -44.1 %.). Subjects with TD were older and had a longer duration of treatment with antipsychotic medications. Diabetes mellitus, hypertension, head injuries and more severe psychiatric symptomatology did not predict TD. Patients in the TD-group had higher rates of extrapyramidal symptoms (EPS) and were more likely to receive an anticholinergic agent. The type of antipsychotic medication was not found to be associated with TD occurrence. Our findings confirm the established relationships between presence of TD and age, duration of antipsychotics treatment, anticholinergic treatment and the presence of EPS. Furthermore, our data support recent findings indicating that TD is still a prevalent disorder representing an unresolved public health issue.

Disentangling the Intricacies of Migraine: A Review

The etiology of migraine, a neurological disorder, has still not been clearly established, although it may be categorized as a headache disorder with specific characteristics such as focal neurological symptoms preceding or accompanying the headache. Many researchers have suggested genetic predisposition as one of the underlying causes of migraine. An insight into the various pathophysiological mechanisms such as the role of cortical spreading depression, abnormal brain stem activity, trigeminal nerves, calcitonin gene related peptide, nitric oxide and serotonin receptors in the development of migraine, has been conferred in the present article. The accurate diagnosis of migraine and identification of its type is a prerequisite for appropriate therapy. Ample opportunity still exists for the improvement in the safety, efficacy and tolerance capacity of the currently available antimigraine medications, through the design and development of targeted drug delivery system. In the present review, an attempt has been made to highlight all the underlying pathophysiological mechanisms of migraine, its diagnosis, treatment and therapeutic area to be explored including mitigation of biochemical pathways and gene therapy.

Proceedings of the Regional Conference of the International Society for Adolescent Psychiatry and Psychology (ISAPP), a Joint Conference with 18^th National Symposium of Adolescent Mental Health, Ankara, Turkey, November 21-24, 2013¹

A Case of Akathisia induced by Escitalopram: Case Report & Review of Literature

Although cases of Selective Serotonin Reuptake Inhibitor (SSRI) induced akathisia have often been reported in literature, this adverse effect has not adequately been mentioned in major pharmacology textbooks. As a result, SSRIinduced akathisia is very frequently under-recognized. A review of literature showed that almost all frequently used SSRIs such as Fluvoxamine, Fluoxetine, Sertraline, Citalopram have been reported to be causing akathisia. SSRI-induced restless legs syndrome and movement disorders have also been reported.

However, Escitalopram-induced akathisia is rare. In our review of literature, we could find only one single case of Escitalopram-induced severe akathisia. And this specific SSRI drug has rarely been implicated with occurrence of restless legs syndrome and extra-pyramidal side-effects like dytonia etc.

Here, we present a case of Escitalopram-induced severe akathisia - a 53year old female, who had developed severe akathisia after taking Escitalopram for a few days. According to the Barnes Akathisia Rating Scale (BARS), her Global Clinical Assessment of Akathisia Score was 5 i.e. severe akathisia. As per Naronjo Adverse Drug Reaction Scale the probability of association of this adverse reaction with Escitalopram was 7 (i.e. probable). Her symptoms continued in spite of prompt discontinuation of the drug. But, she improved rapidly with the use of Propranolol and Clonazepam. On the last follow-up, she was free from any symptoms.

As new generation antidepressants are rarely associated with extra-pyramidal symptoms, the recognition of such adverse effects requires a high index of suspicion. Early recognition of the symptoms and discontinuation of the offending agent along with supportive therapy like a short course of benzodiazepines, beta-adrenergic antagonists or anticholinergics may rapidly relieve the patient from this distressing symptom.

Treatment of Antipsychotic-Induced Hyperprolactinemia: An Update on the Role of the Dopaminergic Receptors D2 Partial Agonist Aripiprazole

Hyperprolactinemia is an unwanted adverse effect present in several typical and atypical antipsychotics. Aripiprazole is a drug with partial agonist activity at the level of dopamine receptors D2, which may be effective for antipsychotic- induced hyperprolactinemia. Therefore, we analyzed the literature concerning the treatment of antipsychoticinduced hyperprolactinemia with aripiprazole by updating a previous paper written on the same topic. More recent studies were reviewed. They showed that there are two options for the treatment of antipsychotic-induced hyperprolactinemia with aripiprazole. The safest strategy may require the addition of aripiprazole to ongoing treatments, in the case patients had previously responded to antipsychotic drugs and then developed hyperprolactinemia. However, it is advisable to monitor the patients in case relapses and/or side effect, although rare, might occur. Switching drugs should be considered when a patient does not appear to be responding to the previous antipsychotic, thus developing hyperprolactinemia. A cross-taper switch should always be considered, but the risk of a relapse in the disorder may occur more frequently and the patients should be closely monitored. However, limitations must be considered and further studies are needed to definitely elucidate this important issue. Some relevant patents are also described in this review.

Current Therapeutic Advances in Patients and Experimental Models of Huntington's Disease

Huntington’s disease (HD) clinical manifestations begin insidiously and are progressively incapacitating. Symptomatic therapies, in particular dopamine blockers and neuroleptics, are presently the only treatment for HD. Identification of neuropathological mechanisms that underlie the selective striatal and cortical neurodegeneration has allowed for the development of novel neuroprotective therapies that may improve HD patients’ quality of life and enhance their survival. In this review we describe the symptomatic and neuroprotective therapies in HD that are currently in a preclinical or clinical stage. Neuroprotective therapies can act at several stages of HD, namely through: i) transcription modulation, ii) regulation of neurotrophic factors levels, iii) inhibition of metabolic dysfunction through metabolic enhancers, iv) apoptosis inhibition, v) autophagy regulation, vi) transglutaminase inhibition, and/or vii) modulation of neurotransmitter receptors. Moreover, emerging therapies in HD, including gene therapy using siRNA and shRNA to silence CAG repeats or deep brain stimulation, have shown promising results. Although most of the therapies are at a pre-clinical stage, phase II-III clinical trials have been performed for each pathophysiological mechanism of the disease. Thus, efforts should continue to ensure that effective therapies are studied and tested to help mitigate HD.

Dual Ligands Targeting Dopamine D2 and Serotonin 5-HT_1A Receptors as New Antipsychotical or Anti-Parkinsonian Agents

Psychiatric disorders like schizophrenia and neurodegenerative diseases like Parkinson’s disease are associated with poly-factorial pathogenic mechanisms, with several neurotransmitter systems closely involved. In addition to the cerebral dopaminergic (DA) system, the serotoninergic (5-HT) system also plays a crucial role in regulating psychoemotional, cognitive and motor functions in the central nervous system (CNS). Among the large 5-HT receptor family, accumulating data have revealed new insights into the therapeutic benefit of the 5-HT_1A receptor in treating various CNS disorders, especially schizophrenia and Parkinson’s disease. The present review discusses the advance of dual agents with mixed actions at the dopamine D₂ and serotonin 5-HT_1A receptors in the treatment of these diseases. Aripiprazole was the only marketed drug with dual D₂ and 5-HT_1A profile. It is a partial D₂ and 5-HT_1A receptor agonist and has been prescribed as an atypical antipsychotical drug. Two other drugs Cariprazine and Pardoprunox are being investigated in clinic. Most of the other candidate compounds, including Bifeprunox, Sarizotan, Mazapertine succinate, PF-217830, and Adoprazine were discontinued due to either non-optimal pharmacokinetic properties or insufficient therapeutical efficacy. Although much effort has been done to highlight the advantages of the 5-HT_1A and D₂ dual approach, it has to be pointed out that many of these drugs showed poly-pharmacological profile by targeting many other receptors and/or transporters besides the D₂ and 5-HT_1A receptors. In this regard, ‘pure’ compounds exclusively acting on the D₂ and 5-HT_1A receptors are highly needed to further validate this approach. Meanwhile, safety concerns and in vivo pharmacokinetic alerts should also be implanted to the drug design art early.

