Dystonic Disorders

Sustained Reduction of Dystonic Tremor and Pain after Cannabis Oil Administration and Physiotherapy in Thalamic Ischemia: A One-Year Case Report

Introduction: Post-stroke tremor and post-stroke thalamic pain (PS-TP) are common and often refractory conditions that significantly impact patients’ quality of life. Conventional pharmacotherapy frequently provides inadequate relief, while cannabis has shown potential for managing movement disorders and pain; however, evidence supporting its efficacy remains limited. On the other hand, physiotherapy is well-documented as an effective therapeutic intervention.

Case Presentation: This case report aimed to evaluate the combined effects of cannabis oil and physiotherapy on dystonic-tremor and PS-TP in a female subject with a history of thalamic ischemia. The patient was monitored over a 1-year follow-up period with assessments focused on pain intensity, tremor severity, and overall functional improvements. After twelve months of treatment, the patient demonstrated a 60% reduction in pain and a 56.88% reduction in tremor severity, accompanied by enhanced motor function. Furthermore, quality of life improved significantly, with a 27.6% increase in the mental component and a 45.46% increase in the motor component. No serious adverse effects were reported during the treatment period.

Conclusion: This case report highlights the potential benefits of combining cannabis oil with physiotherapy for managing post-stroke dystonic tremor and PS-TP. The sustained efficacy of this treatment combination over a prolonged period could constitute a therapeutic novelty and an important advancement in the management of these conditions. These findings suggest the need for further research with larger cohorts and studies of higher methodological rigor to establish the efficacy and safety of this therapeutic approach.

Respiratory Disorders in Rett Syndrome

Rett Syndrome (RTT) is a rare and severe neurodevelopmental disorder affecting children in the early stages of infancy and associated with a MECP2 mutation in 95-97% of individuals with typical RTT. Nearly all of the patients show breathing abnormalities during their lifespan, both in wake and sleep and respiratory illness represents an important cause of morbidity and mortality in RTT. Pathogenic mechanisms underlying breath-holding and other breathing abnormalities in RTT are mainly related to dysautonomia and an alteration in respiratory control at different levels, including several regions of the central and peripheral nervous system. Pathogenic variants in the MECP2 gene have been implicated in the dysfunction of respiratory pathways, affecting chemosensitivity and the response to neurotransmitters. In addition, frequent comorbidities such as scoliosis, dysphagia, sleep disorders, and epilepsy can further impair the respiratory function in these patients.

Efficacy and Safety Analysis of Botox Application and Iatrogenic Botulism: Panacea or Peril?

Clostridium botulinum toxin-A (BoNT-A) creates temporary paralysis in the muscles by acting on the muscle-nerve junction. It is injected into the mimic muscles when a decrease in the movements of the mimic muscles is desired. Despite many favorable applications, the use of BoNT-A is not without drawbacks. Although there is no expected serious side effect on health in BoNT-A treatments, various problems can be encountered in patients treated for aesthetic purposes. Botulism is a rare but potentially life-threatening syndrome, which is caused by the toxin produced by the bacterium Clostridium botulinum, which acts on the nervous system, vegetative forms of C. botulinum can only survive in anaerobic conditions, while spore forms are common in nature and can withstand harsh conditions. Botulism can stem from bacterial spores which release toxin in the body; in the form of enteric botulism, and wound botulism. The cases that develop ‘iatrogenic botulism’ after such procedures are usually those receiving high-dose toxin for therapeutic purposes. The treatment of botulism mainly consists of anti-toxin therapy and, if necessary, intensive care to prevent organ failures, including respiratory support. This article aims to cover all these issues related to botulism and other adverse outcomes related to BoNT-A injection in light of the most recent literature.

A Review of Current and Prospective Treatments for Channelopathies, with a Focus on Gene and Protein Therapy

Reduced cell surface expression or the malfunctioning of ion channels gives rise to a group of disorders known as channelopathies. To treat the underlying cause, the delivery and/or expression of a functional ion channel into the cell membrane of the cell of interest is required. Unfortunately, for most channelopathies, current treatment options are only symptomatic and treatments that rectify the underlying damage are still lacking. Within this context, approaches that rely on gene and protein therapy are required. Gene therapy would allow the expression of a functional protein, provided that the cellular machinery in the diseased cell could correctly fold and traffic the protein to the cell membrane. Whereas protein therapy would allow the direct delivery of a functional protein, provided that the purification process does not affect protein function and a suitable delivery vehicle for targeted delivery is used. In this review, we provide an overview of channelopathies and available symptomatic treatments. The current state of gene therapy approaches mainly using viral vectors is discussed, which is followed by the role of nanomedicine in protein therapy and how nanomedicine could be exploited for the delivery of functional ion channels to diseased cells.

Atypical Manifestations of Severe Acute Respiratory Syndrome Coronavirus 2 Infection in Children: A Systematic Review

Background: In December 2019, a local outbreak of pneumonia was presented in Wuhan (China) and quickly identified to be caused by a novel coronavirus, Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). The disease caused by SARS-CoV-2 was named COVID-19 and was soon declared a pandemic because of the millions of infections and thousands of deaths worldwide. Children infected with SARS-CoV-2 usually develop the asymptomatic or mild type of disease compared to adults. They are also more likely to have atypical and non-specific clinical manifestations than adults.

Methods: A literature search was performed through PubMed and Scopus to summarize the extrapulmonary manifestations of SARS-CoV-2 infection in children since the beginning of the pandemic. Peer-reviewed papers in English were retrieved using the following keywords and combinations: ‘pediatric,’ ‘child,’ ‘infant,’ ‘neonate,’ ‘novel coronavirus,’ ‘SARS-CoV-2,’ ‘COVID 19’ and ‘gastrointestinal,’ ‘renal,’ ‘cardiac,’ ‘dermatologic’ or ‘ophthalmologic’. We included published case series and case reports providing clinical symptoms and signs in SARS-CoV2 pediatric patients.

Results: Although fever and symptoms of upper respiratory infection are the most frequently presented, a variety of other atypical presentations has also been reported. The clinical spectrum includes dermatological, ophthalmological, neurological, cardiovascular, renal, reproductive, and gastrointestinal presentations. In addition, a rare multi-inflammatory syndrome associated with SARS-- CoV-2 infection has been reported in children, often leading to shock and requiring inotropic support and mechanical ventilation.

Conclusion: Clinicians need to be aware of the wider range of extrapulmonary atypical manifestations of SARS-CoV-2 infection in children, so that appropriate testing, treatment, and public health measures can be implemented rapidly.

Effect of Botulinum Toxin on Equinus Foot Deformity in Cerebral Palsy Patients: A Systematic Review and Network Meta-analysis

Background: Cerebral palsy (CP) is a brain disorder that affects the development, movement and posture leading to limitation of Range of Movement (ROM) in the growing children. CP leads to deformities such as equinus foot deformity. We aim to investigate the efficacy of different botulinum toxin (BTX) products with or without serial casting in reducing the muscle spasticity in equinus foot deformity in patients with CP.

Methods: A systematic review of the literature was performed by searching different electronic databases. Pub- Med, Scopus, Web of Science (WOS), and GHL databases were used. We analyzed the extracted data by network meta-analysis method using the R software package (version 3.5.0).

Results: Regarding Modified Ashworth score (MAS), BTX-A was superior compared to placebo and BTX-A plus immediate casting (MD = −0.39, 95% CI [−0.60; −0.18]) and (MD = −0.50, 95% CI [−0.98; −0.02]), respectively. Concerning growth motor function movement Classification System (GMFM), Neuronox ranked above at 3 months (MD = −1.60, 95% CI [−2.87; −0.33]) and at six months (MD = −1.90, 95% CI [−3.48; −0.32]) compared to BTX-A. Regarding the Modified Tardieu scale (MTS) with knee flexion, BTX-A was superior to BTX-A plus immediate casting (MD = 8.60, 95% CI [1.76; 15.44]). Concerning passive range of movement (PROM) with Knee flexion or extension at 3 months, BTX-A showed a significant improvement compared to BTX-A plus immediate casting.

Conclusion: BTX-A ranked best on a physician rating scale (PRS), MAS, MTS with knee flexion and PROM (Knee flexion and extension) compared to Neuronox and Botulax. BTX-A alone was also better than BTX-A plus immediate casting.

Risk Analysis of Lurasidone in Patients with Schizophrenia and Bipolar Depression

Lurasidone was approved by the United States Food and Drug Administration (FDA) for the treatment of schizophrenia, as well as for the treatment of bipolar depression. However, emerging reports have indicated various adverse drug reactions with the use of lurasidone. Thus, in this article, we have analyzed the risk profile of lurasidone in the established therapeutic indication. A total of 419 studies were published from October 2010-July 2019 regarding lurasidone. After the inclusion and exclusion criteria, 17 studies were selected for the analysis of risk. The adverse drug reactions (ADRs) of these studies were categorized as per the innovator summary of product characteristics (SmPC). Finally, the unlisted ADRs were analyzed by using the Naranjo probability algorithm. Telogen effluvium, thrombocytopenia, restless leg syndrome and hypersexuality were found with the use of lurasidone and fall under the unlisted category. The causality assessment has shown a probable correlation of lurasidone with hypersexuality, restless leg syndrome, thrombocytopenia and possible relation with telogen effluvium. In conclusion, lurasidone is a novel and efficacious pharmacological treatment for bipolar depression and schizophrenia. However, more data regarding the safety of this drug in a large population is needed.

Aripiprazole: An FDA Approved Bioactive Compound to Treat Schizophrenia- A Mini Review

Objective: Aripiprazole, a synthetic compound, obtained by chemical modification of the structure of quinolinone is considered as an atypical antipsychotic drug. The present review is an attempt to summarize the updated information related to reported chemistry and pharmacology of Aripiprazole.

Development: Aripiprazole, under development by Otsuka Pharmaceutical, was approved by the U.S. Food and Drug Administration (USFDA) by the end of 2002 with an aim to treat patients with schizophrenia. This drug got approved by European Commission in February 2013 to treat the patients having severe manic episodes in bipolar I disorder Additionally, it got approval in Japan in January 2006 and in Canada in 2014.