The Use of Flavonoids in Central Nervous System Disorders

Neurodegenerative, neurological and psychiatric diseases are a group of pathologies with huge social and economic impacts. Since brain disorders continue to be pathological conditions for which corrective surgery cannot be widely used, treatments are based on drugs that only alleviate the symptoms. Despite all efforts in finding more efficient therapeutic agents, the requirement for neuroprotective drugs able to cross the blood-brain barrier (BBB) has been a hard challenge to overcome. Flavonoids are known by their antioxidant activities thus preventing oxidative stress, which is believe to be one of the causes of disorders affecting the central nervous system. Moreover, they can also modulate both enzymes and receptors activities, being regarded as multi-target botanical therapeutics or drugs. This review will give emphasis to the benefits of flavonoids found in the diet in the treatment of Alzheimer’s disease, Parkinson’s disease, epilepsy, depression, and schizophrenia. The antioxidant effect of several flavonoids, as well as their effects not related with antioxidant activity, in the above mentioned diseases will be reviewed. Aspects concerning structure-activity relationships, but also the bioavailability of these compounds in the brain will be referred.

Repurposed Drugs for the Treatment of Schizophrenia and Bipolar Disorders

Characteristic symptoms of schizophrenia and bipolar disorders have been described and classified about a century ago. Each of these disorders may cause considerable impairment reflecting substantial alterations in cognition, perception, and mood. Though both disease concepts are well established, psychopharmacological treatment strategies, involving first- and second-generation antipsychotics, benzodiazepines and mood stabilizing drugs, often fail to keep their purported alleviating effects on respective characteristic symptom spectra, producing unsatisfactory patient responses. While drug profiles may differ concerning the underlying mechanism of action, the breadth of treatment options remains limited. Besides developing new drugs with different mechanisms of action, side-effect profile and efficacy, it has to be emphasized that repurposed drugs might serve as alternative or adjuvant treatment options for patients, who continue to poorly respond to standard treatment algorithms. Here, we review the current evidence of selected drugs whose repurposed use might expand the range of treatment options for schizophrenia and bipolar disorders.

Schizophrenia: Causes and Treatments

Schizophrenia is a major mental illness that is characterized by psychosis, apathy, social withdrawal and cognitive impairment. These abnormalities in patients results in impaired functioning in work, school, parenting, self-care, independent living, interpersonal relationships, and leisure. Although the search for the biological correlates of schizophrenia has met with limited success, new advances in genetics and pharmacology are promising. Here, we describe the symptoms, causes, diagnosis, strategies for treatment, and clinical impact of the currently available medications.

Improving the Treatment of Schizophrenia: Role of 5-HT Receptors in Modulating Cognitive and Extrapyramidal Motor Functions

Patients with schizophrenia exhibit various clinical symptoms including positive and negative symptoms, neurocognitive impairments and mood disturbances. Although a series of second generation antipsychotics (SGAs) (e.g., risperidone, olanzapine and quetiapine) have been developed in the past two decades, clinical reports do not necessarily show advantages over first generation antipsychotics (FGAs) in the treatment of schizophrenia, especially in their efficacy against cognitive impairment and ability to cause extrapyramidal side effects (EPS). Recently, several lines of studies have revealed therapeutic roles of 5-HT receptors in modulating cognitive impairments and extrapyramidal motor disorders. Specifically, inhibition of 5-HT_1A, 5-HT₃ and 5-HT₆ receptors or activation of 5-HT₄ receptors alleviates cognitive impairments (e.g., deficits in learning and memory). In addition, stimulation of 5-HT_1A receptors or inhibition of 5-HT₃ and 5-HT₆ receptors as well as 5-HT_2A/2C receptors can ameliorate extrapyramidal motor disorders. Thus, controlling the activity of 5-HT_1A, 5-HT₃ or 5-HT₆ receptors seems to provide benefits by both alleviating cognitive impairments and reducing antipsychotic-induced EPS. This article reviews the functional roles and mechanisms of 5-HT receptors in the treatment of schizophrenia, focusing on the serotonergic modulation of cognitive and extrapyramidal motor functions, and illustrates future therapeutic strategies.

Atypicality of Atypical Antipsychotics Revisited

Background: All antipsychotic agents marketed since clozapine have been categorized as “atypical”, without regard for the true definition of “atypicality”. The standard practice of designating every new agent as “atypical” not only ignores the definition, but conveys a false sense of safety for the majority of these medications when considering the risks of movement disorders, both acute and latent. Though receptor profiles are unique to each medication, the antipsychotic effect of all agents is attributed to reducing dopamine activity in the mesolimbic area, usually through the blockade of dopamine type 2 (D2) receptors, whether the agent is “tightly” or “transiently bound”. Yet, antagonism of D2 receptors in the striatum is associated with the potential for extrapyramidal symptoms (EPS), as well as the development of tardive dyskinesia (TD). Clozapine is categorized as “atypical” because its use is not associated with EPS or TD at a rate greater than placebo, as it provides antipsychotic efficacy at a lower saturation of D2 receptors than traditional antipsychotics. As newer second-generation agents came to market, the definition of “atypical” has been modified to include a variety of characteristics unrelated to movement side effects. Nevertheless, many clinicians still assume that “atypicality” indicates a risk of EPS and TD at no-greater-than-placebo rates.

Objective: This paper examines each of the 10 second-generation agents approved in the United States for treatment of schizophrenia (and cariprazine, for which approval is pending), and examines which ones meet the strict definition of “atypical” (ie, risk of EPS and TD no greater than placebo).

Data source: A literature search using PubMed and Google Scholar, involving various combinations of the keywords “antipsychotic,” “atypical,” “typical,” “first generation,” “second generation,” “schizophrenia,” “tardive dyskinesia,” “movement disorders,” and “extrapyramidal symptoms,” in addition to the 11 agents by chemical name, yielded a vast set of clinical trials, systematic reviews, case reports, and receptor-profile studies. These articles and reports were narrowed to the appended reference list, based on the report’s/trial’s contribution to the discussion of “atypicality.”

Results/Conclusions: Of the 10 second-generation agents currently in use, and the one awaiting approval, only clozapine, quetiapine, and iloperidone meet the criteria necessary for the designation of “atypical” (ie, rates of EPS and TD no greater than placebo).