Pharmacology: Aripiprazole shows high specificity for dopamine receptor especially D2 and D3, serotonin 5-HT1A and serotonin 5-HT2A receptors, reasonable specificity for dopamine D4, serotonin 5- HT2C and 5-HT7, alpha1-adrenergic and histamine H1 receptors. It also shows moderate specificity for the serotonin reuptake. The major side effects include headache, agitation, akithesia, anxiety, tachycardia, insomnia, postural hypotension, constipation, vomiting, dizziness, nervousness and somnolence.

Conclusion: The present article embarks the available information on Aripiprazole with emphasis on its clinical pharmacology, mechanism of action, pharmacokinetics, pharmacodynamics, metabolism and clinical trials.

A Developmental Psychopathology Perspective of Obsessive-Compulsive Disorder

Objective: This integrative review explores Obsessive-Compulsive Disorder (OCD) from the perspective of developmental psychopathology, in terms of its multifaceted etiology and course.

Background: Individuals affected by OCD experience intrusive and undesired thoughts accompanied by behaviors used to mitigate the unwanted images. Accordingly, there are several sub-types and personality dispositions reflective of the overall continuum of OCD, spanning normality and psychopathology. The etiology is complex, with generalized psychological and biological vulnerabilities, as well as contributors from life stress. Moreover, OCD is a disorder with a highly comorbid and overlapping presence; therefore, difficulties may arise when differentiating between OCD and other problems.

Conclusion: Treatment non-responsiveness is a pervasive trend in persons afflicted with OCD, but the most effective approach likely involves a stepped-care model incorporating cognitive-behavioral psychotherapy and psychotropic medications. Other considerations will also be discussed.

Different Generations of Type-B Monoamine Oxidase Inhibitors in Parkinson’s Disease: From Bench to Bedside

Three inhibitors of type-B monoamine oxidase (MAOB), selegiline, rasagiline, and safinamide, are used for the treatment of Parkinson’s disease (PD). All three drugs improve motor signs of PD, and are effective in reducing motor fluctuations in patients undergoing long-term L-DOPA treatment. The effect of MAOB inhibitors on non-motor symptoms is not uniform and may not be class-related. Selegiline and rasagiline are irreversible inhibitors forming a covalent bond within the active site of MAOB. In contrast, safinamide is a reversible MAOB inhibitor, and also inhibits voltage- sensitive sodium channels and glutamate release. Safinamide is the prototype of a new generation of multi-active MAOB inhibitors, which includes the antiepileptic drug, zonisamide. Inhibition of MAOB-mediated dopamine metabolism largely accounts for the antiparkinsonian effect of the three drugs. Dopamine metabolism by MAOB generates reactive oxygen species, which contribute to nigro-striatal degeneration. Among all antiparkinsonian agents, MAOB inhibitors are those with the greatest neuroprotective potential because of inhibition of dopamine metabolism, induction of neurotrophic factors, and, in the case of safinamide, inhibition of glutamate release. The recent development of new experimental animal models that more closely mimic the progressive neurodegeneration associated with PD will allow to test the hypothesis that MAOB inhibitors may slow the progression of PD.

Suicide Risk in Obsessive-Compulsive Disorder and Exploration of Risk Factors: A Systematic Review

Background: Historically, OCD has been considered to be associated with a relatively low risk of suicide. Recent studies, on the contrary, revealed a significant association between OCD and suicide attempts and ideation. A huge variation in prevalence rates, however, is reported.

Objective: To estimate prevalence rates of suicide attempts and suicidal ideation in individuals with OCD, and to identify predictors of suicide risk among subjects with OCD.

Methods: We systematically reviewed the literature on suicide risk (ideation and/or attempts) and OCD. We included studies with appropriate definition of OCD, cross-sectional or prospective design, separating clinical samples from epidemiological studies, that employed a quantitative measure of suicidality and/or reported an outcome measure of the association between suicidality and OCD or examined factors associated with suicidality.

Results: In clinical samples, the mean rate of lifetime suicide attempts is 14.2% (31 studies: range 6- 51.7%). Suicidal ideation is referred by 26.3-73.5% of individuals (17 studies, mean 44.1%); current suicidal ideation rate ranges between 6.4 and 75% (13 studies, mean 25.9). Epidemiological studies found that OCD increases significantly the odds of having a lifetime suicidal ideation as compared to the general population (OR: 1.9-10.3) and a history of lifetime suicide attempts (OR: 1.6- 9.9). Predictors of greater suicide risk are severity of OCD, the symptom dimension of unacceptable thoughts, comorbid Axis I disorders, severity of comorbid depressive and anxiety symptoms, past history of suicidality and some emotion-cognitive factors such as alexithymia and hopelessness.

Conclusion: Overall, suicidality appears a relevant phenomenon in OCD.

Brain Stimulation in Obsessive-Compulsive Disorder (OCD): A Systematic Review

Background: Obsessive-compulsive disorder (OCD) is a highly prevalent, severe, and chronic disease. There is a need for alternative strategies for treatment-resistant OCD.

Objective: This review aims to assess the effect of brain stimulation techniques in OCD.

Methods: We included papers published in peer-reviewed journals dealing with brain stimulation techniques in OCD. We conducted treatment-specific searches for OCD (Technique AND ((randomized OR randomised) AND control* AND trial) AND (magnetic AND stimulation OR (rTMS OR dTMS)) AND (obsess* OR compuls* OR OCD)) on six databases, i.e., PubMed, Cochrane, Scopus, CINAHL, PsycINFO, and Web of Science to identify randomised controlled trials and ClinicalTrials.gov for possible additional results.

Results: Different add-on stimulation techniques could be effective for severely ill OCD patients unresponsive to drugs and/or behavioural therapy. Most evidence regarded deep brain stimulation (DBS) and transcranial magnetic stimulation (TMS), while there is less evidence regarding transcranial direct current stimulation (tDCS), electroconvulsive therapy, and vagus nerve stimulation (for these last two there are no sham-controlled studies). Low-frequency TMS may be more effective over the supplementary motor area or the orbitofrontal cortex. DBS showed best results when targeting the crossroad between the nucleus accumbens and the ventral capsule or the subthalamic nucleus. Cathodal tDCS may be better than anodal in treating OCD. Limitations. We had to include methodologically inconsistent underpowered studies.

Conclusion: Different brain stimulation techniques are promising as an add-on treatment of refractory OCD, although studies frequently reported inconsistent results. TMS, DBS, and tDCS could possibly find some use with adequate testing, but their standard methodology still needs to be established.

Safety and Efficacy of Levetiracetam for the Management of Levodopa- Induced Dyskinesia in Patients with Parkinson’s Disease: A Systematic Review

Background: Levetiracetam, a novel antiepileptic drug, has shown antidyskinetic effects in experimental animal models of Parkinson's disease (PD). The tolerability and efficacy of levetiracetam in reducing the levodopa-induced dyskinesia (LID) in PD patients have not been established. Therefore, this study aims to synthesize evidence from published prospective clinical trials about the efficacy of levetiracetam for the management of LID in PD patients.

Methods: We followed the PRISMA statement guidelines during the preparation of this systematic review. A computer literature search of PubMed, EBSCO, Scopus, MEDLINE, and the web of science was carried out. We selected prospective clinical trials assessing the anti-dyskinetic efficacy of levetiracetam for treating LID in patients with PD. The Abnormal Involuntary Movement Scale (AIMS), Clinical Global Impression Score (GCI), UPDRS III, and UPDRS IV were considered as the primary outcome measures; their data were extracted and reviewed.

Results: Our review included seven clinical trials with a total of 150 patients. Of them, three studies were randomized controlled trials, and the remaining were open-label single arm trials. Four studies reported poor tolerability of the levetiracetam with mild anti-dyskinetic effects. Levetiracetam slightly improved the UPDRS-IV and AIMS scores with small effect size. In the remaining three studies, levetiracetam failed to exhibit any anti-dyskinetic effects.

Conclusion: Current evidence does not support the efficacy of the levetiracetam for treating LID in PD patients, however, due to the limited number of published randomized control trials (RCTs), further RCTs are required.

Obsessive-Compulsive Disorder with Suicide Obsessions Triggered by News Reports about the “Blue Whale Game”

Background: Obsessive-compulsive Disorder (OCD) is a relatively common psychiatric disorder among children and adolescents. Apart from the commonly reported obsessions, childhood OCD can present with unusual or unfamiliar obsessions, making the diagnosis difficult. Suicidal ideas and attempts are high in OCD patients. Very rarely OCD patients also present with suicidal obsessions which need to be differentiated from a genuine suicidal desire for proper management.

Methods: We report an uncommon suicidal obsessional fear triggered by “Blue Whale Game” related news in the media in a 14-year-old boy who had been previously well functioning. This patient experienced significant distress and dysfunction due to these repetitive thoughts. After an intervention with medication, his symptoms diminished and he returned to pre-morbid functioning.

Discussion: Environmental stressors are considered to play an important role in the development of OCD. Environment interacts with genetic predisposition, which moderates the vulnerability to a stressful experience, in precipitating OCD. This case is unusual in that suicidal obsessions were triggered by an external event, highlighting the interaction between external events and the onset of the obsessive-compulsive disorder.

A Brief History of Davanloo’s Intensive Short-Term Dynamic Psychotherapy

Background: Short-term dynamic psychotherapy is a well-established treatment modality. Habib Davanloo, MD was a pioneer in bringing it to the forefront of psychotherapy.

Objective: The aim of this paper is to highlight Habib Davanloo’s unique contribution to the field of dynamic psychiatry and psychotherapy by tracing the development of his metapsychological theory of the unconscious, placing it in historical perspective.

Method: The origin and development of dynamic psychiatry, from the early work of Mesmer through classical psychoanalysis and contemporary theories will be reviewed. Next, the movement aimed at shortening the course of psychotherapy while maintaining a psychodynamic perspective will be explored. Davanloo’s unique contributions to the field will be elaborated. The development of Davanloo’s metapsychology of the unconscious from his earliest work beginning in the 1960’s and further developed in his technique of “Unlocking the Unconscious” in the 1980’s will be examined. I will then turn to Davanloo’s work in the 1990’s and early 2000’s, which focused on widening the range of patients who could be successfully treated with his technique, and on expanding his training programs. Davanloo’s most recent work in the 2000’s and 2010’s involving Audiovisual Closed Circuit Training Workshops on the Mobilization of the Unconscious, Total Removal of Resistance and Multidimensional Unconscious Structural Change will be reviewed.