Neuropeptide Systems and Schizophrenia

Schizophrenia affects approximately 1% of the world population, and the majority of pharmacologically based treatments for this disorder are ligands that interact with monoaminergic transmission. However, there is a wealth of evidence that various neuropeptides are often co-released with monoamine neurotransmitters, and that ligands acting at neuropeptide receptors modulate monoaminergic transmission as well as schizophrenia-related behaviors in preclinical animal models. Such neuropeptide systems include neurotensin, cholecystokinin, corticotropin releasing factor, neuropeptide Y, oxytocin, opioid peptides, tachykinins, thyrotropin-releasing hormone, and orexins. The purpose of this review will be to summarize the existing preclinical and clinical literature on the role of various neuropeptide systems as modulators of schizophrenia-related behaviors, and the potential of targeting these systems for the development of novel antipsychotic medications.

From Preclinical to Clinical Trials: An Update on Potential Therapies for Huntington’s Disease

Huntington’s disease (HD) is a neurodegenerative disorder caused by a CAG expansion in the HD gene that codifies the protein huntingtin and characterized by neurodegeneration of certain areas of the brain, particularly the striatum and the cortex. The first symptoms usually appear in mid-life and include cognitive deficits and motor disturbances that progress over time. The disease is invariable fatal and there is currently no cure for individuals affected with this disorder. In a search to find a cure for this devastating neurodegenerative disorder, numerous pharmacological compounds have now been tested through preclinical trials that have heavily relied on the various transgenic mouse models that are currently available to study HD. Unfortunately however, to date the benefits observed in the clinical setting have been somewhat limited. We have recently published a review article comparing the results of these preclinical studies with the outcomes of the corresponding clinical trials involving HD afflicted individuals (Brocardo and Gil- Mohapel, 2012, Current Psychopharmacology 1:137-154). In the present article we present an update to our previous review, where the new preclinical and clinical studies that have been performed over the past year have been also discussed with the goal of further elucidating the efficacy of the pharmacological treatments that have been attempted in both transgenic HD mouse models and human HD patients. By providing and maintaining an up-to-date overview of the most current literature, we hope that patterns will emerge that will guide the design of more effective preclinical and clinical studies, such as the use of combination therapies that utilize different cocktails of pharmacological compounds to simultaneously target different intracellular pathways that are affected in HD.

Antipsychotic Polypharmacy: Still Dirty, But Hardly a Secret. A Systematic Review and Clinical Guide

Treatment resistant psychoses present an enormous burden. Guidelines generally prohibit more than one antipsychotic and the efficacy of this is limited, but multiple surveys suggest such practice is common. Reasons for this include a lack of alternatives, difficulty in discontinuing, successful clinical experience, and inertia. We performed a systematic review on the efficacy of antipsychotic polypharmacy. This identified two broad categories of polypharmacy - clozapine plus a second antipsychotic and two ‘non-clozapine’ antipsychotics - and three domains of efficacy - effects on specific symptoms, cognition, and adverse effects.

The evidence is mixed. There are high quality double blind studies supporting clozapine augmentation, but just as many such studies failing to show benefit. Less evidence supports the combination of two ‘non-clozapine’ drugs. However, there is more consistent emerging data supporting aripiprazole for helping reduce medication induced weight-gain and reregulate lipid profiles. Effects on cognition do not appear to be favourable and polypharmacy is associated with more side effects.

The quantity and quality of the research literature is surprisingly sparse. Clinicians can use selective evidence to support polypharmacy; but the overall context does not support this. Currently there are no clear predictors to suggest which subgroup of patients may be more likely to benefit most from such prescribing. In conclusion, polypharmacy should be carried out with caution with careful baseline and on-going monitoring of the target symptoms, the apriori rationale for initiating treatment with a deadline for cessation, accompanied by a robust assessment of adverse effects and physical health checks.

An Outline of the Historical and Clinical Aspects of Catatonic Schizophrenia

Catatonic schizophrenia has been an integral part of all psychiatric classifications for over a century. However, based on the recommendation of a panel of experts, catatonic schizophrenia as an independent diagnostic entity will probably be removed form DSM-V. This review paper summarizes the history, psychopathology and clinical features of catatonic schizophrenia and argues that a cluster of loosely defined, simple and complex motor phenomena is an inherent aspect of the symptomatology of schizophrenia. In the authors’ opinion, the motor aspects of descriptive psychopathology in general, and in schizophrenia in particular have not received ample attention in modern research and clinical practice. As a consequence, there is a dearth of scientific data on the epidemiology, psychopathology, genetics, treatment response and biological markers that would have justified and cemented its place in modern classifications.

Pediatric Catatonia: Updating An Old Syndrome in Young People

There has been renewed interest in the demarcation of pediatric catatonia from other pediatric conditions including autism. An update on symptoms, prevalence, evaluation, treatment, risk factors, and experimental models of pediatric catatonia is presented.

Recent prevalence rates of pediatric catatonia vary widely across studies, suggesting that catatonia may not be rare in younger patients. Symptoms and diagnostic criteria for pediatric catatonia are the same as in adults. Studies and clinical experience support benzodiazepines and electroconvulsive therapy, including maintenance electroconvulsive therapy, as treatment options. Sometimes catatonia develops after severe psychological trauma. Historical and contemporary clinical and experimental catatonia models are available for future research, focusing on motor circuitry dysfunction, abnormal neurotransmitters, epileptic discharges, genetics, neuroendocrine and immune abnormalities, fear reactions akin to the animal defense strategy of tonic immobility, and developmental risk factors.

There have been advances in demarcating pediatric catatonia in a wide variety of patients as a treatable condition that requires prompt identificiation. A model of developmental impairment complements clinical and experimental catatonia models.

D-Amino Acid Oxidase Inhibitors as a Novel Class of Drugs for Schizophrenia Therapy

Over the years, accumulating evidence has indicated that D-serine represents the endogenous ligand for the glycinemodulatory binding site on the NR1 subunit of N-methyl-D-aspartate receptors in various brain areas. Cellular concentrations of D-serine are regulated by synthesis due to the enzyme serine racemase (isomerization reaction) and by degradation due to the same enzyme (elimination reaction) as well as by the FAD-containing flavoenzyme D-amino acid oxidase (DAAO, oxidative deamination reaction). Several findings have linked low levels of D-serine to schizophrenia: D-serine concentrations in serum and cerebrospinal fluid have been reported to be decreased in schizophrenia patients while human DAAO activity and expression are increased; oral administration of Dserine improved positive, negative, and cognitive symptoms of schizophrenia as add-on therapy to typical and atypical antipsychotics. This evidence indicates that increasing NMDA receptor function, perhaps by inhibiting DAAO-induced degradation of D-serine may alleviate symptoms in schizophrenic patients. Furthermore, it has been suggested that co-administration of D-serine with a human DAAO inhibitor may be a more effective means of increasing D-serine levels in the brain. Here, we present an overview of the current knowledge of the structure-function relationships in human DAAO and of the compounds recently developed to inhibit its activity (specifically the ones recently exploited for schizophrenia treatment).