Conclusion: Davanloo was indeed a pioneer in short-term psychotherapy. He remains at the cutting edge, continuing to shorten the course, increasing the depth and the range of this powerful treatment modality, and developing innovative teaching methods.

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.

Neurological Disorders in Medical Use of Cannabis: An Update

Background & Objective: Medical cannabis is increasingly used as a treatment or adjunct treatment with different levels of efficacy in several neurological disorders or related symptoms (such as multiple sclerosis, autism, Parkinson and Alzheimer disease, Tourette’s syndrome, Huntington’s disease, neuropathic pain, epilepsy, headache), as well as in other medical conditions (e.g. nausea and vomiting, glaucoma, appetite stimulation, cancer, inflammatory conditions, asthma). Nevertheless, a number of neurological adverse effects from use of medical cannabis on the short- and on the longterm have been reported, in addition to other adverse health events.

Conclusion: It has been noticed that the use of medical cannabis can lead to a paradoxical effects depending on the amount of delta-9-tetrahydrocannabinol (THC) -like cannabinoids the preparation contain. Accordingly, some neurological disorders or symptoms (e.g. multiple sclerosis, seizures, epilepsy, headache) may be caused or exacerbated by the same treatment supposed to cure them. The current review presents an update of the neurological adverse effects resulting from the use of cannabis for medical purposes, highlighting the need to weigh the benefits and risks, when using cannabinoidbased treatments.

Neurological Aspects of Medical Use of Cannabidiol

Background: Cannabidiol (CBD) is among the major secondary metabolites of Cannabis devoid of the delta-9-tetra-hydrocannabinol psychoactive effects. It is a resorcinol-based compound with a broad spectrum of potential therapeutic properties, including neuroprotective effects in numerous pathological conditions. CBD neuroprotection is due to its antioxidant and antiinflammatory activities and the modulation of a large number of brain biological targets (receptors, channels) involved in the development and maintenance of neurodegenerative diseases.

Objective: The aim of the present review was to describe the state of art about the pre-clinical research, the potential use and, when existing, the clinical evidence related to CBD in the neurological field.

Method: Collection of all the pre-clinical and clinical findings carried out investigating the effects of CBD alone, not in combination with other substances, in the neurological arena with the exclusion of studies on neuropsychiatric disorders.

Results: Laboratory and clinical studies on the potential role of CBD in Parkinson’s disease (PD), Alzheimer’s disease (AD), multiple sclerosis (MS), Huntington’s disease (HD), amyotrophic lateral sclerosis ALS), cerebral ischemia, were examined.

Conclusion: Pre-clinical evidence largely shows that CBD can produce beneficial effects in AD, PD and MS patients, but its employment for these disorders needs further confirmation from well designed clinical studies. CBD pre-clinical demonstration of antiepileptic activity is supported by recent clinical studies in human epileptic subjects resistant to standard antiepileptic drugs showing its potential use in children and young adults affected by refractory epilepsy. Evidence for use of CBD in PD is still not supported by sufficient data whereas only a few studies including a small number of patients are available.

Cefixime-induced Oromandibular Dystonia in an Adult: A Case Report

Introduction: Cefixime, a third-generation cephalosporin, is commonly used in different infections. Tolerance is pretty good even if some side effects can be frequent like digestive disorders. Other effects, not mentioned in the Summary of Product Characteristics, can occur.

Methods: We report a case of recurrent, acute oromandibular dystonia in a cefixime-treated adult.

Case-report: After the third dose of cefixime, prescribed for a bronchial infection, a patient experienced a first episode of oromandibular dystonia. Then, after each ingestion, the same effects appeared. After the discontinuation of cefixime, there was no recurrence. The diagnosis of acute oromandibular dystonia has been confirmed by a neurologist.

Discussion: Some cases of dystonia have been published with other β-lactams antibiotics and with cefixime but they concerned children. Different mechanisms are proposed to explain the occurrence of dystonia during a treatment with cefixime. They involved certain neurotransmitters like dopamine, acetylcholine or GABA.

Conclusion: Even if dystonia is not a side effect mentioned in the SPC, the drug’s potential causal role must always be considered in case of involuntary contraction of muscles in a patient treated with cefixime or any other β-lactam antibiotics.

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 Male Abnormal Gene Family 21 (Mab21) Members Regulate Eye Development

The male abnormal gene family contains 3 members, named mab21l1, mab21l2 and mab21l3. Since their first discovery in C. elegans, homologues of mab21l1 and mab21l2 have been found in Drosophila, Zebrafish, Xenopus, chicken, mouse and human. A number of studies have revealed that mab21 gene family members, mab21l1 and mab21l2, play important roles in regulating eye development. Here, we review the functions of the mab genes in regulating ocular development.

"Take and Run" and "Take and Hold" Therapeutical Electromagnetic Field Application Modalities in Physiotherapy: Some Clinically Significant Pathways of Action

This paper proposes and for the first time examines in parallel the most likely mechanisms of clinical effects unlocked by two modality applications: the therapeutic (acute) “take and run” and the occupational (chronic) “take and hold” of therapeutic EMFs. Electromagnetic fields (EMFs) for therapeutic use have a long pre-clinical and clinical history. The practical experience worldwide has increased the trust of the medical community due to the EMF potential for speeding up the recovery and reparative processes and for influencing the pathological ones – edema, pain, inflammation. We consider these favourable effects of the triggered stimulation of the production of endothelial NO - a consequence of the biochemical activation of the calcium-calmodulin system as well as the vasodilatative vasomotor changes by low-intensity EMFs of any range as the main clinically significant, universal therapeutic mechanism of action in the stimulation of the reparative processes.

These beneficial health effects on patients look different when assessed as an occupational factor from the perspective of the health of the physiotherapy professionals. Our recent, complex, ambispective study, which as far as we know is the first in this field, has provided evidence about their specific morbidity profile in its somatic and behavioral complexity, where seems to be endocrinal and cell damaging/ irritating processes are involved. The results indicate that the hypothesized endocrinal mechanisms concern the changes in the estrogen and melatonin levels (assessed indirectly). The immuno-endocrine EMF-induced autoreplication and disruption of adipose tissue cells are suspected to amplify the adverse effects of the occupational low-intensity mixed EMFs and were found to be in a causal relation. Our hypothesis of the main mechanism of the occupational (chronical) EMF adverse effects is based on the presumption of selective EMF targeting of the hydrated/hyper hydrated tissues (which is an indispensable physiological parameter of every vital tissue) with probable related maintenance of permanent high levels of reactive oxygen species (ROS). This requires thorough examination due to the great biological/ clinical significance of such a dependence given some common recommendations existing in Bulgarian physiotherapy facilities for an increased water intake during working hours.

Polypharmacological Drugs in the Treatment of Epilepsy: The Comprehensive Review of Marketed and New Emerging Molecules

Epilepsy is a complex neurological disorder which has plagued the human population through the ages and continues to affect about 50 million people worldwide. A better understanding of the pathogenesis of epilepsy unmasks various molecular targets for the treatment of epilepsy. The currently used antiepileptic drugs (AEDs) predominately target voltage-gated ion channels (Na⁺, Ca²⁺ and K⁺), GABAA receptor, glutamate receptor, synaptic vesicle 2A (SV2A) protein and carbonic anhydrase (CA). One group of AEDs acts on a single target while another group acts via multiple targets to control seizure episodes. AEDs which act via multiple mechanisms or polypharmacological mechanisms of action have appeared as broad spectrum anticonvulsant agent and therefore, they provide a better choice to clinicians to manage drug-resistant epilepsies and various other epileptic syndromes. For example, polypharmacological AEDs such as PB, VPA, OXC, FBM etc. are vital for managing epilepsy successfully, since decades. In literature there is no review available which exclusively highlights the polypharmacological mechanisms of action of existing AEDs as well as new emerging molecules. This review covers running marketed AEDs, clinical trial drugs as well as potent preclinical molecules which displayed anti-epileptic activity via multiple mechanisms of action and this appraisal will surely provide a base for discovering potent multi-targeted AEDs.

Combined Treatment Fkt-Botulinum Toxin Type A (Btx-A) in Patients with Strumpell-Lorrain Disease

The Hereditary Spastic Paraparesis (HSP) or Strumpell-Lorrain disease is a heterogeneous neurodegenerative disease of the spinal cord. It is genetically transmitted and characterized by a progressive muscle weakness, spasticity of the lower limbs and awkward gain. There is no specific pharmacological treatment. The pharmacological therapy decreases the muscle tone and prevents stiffening). Physiotherapy restrains the progression of muscle atrophy, delays contraction of the tendons and gives greater mobility to people affected by the disease. The aim of this study is to demonstrate the efficacy of the combined treatment Fkt and Btx-A in patients with HSP.

Retrospective study was conducted recruiting ten patients with spasticity according to Asworth modified scale of at least 2 and with gait deficit. They received treatment for 5 years with incobotulinumtoxinA and physiokinesiotherapy for addressing spasticity in the lower limbs. We evaluated muscle tone with miometric measurement both at the first visit (T0), and at subsequent ones (T1 after 30 days, T2 after 3 months from the first infiltration, T3 after 4 months up to the date of the following infiltration, T4 after 5 months). Baropodometric examination has proven essential for the study of the distribution of loads in statics and dynamics.

The data analysis regarding tone assessment through measurements with Myoton highlighted hypertonus reduction in all the three muscle groups examined at T1 and the maintenance of constant values up to 5 months after the first infiltration. It also showed an increase in the percentage of back foot loading in both feet up to T4 (new inoculation, p<0, 05%). Baropodometric examination in dynamics (in particular the speed of the step) showed a gradual increase in this parameter which reaches a peak at 5 months (p<0, 05%) and then declines again in conjunction with the next infiltration treatment.

This study showed the benefit of combined treatment with Btx and Fkt. The use of a local muscle relaxant drug with a physical targeted exercise guarantees better mobility of the treated segments, reducing tendon retractions as much as possible, and guarantees an adequate postural alignment. Baropodometric examination highlights a more advantageous distribution load, quite essential for avoiding tendinitis due to overload.

Our data observation in the 5 years study shows how the curve relative to the speed of step and the graphics related to the variations of muscle tone remain almost constant with detectable improvement.

Lower K_V7.5 Potassium Channel Subunit Expression in an Animal Model of Paroxysmal Dystonia

Dystonia is a hyperkinetic disabling movement disorder. In the dt^sz hamster, a model of paroxysmal dystonia, pronounced antidystonic effects of the K_V7.2-5 potassium channel opener retigabine and aggravation of dystonia by a selective K_V7.2-5 blocker indicated a pathophysiological role of an abnormal expression of K_V7 channels. We therefore investigated the expression of K_V7 subunits in brains of dystonic hamsters. While K_V7.2 and K_V7.3 subunits were unaltered, lower K_V7.5 mRNA levels became evident in motor areas and in limbic structures of dystonic hamsters. The K_V7.2/3 subunit-preferring channel opener N-(6-chloropyridin-3-yl)-3,4- difluorobenzamide (ICA 27243; 10-30 mg/kg i.p.) failed to reduce the severity of dystonia in mutant hamsters, suggesting that the previously observed antidystonic action of retigabine is mediated by the activation of K_V7.5 channels. The experiments indicate a functional relevance for KV7.5 channels in paroxysmal dystonia. We suggest that compounds highly selective for subtypes of K_V7 channels, i.e. for K_V7.5, may provide new therapeutic approaches.

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

Editorial Review (Thematic Issue: An Update on Central Sensitivity Syndromes and the Issues of Nosology and Psychobiology)

Central sensitization (CS), simply defined as an amplified response of the central nervous system to peripheral input, is a concept of great importance in clinical medicine. It has helped to explain aspects of the pathophysiology of common diseases, e.g. fibromyalgia syndrome (FMS), irritable bowel syndrome, vulvodynia, headaches, chronic pelvic pain and other overlapping conditions (collectively called central sensitivity syndromes, or CSS). It also applies to pain of complex regional pain syndrome, osteoarthritis (OA), rheumatoid arthritis (RA) and post-operative pain. The pathology-pain gap in CSS is readily explained by CS. Many FMS and other CSS patients have peripheral pathology, e.g. nociceptive areas in the muscles, arthritis, small fiber neuropathy and inflammation. Pro-inflammatory cytokines are elevated in some patients. Identification of CS in patients with structural pathology, e.g. OA and RA, has helped to explain why not all patients benefit from nonsteroidal anti-inflammatory drugs or joint replacement surgery, and require therapy directed at CS. Glial cells are important in pain processing. Remarkable advances have been achieved in neuroimaging, including visualization of grey matter and white matter, not only during provoked pain but also pain at rest. Based on CS mechanisms, targeted individual therapy may now be possible. Appropriate nosology is important particularly for effective patient care. Dichotomy of neurochemical-structural (“functional”) and structural (“organic”) pathology should be abandoned; many patients have both. Psychobiology is also biology. Patient-blaming terms like somatization, somatizer and catastrophizing should be avoided. For therapy, both pharmacological and non- pharmacological approaches are important, including recognition of subgroups and person/patient-centered care.

A Review on GABA/Glutamate Pathway for Therapeutic Intervention of ASD and ADHD

Balance between excitatory glutamate and inhibitory GABA neurotransmitter is essential and critical for proper development and functioning of brain. GABAergic (gamma aminobutyric acid) and glutamatergic interneurons maintain excitability, integrity and synaptic plasticity. Several evidences implicated relative loss of inhibitory GABA with corresponding glutamate mediated hyperexcitation in the development of autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD). ASD is the common neurological disorder with an estimated relative occurrence of 0.5-1% of universal population. Several studies have demonstrated the imbalance of excitatory/inhibitory neurotransmitters resulting from neurodevelopmental impairments in glutamatergic and GABAergic system, which might resemble common pathological mechanism for developmental disorders. This review focuses on the necessity for developing GABA enhancing and glutamate suppressing drug candidates, and illustrates the role of GABAergic and glutamatergic system in cognition and memory impairment involved in neurodevelopmental disorders, with emphasis on ASD and ADHD. The review also highlights the emerging drugs for neurodevelopmental disorders.

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.

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.

The Paths to Neurodegeneration in Genetic Parkinson's Disease

Parkinson’s disease (PD) is a neurodegenerative disorder, which results from the loss of specific population of neurons, namely the pigmented dopamine secreting neurons of the substnatia nigra pars compatica (SNPc) of midbrain. The exact cause leading to nigrostriatal cell death is not yet known. In recent years, accumulating evidence from the identified molecular events in familial forms of PD contributed much to unraveling the mechanisms by which dopaminergic neurons die in PD and which hopefully would lead to the development of therapeutic interventions. Several major disease causing pathways were identified so far. These are possibly interconnected and some genes share a common pathway e.g., (i) defects in ubiquitin-proteasome pathway and protein misfolding and aggregation caused by α-synuclein and Parkin gene defects; (ii) defects in mitochondrial morphology and function in PINK1/Parkin and DJ-1 mutations; (iii) increased susceptibility to cellular oxidative stress which appear to underlie defects in α-synuclein, Parkin and DJ-1 genes. The aim of this review is to shed light on the molecular mechanisms by which mutations in familial-linked genes cause PD.

Potential Benefits and Limits of Psychopharmacological Therapies in Pervasive Developmental Disorders

The core symptoms of Autistic Spectrum Disorder (ASD) are impairment in reciprocal social interaction, communication, narrow interests, and stereotyped behaviour. These are frequently severe and persistent, although their severity may change over the course of life. Furthermore, the frequently associated symptoms of self-injury, aggressive behaviour, impulsivity, poor attention, anxiety, depression, and sleep disruption, can become a major source of additional distress and interference in functioning.

The causes of autism are not yet known, but there is a general consensus that ASDs are highly heritable. Comprehension of the neurobiological basis for autism-spectrum disorders is still in its initial stages: a large body of research, however, has established ASD signs and symptoms are of neurological origin, and suggest that autism is a distributed neural system disorder, which disproportionately impairs many higher order abilities. Currently available medical treatments, primarily address co-morbid symptoms, rather than core symptoms. Thus, in spite of recent advances in psychopharmacology, the treatment approach still has important limits and shows poor efficacy on global outcomes.

A potential pathway for improving clinical outcomes is that of the personalised treatment for autism, by using therapeutic drug monitoring (TDM) - a valuable tool for drugs with narrow therapeutic index - as well as systematic genetic background assessment, foreseen in future applications. However, it is already possible to implement an active surveillance programme to address safety concerns and to optimise therapeutic drug interventions in ASD.

The Use and Misuse of Exposure Therapy for Obsessive-Compulsive and Related Disorders

In this article we define and describe the use of exposure-based therapy for OCD. This approach involves confrontation with feared stimulus with the aim of facilitating fear extinction. Exposure, however, is not applicable for a number of psychological conditions now listed as related to OCD in the DSM-5. We explain when it is appropriate to use exposure and when it is not, and raise cautions for clinicians to consider when working with patients with problems putatively related to OCD.

Metabolic Ataxias in Adults

Metabolic ataxias are rare. They usually start in the childhood and often have autosomal recessive inheritance. They may also present in adulthood. The diagnosis is important since some patients may be successfully managed with diet and treatments.

Mitochondrial Diseases in Childhood

Mitochondrial disorders are a group of heterogeneous diseases associated with abnormalities of the oxidative phosphorylation (OXPHOS), the most important source of energy for the cell. The number of mitochondrial syndromes and of identified causative genes is constantly increasing. Taken as a whole they are among the most frequent genetic diseases in humans at any age. The respiratory chain is the only metabolic pathway under double genome control and molecular genetics of these disorders is complicated by the existence of strict interactions between mitochondrial DNA and nuclear DNA. In childhood and infancy, clinical presentation differs from mitochondrial disorders with adult onset. The phenotypes are much more severe, often involving brain, frequently presenting as multisystemic disorders and seldom as isolated myopathy. Mutations in nDNA are more frequent than in adulthood.

The major phenotypes presenting in infancy are here correlated with genetic defects and biochemical data with the aim to facilitate diagnosis work-up.

Mitochondria: Prospective Targets for Neuroprotection in Parkinson's Disease

Parkinson’s disease is the second most common neurodegenerative disorder characterized by persistent loss of dopaminergic neurons in the SN and clinically associated with cognitive, behavioral and motor deficits. There is an enormous amount of data that provides convincing evidence about the prime involvement of mitochondria in the onset and progression of neurodegeneration. Several studies have also emphasized that accumulation of toxic protein and their aggregates in mitochondria lead to energy deficits, excessive ROS generation, mutations in mitochondrial genome and proteins regulating mitochondrial homeostasis, and impaired mitochondrial dynamics in animal models of PD and patients. Here we discuss about the bioenergetic agents, which have been tested for reducing the mitochondrial dysfunction and associated disease pathology in cellular and animal models of PD and PD patients with encouraging outcomes. We also provide a succinct overview of current therapeutic implications of PGC-1α, SIRT, AMPK, and Nrf2-ARE as salutary targets to overcome the deleterious effects posed by mitochondrial dysfunction in the onset and progression of PD.

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.

Cannabinoids (CBD, CBDHQ and THC): Metabolism, Physiological Effects, Electron Transfer, Reactive Oxygen Species and Medical Use

In recent years, cannabinoids, particularly cannabidiol (medical marijuana), have attracted considerable attention. This review addresses various aspects including metabolism. Other cannabinols of interest are THC and the hydroxyl quinone metabolite. Physiological influences are addressed, particularly anticancer action, receptors, antioxidants, and neurological effects. A unifying mechanism is invoked based on electron transfer, reactive oxygen species and oxidative stress.