History and Therapeutic Use of MAO-A Inhibitors: A Historical Perspective of MAO-A Inhibitors As Antidepressant Drug

Since the first generation of MAO inhibitors was developed, more than fifty years ago, this family of drugs has been ups and downs over the last decades. Actually, interest in MAO inhibitors is reviving and the emergence of new advances in the rational design of molecules and new techniques to predict the in vivo behavior has encouraged the research for new drugs with therapeutic potential in this area. The classic MAOIs have been widely used as antidepressants during the two decades after its introduction in clinic. Based on observations made on MAO inhibition by these drugs, it has been postulated hypothesis that have contributed to a better understanding of the mechanism and management of depressive disorders. However, exaggerated concerns about food and drug interactions relegated these drugs from the pharmaceutical landscape. The correct interpretation and the contextualization of side effects and the recent research findings, in which MAO selective inhibitors appear as promising agents in the treatment of emerging and high prevalence diseases, are placing these drugs again into the scientific and pharmacological focus.

Olanzapine Loaded Cationic Solid Lipid Nanoparticles for Improved Oral Bioavailability

Olanzapine, a lipophilic antipsychotic drug, has poor oral bioavailability due to hepatic first-pass metabolism. Solid Lipid Nanoparticles (SLNs) of Olanzapine were developed using lipids (Stearic acid and Glyceryl monostearate), soy lecithin, poloxamer 188 and charge modifier stearyl amine by microemulsion technique. The aim of this research was to find out whether the bioavailability of olanzapine can be improved by administering olanzapine SLN orally to Wistar rats. Area under curve was increased (up to 4-fold) and clearance was decreased when olanzapine entrapped in SLNs with stearylamine were administered orally compared with that of olanzapine suspension. The enhanced relative bioavailability by the SLNs formulation might be attributed to avoidance of first-pass hepatic metabolism by intestinal lymphatic transport, direct uptake of nanoparticles through the GI tract, increased permeability by surfactants, and decreased degradation and clearance. These results indicate that olanzapine can be loaded into solid lipid nanoparticles for improvement of its oral bioavailability.

Restless Legs Syndrome in Multiple Sclerosis

There is a growing interest in sleep disorders in multiple sclerosis (MS) due to their high frequency and possible relationship to fatigue, a hallmark symptom in MS. Among them, insomnia and restless legs syndrome (RLS) are the most common ones. RLS is a sleep-related motor disorder characterized by a strong urge to move associated with uncomfortable sensations in the limbs. It is frequently under diagnosed in patients with MS although its course is often particularly severe. Several arguments support a symptomatic origin of RLS in MS patients. Independently of any causal relationship, the high prevalence of RLS in MS patients has clinical implications.

The purpose of the present review is (i) to summarize the epidemiological data and clinical characteristics of RLS in MS patients in order to increase sensitivity to this disorder; (ii) to document the substantial body of evidence in support of a symptomatic origin of RLS in MS and from this (iii) to delineate the proposition that MS may represent a clinical model to study RLS-associated pathological changes.

A Genetic Dissection of Antipsychotic Induced Movement Disorders

Background. Antipsychotic medications (APM) are the first line pharmacological treatment for psychotic disorders and other behavioral disorders. Nevertheless, their use causes a number of side effects, including extrapyramidal symptoms (EPS). EPS decrease the efficacy of the antipsychotic treatments by causing poorer compliance to the treatment, stigma and a poorer quality of life for patients. Genetic studies hold the potential to unravel the molecular underpinnings of the EPS induced by APM but results are not conclusive and are far to be used in clinical practice despite decades of research. A more sophisticated selection of the list of genetic mutations explaining the genetic variance of EPS induced by APM could help in the definition of a personalized treatments for patients. Moreover, it would increase the quality of the current treatments with APM. Methods: We reviewed the literature searching for the genetic association studies focused on dystonia, parkinsonism, akathisia and tardive dyskinesia. Moreover, we reviewed the current biological knowledge of the APM induced side effects. Finally, we provide a reasoned list of candidate genes and their genetic variations, with the aim of identifying a list of candidates for APM induced EPS genetic investigations. Results: Variations located within PIK3CA (phosphoinositide-3- kinase, catalytic, alpha polypeptide), PLA2G4A (phospholipase A2, group IVA, cytosolic, calcium-dependent), PRKCA (protein kinase C, alpha), PRKACG (Phosphatidylinositol-4,5-bisphosphate 3-kinase 110 kDa catalytic subunit gamma), ERK-1 (extracellular signalregulated kinase 1 (MAPK3)), ERK-2 (extracellular signal-regulated kinase 2 (MAPK1)), GNAS (guanine nucleotide binding protein (G protein), alpha stimulating activity polypeptide 1), PLCB1 (phospholipase C, beta 1 (phosphoinositide-specific)) and ITPR1 (inositol 1,4,5-triphosphate receptor type 1) were found to be relevant for APM induced EPS. Some of the genes are classical candidates for this kind of research, others were never investigated. For each of these genes we provide a list of variations that balances the limitations of multitesting with the advantages of the tagging approach. Conclusions: We undertook a review of the literature about the APM induced EPM to provide some rational genetic candidates to be tested in further genetic investigations.

Antipsychotics in the Treatment of Impulsivity in Personality Disorders and Impulse Control Disorders

In the last years, second generation antipsychotics have shown to be useful in the treatment of disorders with predominant impulse dyscontrol symptoms, in particular borderline personality disorder (BPD) and impulse control disorders (ICDs).

The present review aims to provide a comprehensive examination of data from randomized controlled trials (RCTs), open label studies, and case reports concerning efficacy and safety of atypical antipsychotics in treating symptoms of impulsivity in BPD and ICDs.

Empirical evidences in favor of these pharmacological agents are generally promising, but still initial and heterogeneous among different drugs. Data concerning clozapine are limited in BPD as well as in ICDs, as they usually derive from samples with concomitant psychotic symptoms or disorders. Concerning risperidone and its metabolite paliperidone, only few studies considered the effects on impulsive-aggressive behaviors in BPD patients. Some RCTs found that risperidone was effective against disruptive behaviors in adolescents, suggesting it could be tried in treating ICDs, such as intermittent explosive disorder. Quetiapine was found efficacious to control impulsivity in several open label studies of BPD and in one case report of trichotillomania (TTM). Ziprasidone has been poorly investigated in the treatment of impulsivebehavioral dyscontrol and the only RCT performed in BPD patients produced no significant effects on borderline psychopathology.

At present, more solid and encouraging evidences of efficacy in treating impulsive disturbances of BPD have been provided from several RCTs of olanzapine and from fewer controlled studies of aripiprazole. Olanzapine was also found effective in a single RCT of TTM patient, while it has obtained controversial results in other ICDs. Aripiprazole also produced some benefit in the treatment of TTM, but findings are limited to case-reports.

Further large-scale well-designed investigations are required to replicate and complete these data

Pharmacological Management of Psychosis in Parkinson Disease: A Review

Psychosis in Parkinson Disease (PDP) is a common clinical problem and presents a pharmacological therapeutic conundrum. Many patients with PDP require anti-parkinsonian drugs for motor control, but the use of these medications has been associated with worsening of the psychotic symptoms. Differences from other psychotic disorders include the association with the use of anti-parkinsonian drugs, and the common presentation with visual hallucinations. Understanding of the pathophysiology of this phenomenon in PD has grown over the last few decades with the realization that the dopaminergic system is not the sole player. This has led to pharmacological research beyond antipsychotics. In this article we review the general management of PDP, the available evidence for the pharmacological management of PDP, and the medications profile and safety. Useful tables, practical recommendations and treatment algorithm are proposed.

Non-Analgesic Effects of Opioids: Opioid-induced Nausea and Vomiting: Mechanisms and Strategies for their Limitation

Nausea and vomiting are common gastrointestinal symptoms following opioid administration, for either chronic or acute pain management. As a consequence, patients’ dissatisfaction has a negative impact on treatment efficacy. A number of mechanisms have been identified, involving both central and peripheral sites. This article will review the pathophysiology of opioid-induced nausea and vomiting and the various pharmacological treatments currently available for its management. Preventive strategies and therapeutic approaches are evaluated in the perioperative setting and in chronic pain. Newer drugs include second generation serotonin receptor antagonists (palonosetron) and neurokinin-1 (NK-1) antagonists (aprepitant).

Substance Abuse and Movement Disorders: Complex Interactions and Comorbidities

The relationship between movement disorders and substance abuse, which we previously reviewed, is updated. We examine these relationships bidirectionally with focus on drugs of abuse that are known to cause movement disorders, as well as primary movement disorders that are associated with use and abuse of alcohol and dopaminergic medications. First, we review the movement disorders that may develop from the acute use or withdrawal of frequent drugs of abuse, including alcohol, cocaine, heroin, amphetamine and methcathinone. We then comment on the interaction between alcoholism and alcohol-responsive movement disorders, such as essential tremor and myoclonus-dystonia. Lastly, we discuss the potential for abuse of antiparkinsonian dopaminergic agents in patients with Parkinson’s disease (PD).

The Risk That DSM-5 Will Promote Even More Inappropriate Antipsychotic Exposure In Children and Teenagers

DSM-5 is considering adding a diagnostic category for young people who may be at higher risk of developing schizophrenia. Changing what otherwise would be risk factors for a future disease onset into a disease into its own right would open up floodgates for inappropriate and potentially harmful exposure to antipsychotic medication. The “at risk” population would not benefit from receiving a formal diagnosis because the proposed criteria stipulate that the individual already has to be help-seeking and desire psychiatric treatment, so already by definition these individuals are receiving psychiatric services. The implication that presence of risk factors implies future disease is not supported in epidemiologic studies in that there is insufficient specificity or sensitivity. Including the proposed risk category into DSM-5 therefore violates the basic medical principle of “first do no harm.”

Transcriptomics of Antipsychotic Drug Function: What have we Learned from Rodent Studies?

Antipsychotic medications remain the first-line treatment for several psychiatric disorders. These compounds, classified as typical or atypical antipsychotics, have well-established neurotransmitter receptor binding profiles; however, long-term therapeutic benefits likely result from molecular changes in the brain occurring downstream from receptor blockade. In the past decade, researchers have utilized high-throughput gene expression approaches to study post-receptor mechanisms of antipsychotic drug function and have implicated several systems, including synaptic- and ubiquitinationrelated pathways, in the mechanisms of actions of antipsychotic drugs. In recent years, additional transcriptome data from updated and improved microarray platforms have been published. The most widely studied antipsychotics have been haloperidol, olanzapine and clozapine, representing both typical and atypical drugs, and several studies have highlighted both the similarities and differences in the transcriptome profiles associated with both classes of drugs. Furthermore, some studies have additionally investigated the effects of antipsychotic drugs in combination with psychostimulant exposure to rodents, in order to identify convergent gene expression alterations. This review will summarize recent transcriptomewide studies that have investigated differential gene expression in response to antipsychotic drug treatment in rodent brain, highlighting the most reproducible findings across studies. Emerging evidence has also suggested that epigenetic mechanisms of gene regulation are associated with antipsychotic drug action; this will also be reviewed herein. Examination of transcriptomic profiles of antipsychotic drug action should reveal key information regarding the beneficial mechanisms associated with drug treatment and may reveal gene ‘signatures’ for known drugs, which could be used to develop improved therapeutics.

Neurological Soft Signs in Patients with Psychosis and Cannabis Abuse: A Systematic Review and Meta-Analysis of Paradox

Background: Although neurological soft signs (NSSs) have been consistently associated with schizophrenia and a variety of risk factors, few studies have focused on the association between NSSs and environmental factors such as cannabis use, particularly in patients with first episode psychosis (FEP). Aims: To review studies that have specifically investigated the association between NSSs and cannabis use in subjects who suffer from psychosis, and more specifically in FEP. Methods: A review of studies investigating the associations between neurological function in psychotic patients and cannabis use. Results: A total of 5 studies met our inclusion criteria. Two of these included data only from patients with FEP. Four studies concluded that patients with psychosis and particularly FEP who consumed cannabis showed fewer NSSs. Conclusions: Four possible explanations are suggested for the paradoxical relationship between cannabis use and NSSs in FEP. First, heavy cannabis users present with different acute responses to cannabis use than do occasional cannabis users. Second, the psychoses developed by patients who consume cannabis follow different physio-pathological pathways that include fewer neurodevelopmental abnormalities. Third, the direct effect of cannabis on the Central Nervous System (CNS) may be responsible for the paradox. Finally,severe NSSsare associated with other clinical characteristics that would limit a subject's personal access to cannabis.

Antidepressants: Update on Benefits and Risks

Since the initial discovery of the first antidepressants in the 1950s, at least two generations of these medications have come to market. Following a brief historical introduction, this paper reviews the first- and second-generation (FGA and SGA) antidepressant medications and their class-related and individual side effect profiles. Class-related adverse reactions include dietary interactions of monoamine oxidase inhibitors (MAOIs) with tyramine, cardiovascular toxicities of the FGAs, and the behavioral syndrome and sexual dysfunction produced by selective serotonergic reuptake inhibitors (SSRIs). Adverse effects common to the different classes include discontinuation syndromes, possible cognitive impairment, suicidality, and a variety of cardiovascular, gastrointestinal and motoric disturbances. Recent reports of side effects elicited by specific agents are noted. Current concerns raised by antidepressant use in pregnancy are discussed. Recent criticisms of the effectiveness claims of antidepressants are summarized. These include the significant placebo contribution to antidepressant outcomes and the ongoing debate about the long-term usefulness of psychotropic medications in general. Most relevant to antidepressants is the recently proposed phenomenon of “tardive dysphoria” that may occur after prolonged antidepressant use and promote resistance to further treatment.

Pharmacotherapy in Pedatric PTSD: A Developmentally-Focused Review of the Evidence

After the experience of a traumatic event, children and adolescents are especially vulnerable to developing debilitating symptoms of Posttraumatic Stress Disorder (PTSD). Criteria for diagnosing this disorder in the pediatric population have proven insufficiently sensitive for children, especially those who are very young. Age-related PTSD symptom expression suggests PTSD assessment and treatment requires developmental consideration. Preschool age children, school age children, adolescents, and adults also possess potentially distinct differences from one another in pharmacokinetics, psychosocial influences, and neurobiology. Pharmacotherapy is often indicated for use in the treatment of pediatric PTSD. Extrapolation of evidence in adult literature for safety, tolerability, and efficacy is nonlinear and should not substitute for dedicated drug trials in pediatric PTSD. This paper reviews all identified randomized controlled trials (RCTs), uncontrolled and open label trials, and case reports/series regarding pharmacotherapy in this population. Emphasis is placed on methodologic rigor and developmental consideration. These trials are discussed in sufficient detail to inform readers of their relative strengths and weaknesses, and of the generalizability of the studies’ conclusions. This review summarizes reports by drug class and developmental cohorts (preschool age, school age, and adolescents). The review will help clinicians a) decide when medications are needed, b) understand current evidence-based alternatives and c) utilize a developmental approach in the selection of medication.