Disorders of Consciousness and Electrophysiological Treatment Strategies: A Review of the Literature and New Perspectives

The last years have witnessed a significant increase in our understanding of brain functions in survivors of severe brain injuries with disorders of consciousness (DOC). Despite there is currently no effective standardized treatment for DOC patients, in the past decade many potential pharmacological as well as non-pharmacological therapies have been proposed. A promising and increasingly growing field of non-pharmacological therapeutic trials has been supported by the application of electrophysiological techniques. This article reviews the most relevant studies in the literature in order to provide the reader with a clear picture of the current available neurophysiological instruments that could be used to treat DOC patients. We will hereinafter briefly discuss the basic principles of deep brain stimulation (DBS), repetitive transcranial magnetic stimulation (rTMS), spinal cord stimulation (SCS) and peripheral nerve stimulation (MNS) that are the main techniques now used by researchers as a treatment and we will explain the rationale of these therapies. Then, we will outline the more relevant studies regarding their application in DOC patients. Finally, due to the fact that only a moderate amount of individual or clinically-dependent approaches are available, we conclude that more standardized studies are necessary to address the role of electrophysiological treatment strategies in DOC as well as to further elucidate their therapeutic effects and define optimal stimulation parameters. Undoubtedly, at present the multidimensional approach is the most interesting.

Disorders of Consciousness and Pharmaceuticals that Act on Oxygen Based Amino Acid and Monoamine Neurotransmitter Pathways of the Brain

Oxygen based neurotransmitters in the synapses of the brain are proposed to play an important role in the generation of consciousness. They include the amino acids glutamate and GABA which use Krebs cycle precursors for their synthesis, and the monoamines dopamine, noradrenalin, adrenalin and serotonin, which are derived from tyrosine and tryptophan.

During ischemia after an acute brain injury, a GABA surge often initiates brain suppression. It has been proposed that with chronic ischemia, a secondary, possibly epigenetic response occurs when neurotransmitters deplete, a glucose and oxygen saving mechanism termed neurodormancy that may invoke alternative long term low energy metabolic pathways in the brain, encountered in Disorders of Consciousness.

Some medications can reverse Disorders of Consciousness in some patients. Virtually all of them act on neurotransmitter systems that use oxygen as a building block or as an energy source within the brain. Pharmaceuticals that act in the oxygen based amino acid systems of the brain include the GABAergic medications zolpidem and baclofen, while those that act in the monoamine axes include the dopaminergic medications L Dopa, amantadine, bromocriptine, apomorphine and methylphenidate, and the noradrenergic and serotonergic medications desipramine, amitriptyline, protriptyline and fluoxetine. Another group are the cholinesterase inhibitors, responsible for increasing acetylcholine, which is synthesized from the Krebs cycle initiator, acetyl CoA.

It appears that pharmaceuticals that are active in the oxygen based neurotransmitter pathways of the brain are successful to arouse to consciousness patients that suffer from its disorders. Research needs to be supported as foundation to understand the biochemical mechanisms that are involved in consciousness disorders and to explore further the pharmacological treatment possibilities for these devastating neurological conditions.

The Glutamatergic Aspects of Schizophrenia Molecular Pathophysiology: Role of the Postsynaptic Density, and Implications for Treatment

Schizophrenia is one of the most debilitating psychiatric diseases with a lifetime prevalence of approximately 1%. Although the specific molecular underpinnings of schizophrenia are still unknown, evidence has long linked its pathophysiology to postsynaptic abnormalities.

The postsynaptic density (PSD) is among the molecular structures suggested to be potentially involved in schizophrenia. More specifically, the PSD is an electron-dense thickening of glutamatergic synapses, including ionotropic and metabotropic glutamate receptors, cytoskeletal and scaffolding proteins, and adhesion and signaling molecules. Being implicated in the postsynaptic signaling of multiple neurotransmitter systems, mostly dopamine and glutamate, the PSD constitutes an ideal candidate for studying dopamine-glutamate disturbances in schizophrenia. Recent evidence suggests that some PSD proteins, such as PSD-95, Shank, and Homer are implicated in severe behavioral disorders, including schizophrenia. These findings, further corroborated by genetic and animal studies of schizophrenia, offer new insights for the development of pharmacological strategies able to overcome the limitations in terms of efficacy and side effects of current schizophrenia treatment. Indeed, PSD proteins are now being considered as potential molecular targets against this devastating illness.

The current paper reviews the most recent hypotheses on the molecular mechanisms underlying schizophrenia pathophysiology. First, we review glutamatergic dysfunctions in schizophrenia and we provide an update on postsynaptic molecules involvement in schizophrenia pathophysiology by addressing both human and animal studies. Finally, the possibility that PSD proteins may represent potential targets for new molecular interventions in psychosis will be discussed.

Therapeutic Potential of Cannabinoids in Neurodegenerative Disorders: A Selective Review

The endocannabinoid system (ECS) is now recognised as an important modulator of various central nervous system processes. More recently, an increasing body of evidence has accumulated to suggest antioxidant, anti-inflammatory and neuroprotective roles of ECS. In this review we discuss the role and therapeutic potential of ECS in neurodegenerative disorders such as Alzheimer’s disease (AD), Parkinson’s disease, multiple sclerosis, Huntington’s disease, Tourette’s syndrome, brain ischemia and amyotrophic lateral sclerosis (ALS). Elements of the ECS, such as fatty acid amide hydrolase or the cannabinoid receptors are now considered as promising pharmacological targets for some diseases. Although still preliminary, recent reports suggest that modulation of the ECS may constitute a novel approach for the treatment of AD. There are windows of opportunity in conditions caused by acute events such as trauma and ischemia as well in conditions that may involve altered functionality of the target receptors of the ECS, such as in AD. The ECS changes in Parkinson’s disease could be compensatory as well as pathogenic of the illness process and needs further understanding and clinical studies are still in the preliminary stage. There is not enough evidence to support use of cannabinoids in treating Huntington’s disease, tics and obsessive compulsive behaviour in Tourette's syndrome. Evidence on therapeutic use of cannabinoids in multiple sclerosis and ALS is currently limited. A major challenge for future research is the development of novel compounds with more selectivity for various components of the ECS which could target different neurotoxic pathways and be used in combination therapy.

Genetic Variants in Diseases of the Extrapyramidal System

Knowledge on the genetics of movement disorders has advanced significantly in recent years. It is now recognized that disorders of the basal ganglia have genetic basis and it is suggested that molecular genetic data will provide clues to the pathophysiology of normal and abnormal motor control. Progress in molecular genetic studies, leading to the detection of genetic mutations and loci, has contributed to the understanding of mechanisms of neurodegeneration and has helped clarify the pathogenesis of some neurodegenerative diseases. Molecular studies have also found application in the diagnosis of neurodegenerative diseases, increasing the range of genetic counseling and enabling a more accurate diagnosis. It seems that understanding pathogenic processes and the significant role of genetics has led to many experiments that may in the future will result in more effective treatment of such diseases as Parkinson’s or Huntington’s. Currently used molecular diagnostics based on DNA analysis can identify 9 neurodegenerative diseases, including spinal cerebellar ataxia inherited in an autosomal dominant manner, dentate-rubro-pallido-luysian atrophy, Friedreich’s disease, ataxia with oculomotorapraxia, Huntington's disease, dystonia type 1, Wilson’s disease, and some cases of Parkinson's disease.

Dystonia Associated with Lamotrigine Therapy: A Case Report and Review of the Literature

The association of extrapyramidal side effects (EPS) with the use of conventional antipsychotics is well established, however, EPS can occur during treatment with anticonvulsant medications as well. We will present the case of a patient who developed an acute dystonic reaction during treatment with lamotrigine and again during re-challenge with the same agent. We will review common side effects of this medication and the previous reports of lamotrigineassociated dystonias. We will also discuss a possible underlying mechanism.

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.

Boundaries and Overlap between Hypochondriasis and Other Disorders: Differential Diagnosis and Patterns of Co-occurrence

Hypochondriasis has common features with a number of other mental disorders, its boundaries are not always easy to draw and it occurs frequently with several psychiatric conditions. This review examines the relationships between hypochondriasis and other psychopathology in two ways. First, it discusses the differential diagnosis of hypochondriasis by identifying both the similarities and differences between hypochondriasis and organic diseases, psychotic disorders, depression, panic disorder, obsessive-compulsive disorder, generalized anxiety disorder, specific phobia of illness and somatization disorder. The greatest overlap seems to exist between hypochondriasis and panic disorder, but hypochondriasis can still be distinguished from it, as well as from other disorders. The diagnosis of hypochondriasis is not warranted in the presence of psychotic features, but it can be made alongside diagnoses of most other disorders, provided that hypochondriacal features are not better explained by them. In the second part, the article reviews studies of the cooccurrence of hypochondriasis and other disorders. The literature reveals some inconsistencies and discrepant findings, which is largely due to different settings in which studies have been conducted and various other methodological issues. Still, it appears that hypochondriasis is more likely to co-occur with depression, panic disorder and somatization disorder than with other psychiatric conditions, suggesting a closer relationship with them. The implications of these findings for the conceptualization of hypochondriasis, its diagnostic status and classification are briefly considered.

The Boundary between Hypochondriasis, Personality Dysfunction, and Trauma

Hypochondriasis (HC) has presented physicians and researchers with nosological challenges since Freud’s era. Part of the difficulty lays in the significant overlap between the constructs of mental illness and personality disorders that already exists when it comes to understanding almost any psychological phenomena (i.e., state versus trait debate). Indeed, many of the symptoms of HC are similar to those of other mental illnesses such as anxiety, yet HC has also been associated with particular personality traits, cognitive styles, attitudes, and personality disorders. Likewise, there has been debate as to whether HC should be considered secondary to some other disorder or as a primary diagnosis in its own right. Finally, the etiology of HC is not well understood. Empirical literature suggests possible genetic components to HC, in addition to several potential environmental factors. In this article we review key theoretical works and empirical studies on the intersection of personality dysfunction and HC. In addition, we consider the role that trauma may play in the development of HC in certain individuals. Traumatic experiences are already widely linked to somatoform disorders. However, the characteristic features of hypochondriacal presentation (e.g., illness conviction, illness phobia, and failure to respond to reassurance from physicians) may be related to particular types of traumatic experiences which, when they occur in infancy and/or childhood, interfere with secure attachment and identity formation.