Impulsive and Compulsive Behaviors During Dopamine Replacement Treatment in Parkinson’s Disease and Other Disorders

Impulsive and compulsive behaviors, including pathologic gambling, hypersexuality, compulsive shopping, compulsive eating, excessive engagement in hobbies, punding, and Dopamine Dysregulation Syndrome (DDS), are increasingly reported serious side-effects of dopaminergic medication, used in the treatment of Parkinson's Disease (PD) and other disorders. Dopamine Agonists (DA) are strongly related with Impulse Control Disorders (ICDs), while L-dopa is associated with DDS. The present paper focuses on ICDs. The estimated prevalence of ICDs in PD patients treated with DA is as high as 14%. ICDs pathophysiology is complex, due to multiple contributing factors. Dopamine neurotransmission along the meso-cortico-limbic pathway is a modulator of risk behavior and can be altered in PD and in the course of dopaminergic treatment. Psychiatric complications, associated with treatment of PD are still underdiagnosed, although their consequences can be serious, even catastrophic. Physicians treating PD with DA should warn the patients and their relatives of the risk of inducing ICDs. Psychiatrists should be trained to recognize these side effects, that can mimic primary psychiatric conditions. The management of ICDs includes discontinuation of DA or switching from DA to other drugs for the treatment of PD. Cognitive behavior therapy, serotonin selective reuptake inhibitors, nalmefene, zonisamide, low dose of anti-dopaminergic drugs, as quetiapine or clozapine, can be effective. Psychological, spiritual, and ethical support (familial or individual) can help.

Aripiprazole in Children and Adolescents with Schizophrenia

Background: Aripiprazole is an atypical antipsychotic that was approved, relatively recently, for use in adolescents with schizophrenia. Objective: The aim was to discuss efficacy and tolerability issues of aripiprazole in adolescents suffering from schizophrenia. Method: A Medline search identified only three studies and one post hoc analysis for one of them, concerning the use of aripiprazole in adolescents with schizophrenia. Finally, one of the studies was excluded because of the small number of cases treated with aripiprazole. Results: Based on the clinical evidence, including data from two short-terms clinical trials and one post-hoc analysis of one of the abovementioned studies, aripiprazole seemed generally safe and well tolerated in children and adolescents. Aripiprazole at doses of 10 to 30 mg/day was more efficacious in ameliorating the symptoms (including hostility) of schizophrenia than was placebo. It was associated with low number and mild-to-moderate intensity of adverse events, and with no clinically relevant findings in ECGs, vital signs, and clinical laboratory tests. The most common adverse events were extrapyramidal disorder, somnolence, and tremor. Also aripiprazole is unlikely to be associated with hyperprolactinemia and clinically significant weight gain. Conclusion: Scant information exists to evaluate the use of aripiprazole in early-onset schizophrenia, due to the lack of published studies. The initial encouraging results provide further support and point out the necessity for systematic research on the efficacy and tolerability of aripiprazole in pediatric patients suffering from schizophrenia.

Therapeutic Strategies for Huntingtons Disease: From the Bench to the Clinic

Huntingtons disease (HD) is a neurodegenerative disorder caused by a CAG expansion in the HD gene that codifies the protein huntingtin. The disease is characterized by neurodegeneration of certain areas of the brain, particularly the striatum and the cortex. The first symptoms usually appear in mid-life and include cognitive deficits and motor disturbances that progress over time. The disease is invariable fatal and there is currently no cure for individuals affected with this disorder. HD transgenic mouse models have served as useful tools not only to elucidate the mechanisms underlying neurodegeneration in the HD brain, but also to test a number of therapeutic strategies for this disease. As a consequence of the promising results obtained in some of these preclinical studies, various pharmaceutical compounds have now been used in clinical trials. However, in most cases, the benefits observed in the clinical setting have been somewhat limited and, as such, the search for effective treatments still continues. In this review we present an overview of the various therapeutic strategies for HD that have received attention during the past decades, including the use of essential fatty acids, creatine, co-enzyme Q10, remacemide, riluzole, memantine, cystamine, minocycline, and tetrabenazine. We compare their efficacy in mitigating the neuropathology and symptoms of HD transgenic mouse models with the results that have been obtained with these compounds in clinical trials. Finally, we outline some recommendations that should be considered when designing future preclinical and clinical trials for the screening of potential therapeutic strategies for HD.

Long-Acting Antipsychotic Medications

Antipsychotic medicines are the cornerstone pharmacotherapy for patients with psychotic disorders. Early and continuous management of psychoses improves the quality of life, decreases hospitalization and reduces medical costs. However, many psychotic patients are not fully compliant with treatment, and thus they more often experience a relapsing course with a suboptimal clinical outcome. Long-term parenteral antipsychotic agents may improve compliance by offering clear evidence of medication non-compliance and documented drug administration monitoring. Using injection therapy might be especially beneficial to poorly compliant individuals with their first-psychotic episode and those with severe psychopathology or comorbid substance abuse. The availability of five different antipsychotic drug depot medications offers diverse treatment options which can be individualized for each case.

The Therapeutic Potential of Sigma (σ) Receptors for the Treatment of Central Nervous System Diseases: Evaluation of the Evidence

Since their proposal in 1976, sigma (σ) receptors have been increasingly implicated in the pathophysiology of virtually all major central nervous system (CNS) disorders, including anxiety, depression, schizophrenia, and drug addiction. Due to their involvement in motor function and higher cognitive function,σ receptors have also been implicated in movement disorders (such as Parkinson's disease) and memory deficits (including Alzheimer's disease). In most cases the precise mechanism(s) linking σ receptors to CNS disease are unknown or yet to be fully elucidated. However, many σ ligands have shown promise in pharmacological studies and animal models of the aforementioned diseases, and some have entered clinical trials. This review will assess the validity of σ receptors as a target for various CNS diseases based on evidence from animal models of human diseases, preclinical studies in humans, and full clinical trials.

Pharmacological Prevention and Treatment in Clinical At-Risk States for Psychosis

Over the last couple of decades, the treatment of psychoses has much advanced; yet, despite all progress, the individual and societal burden associated with psychosis and particularly schizophrenia has largely remained unchanged. Therefore, much hope is currently placed on indicated prevention as a mean to fight these burdens before they set in. Though the number of studies investigating pharmacological interventions is still limited, encouraging results have been reported from the pioneering trials, despite several methodological limitations. Furthermore, it has become clear that persons characterized by the at-risk criteria are already ill and do not only need preventive intervention, but also treatment. In consequence, outcome criteria have to be broadened to cover the current needs of the patients. As is indicated by a recent study successfully using Omega-3 fatty acids for both purposes, it may be promising to develop and investigate interventions especially for the at-risk state, independent of their effectiveness in manifest disease states. Treatment studies may become promoted by the proposed introduction of a new disorder category into DSM-V. Future prevention studies, however, need to solve the challenge of changing immediate transition rates, demanding for new risk enrichment strategies as a prerequisite for feasible trial designs.