Drug Therapy of Neuropathic Pain: Current Developments and Future Perspectives

Understanding mechanism of neuropathic pain is too complex and involves both peripheral and central pathophysiological phenomenon. Accordingly the treatment of neuropathic pain is also very complex and is unsatisfactory. The present review attempts to discuss the currently employed pharmacological agents for the management of neuropathic pain including anti-depressants, anti-convulsants, NMDA receptor antagonists, topical & local anesthetics, and upload analgesics. However, the existing pharmacotherapy has marginal efficacy and significant side effects. The review also gives an insight into various pharmacological agents with potential neuropathic pain attenuating properties in experimental models that include NSAIDs, corticosteroids, ion channel blockers (Ca²⁺, Na⁺, K⁺, and TRP channel); ion exchange modulators (NCE and NHE); ion/molecule transport modulators (NKCC-1 and glycine); receptor modulators (kinin, histamine, 5-HT_1A, dopamine, alpha & beta adrenergic, purinergic, excitatory amino acid, sigma, ORL1, endothelin, melanocortin, ephrin and PAR); enzyme inhibitors (cytosolic kinase, metalloproteinase, protease, vasopeptidase, D-amino acid oxidase, fatty acid amide hydrolase, aldose reductase and sorbitol dehydrogenase); other ligands (AGE, RAGEs, neuropeptides, neurotrophic factor, complement cascade, cytokine, glial cell & gap junction, nitrous oxide, growth factor, cell adhesion molecule and neuronal sprouting molecule). Moreover, some advanced therapeutic approaches such as neuronal cell transplantation, stem cell therapy, anti-sense oligonucleotide and recombinant therapy have also been dicussed.

Editorial (Adolescence—plus ca change, plus c' est la meme chose?)

Encephalopathy: A Vicious Cascade Following Forebrain Ischemia and Hypoxia

Post ischemic/hypoxic encephalopathy is a progressive and widespread damage syndrome in human brain, which includes production of new ischemic foci as well as neurodegeneration associated with accumulation of amyloid protein (Aβ), which emerges within days after the primary ischemic or hypoxic ictus. Patients may suddenly suffer severe dementia and Parkinson’s syndrome after a symptom-free period averaging 2 weeks following resuscitation. Death of neurons in the cortex, limbic system, globus pallidus (GP) and substantia nigra (SN) and damage to white matter are responsible. From experimental studies in animals evidence is obtained to reveal the mechanisms. Injured endothelia and activated platelets lead to secondary injury via thrombosis and vasoconstriction resulting in infarction and new foci of necrosis. Blood-brain barrier (BBB) breakdown allows penetration of blood-borne toxic substances into brain resulting in neuronal degeneration and enhanced inflammatory destruction. These secondary injuries happen within two weeks after moderate global ischemia. As these pathological changes cycle between the vascular and neuronal compartments, the damage expands and worsens. Aβ, β amyloid precursor protein (βAPP) and the inflammation mediator cyclooxygenase-2 (COX2) as well as γ-aminobutyric acid (GABA) system degeneration participate in producing secondary injury. Thus, implementing multi-targeted prophylaxis before or at the brain-at-risk stage is desirable. A combination of protecting endothelia, inhibiting platelet activity and improving cerebral circulation is a fundamental strategy to block this vicious cascade, thereby ameliorating or preventing the encephalopathy.

Fragile X Syndrome: Psychiatric Manifestations, Assessment and Emerging Therapies

Fragile X Syndrome (FXS), the most common inherited cause of intellectual disabilities, is an X-linked dominant disorder caused by the amplification of a CGG repeat in the 5' untranslated region of the fragile X mental retardation gene 1 (FMR1). Prevalence estimates of the disorder are approximately 1/3600. Psychiatric manifestations of the disorder include anxiety, attention deficit hyperactivity disorder, autism, mood instability and aggression. In this article we review the above psychiatric manifestations and challenges to accurate assessment. We also discuss how the neurobiological underpinnings of these symptoms are beginning to be understood and can help guide treatment.

Imaging Studies in Focal Dystonias: A Systems Level Approach to Studying a Systems Level Disorder

Focal dystonias are dystonias that affect one part of the body, and are sometimes task-specific. Brain imaging and transcranial magnetic stimulation techniques have been valuable in defining the pathophysiology of dystonias in general, and are particularly amenable to studying focal dystonias. Over the past few years, several common themes have emerged in the imaging literature, and this review summarizes these findings and suggests some ways in which these distinct themes might all point to one common systems-level mechanism for dystonia. These themes include (1) the role of premotor regions in focal dystonia, (2) the role of the sensory system and sensorimotor integration in focal dystonia, (3) the role of decreased inhibition/increased excitation in focal dystonia, and (4) the role of brain imaging in evaluating and guiding treatment of focal dystonias. The data across these themes, together with the features of dystonia itself, are consistent with a hypothesis that all dystonias reflect excessive output of postural control/stabilization systems in the brain, and that the mechanisms for dystonia reflect amplification of an existing functional system, rather than recruitment of the wrong motor programs. Imaging is currently being used to test treatment effectiveness, and to visually guide treatment of dystonia, such as placement of deep brain stimulation electrodes. In the future, it is hoped that imaging may be used to individualize treatments across behavioral, pharmacologic, and surgical domains, thus optimizing both the speed and effectiveness of treatment for any given individual with focal dystonia.

Invertebrate Models of Dystonia

The neurological movement disorder dystonia is an umbrella term for a heterogeneous group of related conditions where at least 20 monogenic forms have been identified. Despite the substantial advances resulting from the identification of these loci, the function of many DYT gene products remains unclear. Comparative genomics using simple animal models to examine the evolutionarily conserved functional relationships with monogenic dystonias represents a rapid route toward a comprehensive understanding of these movement disorders. Current studies using the invertebrate animal models Caenorhabditis elegans and Drosophila melanogaster are uncovering cellular functions and mechanisms associated with mutant forms of the well-conserved gene products corresponding to DYT1, DYT5a, DYT5b, and DYT12 dystonias. Here we review recent findings from the invertebrate literature pertaining to molecular mechanisms of these gene products, torsinA, GTP cyclohydrolase I, tyrosine hydroxylase, and the alpha subunit of Na+/K ATPase, respectively. In each study, the application of powerful genetic tools developed over decades of intensive work with both of these invertebrate systems has led to mechanistic insights into these human disorders. These models are particularly amenable to large-scale genetic screens for modifiers or additional alleles, which are bolstering our understanding of the molecular functions associated with these gene products. Moreover, the use of invertebrate models for the evaluation of DYT genetic loci and their genetic interaction networks has predictive value and can provide a path forward for therapeutic intervention.

Recent Advances in the Molecular Pathogenesis of Dystonia-Plus Syndromes and Heredodegenerative Dystonias

The majority of studies investigating the molecular pathogenesis and cell biology underlying dystonia have been performed in individuals with primary dystonia. This includes monogenic forms such as DYT1and DYT6 dystonia, and primary focal dystonia which is likely to be multifactorial in origin. In recent years there has been renewed interest in non-primary forms of dystonia including the dystonia-plus syndromes and heredodegenerative disorders. These are caused by a variety of genetic mutations and their study has contributed to our understanding of the neuronal dysfunction that leads to dystonia These findings have reinforced themes identified from study of primary dystonia including abnormal dopaminergic signalling, cellular trafficking and mitochondrial function. In this review we highlight recent advances in the understanding of the dystonia-plus syndromes and heredodegenerative dystonias.

Motor and Sensory Dysfunction in Musician's Dystonia

Musicians’ dystonia is a task-specific and painless loss of motor control in a previously well-executed task. It is increasingly recognized in the medical and musical community. Recent advances in neuroimaging, transcranial magnetic stimulation and novel techniques in electroencephalography have shed light on its underlying pathophysiology. To date, a deranged cortical plasticity leading to abnormal sensorimotor integration, combined with reduced inhibition across several levels of the motor pathway are likely mechanisms.This paper reviews the various phenomenology of musician’s dystonia across keyboard, string, brass, flute and drum players. Treatment is often challenging. Medical therapies like botulinum toxin injection and rehabilitation method with sensorimotor training offer symptomatic relief and return to baseline performance to some musicians.

Defining Dystonic Tremor

A strong association between dystonia and tremor has been known for more than a century. Two forms of tremor in dystonia are currently recognized: 1) dystonic tremor, which is tremor produced by dystonic muscle contraction and 2) tremor associated with dystonia, which is tremor in a body part that is not dystonic, but there is dystonia elsewhere. Both forms of tremor in dystonia frequently resemble essential tremor or another pure tremor syndrome (e.g., isolated head and voice tremors and task-specific writing tremor), and relationships among these tremor disorders have long been debated. Misdiagnosis is common because mild dystonia is frequently overlooked in patients with tremor. It is now clear that essential tremor is a syndrome, not a specific disease, and the use of essential tremor as a specific clinical diagnosis is arguably an impediment to elucidating this and other pure tremor syndromes and their relationship to dystonia. A new classification, primary tremor, is proposed and would be used for any disorder in which tremor is the sole or principal abnormality with no identifiable etiology other than possible genetic inheritance. This classification scheme would facilitate tremor research by moving the focus from the narrow question “Is it essential tremor?” to a broader consideration of what genetic and environmental factors cause primary tremor disorders, and how do they relate to dystonia and other neurological disorders.

Animal Models for Investigating Benign Essential Blepharospasm

The focal dystonia benign essential blepharospasm (BEB) affects as many as 40,000 individuals in the United States. This dystonia is characterized by trigeminal hyperexcitability, photophobia, and most disabling of the symptoms, involuntary spasms of lid closure that can produce functional blindness. Like many focal dystonias, BEB appears to develop from the interaction between a predisposing condition and an environmental trigger. The primary treatment for blepharospasm is to weaken the eyelid-closing orbicularis oculi muscle to reduce lid spasms. There are several animal models of blepharospasm that recreate the spasms of lid closure in order to investigate pharmacological treatments to prevent spasms of lid closure. One animal model attempts to mimic the predisposing condition and environmental trigger that give rise to BEB. This model indicates that abnormal interactions among trigeminal blink circuits, basal ganglia, and the cerebellum are the neural basis for BEB.

Genetics and Pathophysiology of Neurodegeneration with Brain Iron Accumulation (NBIA)

Our understanding of the syndromes of Neurodegeneration with Brain Iron Accumulation (NBIA) continues to grow considerably. In addition to the core syndromes of pantothenate kinase-associated neurodegeneration (PKAN, NBIA1) and PLA2G6-associated neurodegeneration (PLAN, NBIA2), several other genetic causes have been identified (including FA2H, C19orf12, ATP13A2, CP and FTL). In parallel, the clinical and pathological spectrum has broadened and new age-dependent presentations are being described. There is also growing recognition of overlap between the different NBIA disorders and other diseases including spastic paraplegias, leukodystrophies and neuronal ceroid lipofuscinosis which makes a diagnosis solely based on clinical findings challenging. Autopsy examination of genetically-confirmed cases demonstrates Lewy bodies, neurofibrillary tangles, and other hallmarks of apparently distinct neurodegenerative disorders such as Parkinson’s disease (PD) and Alzheimer’s disease. Until we disentangle the various NBIA genes and their related pathways and move towards pathogenesis-targeted therapies, the treatment remains symptomatic.

Our aim here is to provide an overview of historical developments of research into iron metabolism and its relevance in neurodegenerative disorders. We then focus on clinical features and investigational findings in NBIA and summarize therapeutic results reviewing reports of iron chelation therapy and deep brain stimulation. We also discuss genetic and molecular underpinnings of the NBIA syndromes.

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.

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.

The Use of Stem Cells in Regenerative Medicine for Parkinson’s and Huntington’s Diseases

Cell transplantation has been proposed as a means of replacing specific cell populations lost through neurodegenerative processes such as that seen in Parkinson's or Huntington’s diseases. Improvement of the clinical symptoms has been observed in a number of Parkinson and Huntington’s patients transplanted with freshly isolated fetal brain tissue but such restorative approach is greatly hampered by logistic and ethical concerns relative to the use of fetal tissue, in addition to potential side effects that remain to be controlled. In this context, stem cells that are capable of self-renewal and can differentiate into neurons, have received a great deal of interest, as demonstrated by the numerous studies based on the transplantation of neural stem/progenitor cells, embryonic stem cells or mesenchymal stem cells into animal models of Parkinson's or Huntington’s diseases. More recently, the induction of pluripotent stem cells from somatic adult cells has raised a new hope for the treatment of neurodegenerative diseases. In the present article, we review the main experimental approaches to assess the efficiency of cell–based therapy for Parkinson's or Huntington’s diseases, and discuss the recent advances in using stem cells to replace lost dopaminergic mesencephalic or striatal neurons. Characteristics of the different stem cells are extensively examined with a special attention to their ability of producing neurotrophic or immunosuppressive factors, as these may provide a favourable environment for brain tissue repair and long-term survival of transplanted cells in the central nervous system. Thus, stem cell therapy can be a valuable tool in regenerative medicine.

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).

Post-stroke Movement Disorders: Clinical Manifestations and Pharmacological Management

Involuntary abnormal movements have been reported after ischaemic and haemorrhagic stroke. Post stroke movement disorders can appear as acute or delayed sequel. At the moment, for many of these disorders the knowledge of pharmacological treatment is still inadequate. Dopaminergic and GABAergic systems may be mainly involved in poststroke movement disorders. This article provides a review on drugs commonly used in post-stroke movement disorders, given that some post-stroke movement disorders have shown a partial benefit with pharmacological approach.

Therapeutic Potential of Natural Products in Parkinson’s Disease

The central objective in treating patients with Parkinson’s disease (PD) is two-fold (i) to increase the striatal dopamine content and (ii) to prevent further degeneration of the surviving dopaminergic neurons in the substantia nigra region of the ventral midbrain. Most of the current PD drugs contribute to the former and provide symptomatic relief. Although compounds such as Levodopa (L-DOPA) improve the striatal dopamine content, their long-term usage is associated with progressive decrease in drug response, motor fluctuations, dyskinesias and drug-induced toxicity. In addition, these drugs fail to prevent the progression of the degenerative process. This has shifted the focus onto alternative therapeutic approaches involving natural products that could provide independent therapy or offer neuroprotective support to the existing drugs. The current review describes the neuroprotective and therapeutic utility of such natural products including herbal extracts, phytochemicals and bioactive ingredients from other natural sources either in isolation or in combination, with potential application in PD, highlighting the relevant patents.

Advanced Tools of Regenerative Medicine for Neurodegenerative Diseases

The goal of regenerative medicine for neurodegenerative diseases is the design of a patient-specific therapeutic approach. A plethora of patents promoting innovative therapeutic tools will contribute to this ambitious purpose. Pioneering technologies such as gene transfer, stem cells and biomaterials, regulatory molecules such as microRNAs or chaperone proteins and innovative clinical practices, represent the most important therapeutic instruments for generating more effective clinical trials for patients suffering from these disorders. In this review, we report a landscape of the most recent patents related to the development of new tools for regenerative medicine for neurodegenerative diseases.

Evaluation of Specific Immune Responses to BoNT/A and Tetanus Toxoid in Patients Undergoing Treatment for Neurologic Disorders

Botulinum neurotoxins (BoNTs) are used in the treatment of many neurological disorders. The primary structure of BoNTs shows a high degree of homology with the tetanus neurotoxin, the toxoid of which is used as a vaccine. Because of the potential cross-reactivity between these toxins, we investigated the effects of Botulinum neurotoxin A (BoNT/A) and tetanus toxoid on peripheral blood mononuclear cells (PBMC) and the corresponding serum antibody levels, in twenty patients who had been treated with BoNT/A. We observed very low PBMC immunostimulation by BoNT/A at the tested dose (15 units/ml), as demonstrated by the low lymphocyte proliferation, and the absence of detectable antibodies cross-reacting with tetanus. However, exposure of PBMC from tetanus-sensitized patients to both neurotoxins showed that BoNT/A exerted a co stimulatory effect on tetanus-stimulated cells. Interestingly, in flow cytometry analysis, BoNT/A seemed to also alter the ratio of naïve (CD45RA) : memory/effector (CD45RO) T lymphocyte subsets, in favour of CD45RO. These preliminary data give a new insight on the potential immune crossreactivity between the two antigens. In view of the wide use of both neurotoxins, these immunotoxic effects merit a more detailed investigation.

Tyrosine Hydroxylase Gene: Another Piece of the Genetic Puzzle of Parkinson’s Disease

The tyrosine hydroxylase (TH) gene encodes a monoxygenase that catalyzes the rate limiting step in dopamine biosynthesis. A hallmark of Parkinson’s disease (PD) is the loss of dopaminergic neurons in the substantia nigra. Consistent with the essential role of TH in dopamine homeostasis, missense mutations in both alleles of TH have been associated with severe Parkinsonism-related phenotypes including infantile Parkinsonism. It has been speculated for a long time that genetic variants in the TH gene modify adult-onset PD susceptibility but the answer has not been clear. Genetic variants (both sequence variations and structural variations) can be classified into three categories based on their relative frequency in population: common variants (polymorphisms), rare variants and mutations. Each of these factors has a different mode in influencing the genetic risk and often requires different approaches to decipher their contributions to the disease. In the past few years, the revolutionary advances in genomic technology have allowed systematic evaluations of these genetic variants in PD, such as the genome-wide association study (GWAS, to survey common variants), copy number variation analysis (to detect structural variations), and massive parallel next generation sequencing (to detect rare variants and mutations). In this review, we have summarized the latest evidence on TH genetic variants in PD, including our ongoing effort of using whole exome sequencing to search for rare variants in PD patients.

The Perfect Storm: The High Prevalence Low Severity Outcomes of the Preterm Survivors

The landscape of neonatal follow up is starting to shift. While there is continued emphasis on the traditional outcomes studied, including cerebral palsy, vision/hearing impairment, and cognitive impairment, there is a shift in focus to those outcomes which are much more prevalent and collectively can contribute to significant morbidity. The purpose of this review is to explore the outcomes of the preterm survivor, in the context of the principles of neurodevelopment. Approaching these outcomes from a developmental perspective provides insight into the challenges in early identification and management of these highly prevalent outcomes. In addition, we will explore the underlying brain injury associated with the preterm infant, particularly as it relates to the high prevalence low severity outcomes. We will also review the impact of this pattern in terms of clinical presentation and academic performance. Finally, we will look at the limitations within the medical system and community that potentially exacerbate the difficulties of the preterm survivor.

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.

A Review of Family-Based Treatment for Adolescents with Eating Disorders

This review focuses on the use of family-based treatment (FBT) for adolescents with eating disorders, including anorexia nervosa (AN) and bulimia nervosa (BN). AN and BN are serious disorders with significant psychiatric and medical morbidity. Data support the use of family treatments for adolescents with eating disorders. Developed at the Maudsley Hospital, FBT is a theoretically agnostic approach that externalizes the illness from the patient and empowers families to actively work to bring about recovery in their relative with an eating disorder. FBT appears to be an effective treatment for adolescents with AN and support is developing for the treatment of adolescents with BN. Manual development is currently underway for the implementation of FBT for young adults with eating disorders, overweight adolescents, and those with subsyndromal AN. Further research is needed to determine the effectiveness of FBT with other populations. In this review, we will provide a critical overview of the literature by focusing upon empirical findings regarding FBT, with particular emphasis on studies conducted with adolescents.