Polyunsaturated Fatty Acids in Emerging Psychosis

The role of polyunsaturated fatty acids and their metabolites for the cause and treatment of psychotic disorders are widely discussed. The efficacy as an augmenting agent in chronic schizophrenia seems to be small or not present, however epidemiological data, as well as some recent controlled studies in emerging psychosis point towards possible preventive effects of long-chain polyunsaturated fatty acids in early and very early stages of psychotic disorders and some potential secondary or tertiary beneficial long-term effects in later, more chronic stages, in particular for metabolic or extra-pyramidal side effects. In this comprehensive review, we describe the physiology and metabolism of polyunsaturated fatty acids, phospholipases, epidemiological evidence and the effect of these fatty acids on the brain and neurodevelopment. Furthermore, we examine the available evidence in indicated prevention in emerging psychosis, monotherapy, add-on therapy and tolerability. The neuroprotective potential of n-3 LC-PUFAs for indicated prevention, i.e. delaying transition to psychosis in high-risk populations needs to be further explored.

Clinical Pharmacology of Paliperidone Palmitate A Parenteral Long-Acting Formulation for the Treatment of Schizophrenia

Paliperidone Palmitate is a long-acting intramuscular atypical antipsychotic drug indicated for the acute maintenance treatment of schizophrenia in adults. Its mechanism of action, like all other atypical agents, is attributed to the antagonism of brain dopamine D2 and serotonin 5-HT2A receptors. The pharmacodynamics, pharmacokinetics, and metabolism of paliperidone palmitate are reviewed. Current studies for clinical efficacy of paliperidone palmitate for both acute and maintenance treatment and adherence in adults with schizophrenia are discussed. Studies for safety and tolerability are also reviewed.

Second-Generation Antipsychotic Agents: A Review of Safety Profiles

Early clinical trials had suggested a better safety profile for the second-generation antipsychotics (SGAs; e.g. risperidone, olanzapine, quetiapine, aripiprazole) compared to the older first-generation agents (FGAs; e.g. haloperidol and phenothiazines); however, new long-term studies have determined that important adverse events are associated with the use of the SGAs and that their safety profiles differ significantly. This article reviews the most recent publications (September 2007 to September 2011) of long-term studies of antipsychotic pharmacotherapy with a focus on adverse events and tolerability of second-generation antipsychotic medications. A total of 55 studies were included. Most commonly reported adverse events were weight gain, dyslipidemias, glycemic abnormalities, hyperprolactinemia, movement disorders and cardiovascular events.

It would appear that overweight patients and those with dyslipidemia or risk factors for cardiovascular disease are candidates for agents such as aripiprazole or ziprasidone, which have neutral lipid and weight gain profiles. Patients who are not comfortable with the potential risk of developing hyperprolactinemia should not be prescribed risperidone as first line therapy. Those who have arrhythmias should not be treated with clozapine or ziprasidone. More challenging it is to make a straight recommendation for a first-line treatment in patients at risk of movement disorders. Severe SGA-induced adverse events including death have been reported in elderly patients affected by dementia. Adolescents appear to be more susceptible to SGAs adverse events. Potential risks and benefits should always be considered for each individual patient prior to therapy initiation in order to minimize discontinuation rates and treatment failure.

Selected Abstracts from 2011 ISAPP Congress in Berlin Adolescence-A Second Chance?

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Psychopharmacological Interventions for Adolescents with Eating Disorders

The purpose of this article is to review evidence-based pharmacological treatments for eating disorders with a special focus on the adolescent population. Eating disorders commonly present in adolescence, yet little published data are available to guide the adolescent psychiatrist. The use of medications in the context of evidence-based psychotherapeutic interventions and co-morbid psychiatric conditions will be discussed. Defined will be the unique role of the adolescent psychiatrist in orchestrating treatment by a multidisciplinary team, determining the appropriate level of care, monitoring safety, and evaluating treatment response. Risks and benefits of the use of pharmacological interventions in individuals who are malnourished or engaging in eating disordered behaviors, such as purging or laxative abuse, will be delineated along with proposed monitoring. Each potentially affected organ system will be addressed. Sequentially described is the existing evidence for use of medications for anorexia nervosa, bulimia nervosa, and binge eating disorder in adults and, where available, adolescents. Atypical antipsychotics, particularly olanzapine, have shown promise for adults with anorexia nervosa. However, in a recent trial of adolescents, no benefit for olanzapine over placebo was found. Several antidepressants have been shown to be effective treatments for bulimia nervosa, and fluoxetine has the FDA approval for treatment of this disorder in adults. Although fluoxetine has been deemed safe and effective in an open trial of adolescent patients, controlled studies in this population are lacking. Special considerations for the use of these medications in adolescents are discussed.

Age-related Changes in Pharmacodynamics: Focus on Drugs Acting on Central Nervous and Cardiovascular Systems

Aging is characterized by progressive impairment of functional capacities of all system organs, reduction in homeostatic mechanisms, and altered response to receptor stimulation. These age-related physiologic changes influence both pharmacokinetics and pharmacodynamics of drugs in elderly patients. Pharmacokinetic and pharmacodynamics changes as well as polypharmacy and comorbidities may alter significantly the effect of pharmacological treatment with advancing age. With the same drug concentration at the site of action, significant differences in the response to several drugs have been observed in older patients as compared to younger patients. Elderly patients are particularly suceptibles to the effects of frequently prescribed drugs acting on central nervous system, such as benzodiazepines, antidepressants, antipsychotics and lithium, with high potential for adverse drug reactions. Moreover, in older patients increased sensitivity to warfarin resulting in increased risk of bleeding has been previously documented. On the other hand, reduced effectiveness of conventional doses of cardiovascular drugs, such as diuretics and β-blockers, has been observed. Due to pharmacodynamic changes, therefore, dose adjustment of the above mentioned cardiovascular and psychotropic drugs is recommended in elderly. Clinicians should be aware of the age-related physiologic changes affecting several organ systems and their implications on the effect of drugs that are commonly prescribed to elderly patients.

Propranolol Safety Profile in Children

Data regarding the use of propranolol in pediatrics are limited despite its widespread use in adults. Since 1984, Propranolol has been used for the prevention of portal hypertensive hemorrhage in pediatric patients. Recently it has been also used for the managemnet of hemangiomas in addition to other indications. The purpose of this review is to evaluate safety and efficacy of propranolol use in the pediatric population, highlighting the most important reported side effects, warnings and precautions.

Management of Postoperative Nausea and Vomiting in Women Undergoing Major Gynecological Surgery: A Review and Update

Postoperative nausea and vomiting (PONV) are distressing and frequent adverse events associated with anesthesia and surgery, with a high incidence after major gynecological surgery (e.g., abdominal hysterectomy). Numerous antiemetics have been studied for the prevention and treatment of PONV after this surgical procedure.

Most of the published trials indicate the improved prevention of PONV by avoiding risk factors and/or by using antiemetic therapy in women undergoing major gynecological surgery. Pharmacological approaches include phenothiazines (e.g., perphenazine), butyrophenones (e.g., droperidol), benzamides (e.g., metoclopramide), antihistamines (e.g., cyclizine), proppofol, dexamethasone, ephedrine, serotonin receptor antagonists (e.g., ondansetron, granisetron) and neurokinin-1 receptor antagonists (e.g., aprepitant). None of the currently available antiemetics is entirely effective, perhaps because most of them act through the blockade of one type of receptor. There is a possibility that combined antiemetics with different sites of activity would be more effective than one drug alone preventing PONV. Combination antiemetic regimens (e.g., ondansetron plus droperidol) are highly effective in the prevention of PONV. As non-pharmacological therapy, acupressure and acupuncture at the P6 (Nei-Kuwan) point are effective for preventing PONV. For the treatment of established PONV, granisetron is more effective than droperidol or metoclopramide.

In the management of PONV after major gynecological surgery, the benefits and risks of these clinical strategies should be considered.

Oxidative Stress in Schizophrenia

Increasing evidence indicates that oxidative damage exists in schizophrenia. Available literature about possible mechanisms of oxidative stress induction was reviewed. Furthermore, possibilities of measuring biomarkers of schizophrenia outside the central nervous system compartment, their specificity for different types of schizophrenia and potential therapeutic strategies to prevent oxidative injuries in schizophrenia were discussed. Data were extracted from published literature found in Medline, Embase, Biosis, Cochrane and Web of Science, together with hand search of references. Search terms were: schizophrenia, oxidative stress, antipsychotics, antioxidants and fatty acids. Finding a sensitive, specific and non invasive biomarker of schizophrenia, which could be measured in peripheral tissue, still stays an important task. Antioxidant enzymes, markers of lipid peroxidation, oxidatively modified proteins and DNA are most commonly used. As it considers the supplemental therapy, according to our meta-analysis vitamin E could potentially improve tardive dyskinesia, while for the effect of therapy with polyunsaturated fatty acids there is no clear evidence. Oxidative stress is a part of the pathology in schizophrenia and appears as a promising field to develop new therapeutic strategies. There is a need for well designed, placebo controlled trials with supplementation therapy in schizophrenia.

Ethical and Policy Considerations in the Application of Pharmacogenomic Testing for Tardive Dyskinesia: Case Study of the Dopamine D3 Receptor

Tardive dyskinesia (TD) is a serious adverse effect often associated with the first generation antipsychotic medications used in the management of mental health disorders such as schizophrenia. Pharmacogenomics is the study of human genomic variation in relation to individual and population variability in medication response and side effects. Neuropsychiatry is one of the clinical domains in which pharmacogenomic approaches have been extensively studied. In the late 1990s, the Glycine9 (Gly9) allele of the Serine-9-Glycine (Ser9Gly) polymorphism in dopamine D3 receptor gene (DRD3) was found to be associated with both a liability to, and worsened severity of, TD in schizophrenic patients treated with typical antipsychotics. This initial discovery has been subsequently replicated and testing for the Ser9Gly polymorphism has now become commercially available. The question that currently presents itself is whether its use should be encouraged for patients who may be prescribed a typical or atypical antipsychotic medication. However, the translation of this new technology to clinical practice presents multiple social, ethical and policy challenges. Though pharmacogenomic testing holds much promise in this scenario, many important questions remain to be answered before its widespread use can be medically and ethically justified. This article highlights the key advances in our understanding of the role of human genetic variation in the D3 receptor in relation to TD. Then, issues of uncertainty, consent, confidentiality, and access are considered with respect to the use of DRD3 polymorphism testing in risk stratification for susceptibility to tardive dyskinesia. We propose three recommendations that may help bring this technology into the clinic: 1) prospective pharmacogenomic studies of DRD3 polymorphism and TD risk should be conducted; 2) the design of such studies should be influenced by scientists, ethicists and policy makers to protect potentially vulnerable patients; and 3) appropriate knowledge transfer to front-line health care workers must take place.

Metoclopramide as an Analgesic in Severe Migraine Attacks: An Open, Single-blind, Parallel Control Study

Metoclopramide is a well-known anti-emetic drug with central and peripheral pharmacological effects. Some authors have reported metoclopramide as an adjunct therapy to other analgesics in patients with migraine attacks. Treatment of migraine headache using a mix of metoclopramide and an NSAID has been patented (European Patent EP1014961) as well as a short series showing great efficacy and tolerability of metoclopramide in patients wtih migraine attacks. We decided to conduct an open, single-blind, parallel control study in the emergency department to evaluate the efficacy and tolerability of metoclopramide in patients with severe migraine attacks.

93 consecutive patients with severe migraine attacks were randomized into two groups (groups A and B). Patients in group A received 10mg of intravenous metoclopramide and patients in group B received 1 g of intravenous paracetamol. Patients were evaluated 5minutes before (baseline), 15, 30, 60 and 120 minutes after drug delivery, and before being discharged from the emergency department They were then contacted by phone 48 hours after being discharged from the hospital (phone questionnaire).

Patients treated with either metoclopramide or paracetamol showed a significant reduction in the intensity of pain at the 120 minute time point, with an 86% and 82% improvement respectively. However, patients treated with metoclopramide showed a more rapid improvement at the 15 and 30 minute evaluations.

Patients with severe migraine attacks treated with metoclopramide as monotherapy showed a significant improvement in terms of pain relief and a faster improvement in pain intensity compared to those treated with paracetamol. Metoclopramide and other dopamine antagonistic drugs should be considered a therapeutic option in severe migraine headache attacks

The Psychoactive Effects of Antidepressants and their Association with Suicidality

Although antidepressants are known to produce some adverse mental effects, their full range of psychoactive effects has not been systematically described. It has been suggested that some antidepressants are associated with increased suicidal thoughts and actions, but the issue remains controversial, and the mechanism of association, if any, is unclear. In the current study we examined descriptions of the major psychoactive and physical effects experienced by users of two commonly used antidepressants, fluoxetine and venlafaxine, as reported on a patient-oriented web site. We categorised responses into common psychoactive effects and explored associations among those effects, including reported increases in suicidal ideation. In the 468 descriptions we examined, the most commonly reported drug-induced psychoactive effects were sedation, impaired cognition, reduced libido, emotional blunting, activation (feelings of arousal, insomnia and agitation) and emotional instability. There were no differences between the two drugs in the prevalence of reporting of these effects. Activation effects were associated with involuntary movements, suggesting a physical basis. Emotional blunting was associated with cognitive impairment, reduced libido and sedation. Emotional instability, which included the reported side effects of increased anxiety, anger, aggression and mood swings, was related to activation effects and was more commonly reported by younger respondents. Increased suicidal thoughts were rare but were associated with both types of emotional effect. The effects identified are consistent with other data, and suggest that some antidepressants may induce emotional effects that are experienced as unpleasant, may impact on the symptoms of mental disorders, and may account for the suggested occurrence of increased suicidal impulses in some users.