Pharmacology of Sigma (σ) Receptor Ligands from a Behavioral Perspective

The σ receptors are regarded as unique binding sites, distinct from opiate and PCP receptors and implicated in higher brain function. They were classified into σl and σ2 subtypes, the former was cloned from rodent and human tissues while the latter has not yet been fully characterized. Although the precise mechanism of the functional response of σ receptors is still uncertain, it has been accepted that they can modulate a number of central neurotransmitter systems, including glutamate/NMDA, serotonergic, dopaminergic, noradrenergic routes, as well as some other signaling pathways (e.g. neurotrophin and growth factor signaling) which are seemingly important for the brain function. In accordance with their modulatory role, σ receptor ligands have been proposed to be useful in several therapeutic areas such as schizophrenia, depression and anxiety, amnesic and cognitive deficits, drugs of abuse. The present review summarizes the findings related to the pharmacological effects and potential activity of σ receptor ligands from behavioral models predictive of some neuropsychiatric disorders.

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.

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.

Overview of Pediatric Epilepsy

Accurately diagnosing pediatric patients with specific epilepsy syndromes remains a major challenge today. The diagnosis of epilepsy syndrome is established on the basis of the age of onset, type of epilepsy, progressive nature of the disease, interictal EEG abnormalities, gender predominance, precipitating factors, family history, neuropsychological features and prognosis. A diagnosis of pediatric epilepsy syndrome can be complicated by a number of factors and the established diagnosis affects the treatment options. Further, pediatric epilepsy patients respond differently to various treatments making prognosis difficult. Epilepsy syndromes are further divided into generalized, focal, undetermined and “special” syndromes based on the Committee on Classification and Terminology of the International League Against Epilepsy (1989). In this chapter, we will discuss the major epileptic syndromes seen in childhood and adolescence, their salient clinical features, ictal and interictal EEG characteristics, prognosis and treatment options.

Selection and Evaluation of the Pediatric Epilepsy Surgical Candidates

Pediatric patients who have failed two or more medications are less likely to respond to medical management. Intractable epilepsy leads to neurological deterioration and cognitive deficits. In this modern age of new technology, it is better to evaluate these patients for early resection of the seizure focus. Patients with an identifiable lesion on imaging and a localized seizure focus detected during intensive seizure monitoring have much higher chances of seizure freedom than with medical management alone. It has also been shown that pediatric epilepsy surgery has improved the quality of life of patients and reduced burden on the caregivers. The selection of candidates for surgery includes a battery of tests. Inpatient video EEG monitoring and phase 2 intracranial EEG monitoring for precise seizure localization are the most important tests. The other tests include neuropsychological and WADA testing to predict and protect against any deficits in memory and language post surgery. Specialized epilepsy centers also have functional MRI (fMRI) to supplement the WADA test. Other specialized imaging techniques including brain MRI with seizure protocol, SPECT, interictal and Ictal SPECT and PET scans are utilized to identify the responsible lesions. Based on the results of the testing, patients can undergo epilepsy surgery. The most common epilepsy surgeries are temporal lobectomies, lesionectomies, extratemporal resections, corpus callosotomies, subpial transections and functional hemispherectomy. The decision regarding the type of epilepsy surgery depends on the localization of the seizure focus.

Adenosine A1 Receptors in the Central Nervous System: Their Functions in Health and Disease, and Possible Elucidation by PET Imaging

Adenosine is a neuromodulator with several functions in the central nervous system (CNS), such as inhibition of neuronal activity in many signaling pathways. Most of the sedating, anxiolytic, seizure-inhibiting and protective actions of adenosine are mediated by adenosine A1 receptors (A1R) on the surface of neurons and glia. Positron Emission Tomography (PET) is a powerful in vivo imaging tool which can be applied to investigate the physiologic and pathologic roles of A1R in the human brain, and to elucidate the mechanism of action of therapeutic drugs targeting adenosine receptors, nucleoside transporters and adenosine-degrading enzymes. In this review article, we discuss (i) functions of adenosine and its receptors in cerebral metabolism; (ii) radioligands for A1R imaging: xanthine antagonists, non-xanthine antagonists, and agonists; (iii) roles of A1R in health and disease, viz. sleep-wake regulation, modulation of memory retention and retrieval, mediating the effects of alcohol consumption, protecting neurons during ischemia and reperfusion, suppression of seizures, modulating neuroinflammation and limiting brain damage in neurodegenerative disorders. The application of PET imaging could lead to novel insights in these areas. Finally (iv), we discuss the application of PET in pharmacodynamic studies and we examine therapeutic applications of adenosine kinase inhibitors, e.g. in the treatment of pain, inflammation, and epilepsy.

Targeting Monoamine Oxidases with Multipotent Ligands: An Emerging Strategy in the Search of New Drugs Against Neurodegenerative Diseases

The socioeconomic burden of multi-factorial pathologies, such as neurodegenerative diseases (NDs), is enormous worldwide. Unfortunately, no proven disease-modifying therapy is available yet and in most cases (e.g., Alzheimer's and Parkinson's disease) the approved drugs exert only palliative and symptomatic effects. Nowadays, an emerging strategy for the discovery of disease-modifying drugs is based on the multi-target directed ligand (MTDL) design, an innovative shift from the traditional approach one-drug-one-target to the more ambitious one-drug-more-targets goal. Herein, we review the discovery strategy, the mechanism of action and the biopharmacological evaluation of multipotent ligands exhibiting monoamine oxidase (MAO) inhibition as the core activity with a potential for the treatment of NDs. In particular, MAO inhibitors exhibiting additional acetylcholinesterase (AChE) or nitric oxide synthase (NOS) inhibition, or ion chelation/antioxidant-radical scavenging/anti-inflammatory/A2A receptor antagonist/APP processing modulating activities have been thoroughly examined.

Pharmacotherapy of Borderline Personality Disorder: A Systematic Review

Borderline Personality Disorder (BPD) is a common disorder in psychiatric practice and drugs are widely used in its treatment, targeting symptom clusters, such as affective dysregulation, impulsive-behavioural dyscontrol, and cognitive-perceptual symptoms. In last period, a growing number of studies on pharmacological treatment of BPD have been performed, but different proposals of treatment guidelines are not completely in accordance on drug indications for BPD patients. This article reviews double-blind randomized controlled trials comparing active drugs versus placebo and drugs versus drugs, published between 1990 and 2010 and focused on the treatment of borderline personality disorder. Different classes of psychoactive agents, such as antipsychotics, mood stabilizers, antidepressants, and dietary supplementation were tested in BPD patients. More recent evidences suggest that mood stabilizers (topiramate, valproate and lamotrigine), second generation antipsychotics (olanzapine and aripiprazole) and omega-3 fatty acids can be useful to treat affective symptoms and impulsive-behavioural dyscontrol in BPD patients. Moreover, antipsychotics significantly improve cognitive symptoms in patients with BPD. SSRIs were found effective in decreasing severity of depressed mood, anxiety and anger, mainly in subjects with a concomitant affective disorder. Effects of antidepressants on impulsive behaviours are uncertain. Further studies are needed to improve methods of trials and confirm these findings.

Anti-NMDA Receptor Encephalitis in Psychiatry

Anti-NMDA receptor encephalitis is an autoimmune disorder in which antibodies attack NMDA (N-methyl-Daspartate)-type glutamate receptors at central neuronal synapses. Symptoms include a highly characteristic set of neurologic deficits, but also prominent psychiatric manifestations that often bring mental health professionals into the course of care. Distinct phases of illness have become increasingly appreciated, and include a range of psychotic symptoms early in the course of the disease followed by more severe fluctuations in consciousness with neurologic involvement, and ultimately protracted cognitive and behavioral deficits. Young women are most commonly impacted and an ovarian teratoma is sometimes associated with the syndrome. Patients respond well to immunotherapy, but psychiatric symptoms can be challenging to manage. We provide an up to date review of this disorder and highlight the role of psychiatry in diagnosis, symptomatology, and treatment.

The Role and Impact of SNPs in Pharmacogenomics and Personalized Medicine

Over 10 million SNPs have been discovered to date as the result of both a private and public effort in the past two decades. Extensive investigations on SNPs have been performed to assess clinical applications for pharmacogenomics and Personalized Medicine. Recently, around the 10th anniversary of the first publication by the Human Genome Project, Hamburg and Collins addressed questions regarding the progress of the genomics field and its impact on pharmacogenomics / Personalized Medicine. Similar questions remain around the potential link of SNPs to Personalized Medicine applications, and the extent to which they have impacted “real world” clinical practices. Built upon these previous efforts, and to achieve our objectives of describing and assessing the role of SNPs and their impact on Personalized Medicine, this article analyzes and summarizes the clinical relevance, molecular mechanisms, clinical evidence, and preliminary regulatory and clinical guideline information of relevant SNPs. In addition, it focuses on two applications directly related to Personalized Medicine drug therapeutics: predictive biomarkers for patient stratification and dose selection. In summary, this article attempts to provide a general and comprehensive view of the role of SNPs in pharmacogenomics and Personalized Medicine, as well as a practical view of their impact on clinical practice today.

Recent Advances in Progressive Supranuclear Palsy: A Review

Progressive Supranuclear Palsy (PSP) has been used to denote a unifying disorder with progressive parkinsonism with early falls, vertical supranuclear gaze palsy, pseudobulbar dysfunction and cognitive decline. Over the last decade, heterogeneity of the disease into different clinical subtypes has been recognized in clinicopathological studies. Although neuroimaging features and laboratory findings may support the diagnosis, true biomarkers are still lacking in the clinical setting. Neuronal and glial tau positive aggregates are predominantly found in basal ganglia and brainstem, and the significant association of PSP with the common H1 tau haplotype likely points to a pathophysiological role of the tau protein in the disease process. Future genetic studies of familial cases and an ongoing genome-wide association study of large series of pathological-proven cases may reveal additional genetic factors in the near future.

Conceptualizing Excessive Behaviour Syndromes: A Systematic Review

Debates about EBs (gambling, Internet use, shopping, working, exercising, eating, video game playing and sex) have gained momentum among researchers, clinicians, and the media. Controversy exists in the scientific literature about whether EBs are primary psychiatric disorders and, if so, where they fit into current and emerging diagnostic classification systems. The lack of consensus and associated confusion was the impetus for this systematic review.

The key search terms were: abuse/misuse, dependence, addiction, impulse control, compulsivity, pathological, and excessive, in combination with: buying/shopping, work, gaming/video games, exercise, Internet, sex, eating, and gambling.

361 articles were analyzed according to their conceptualization. In total, 47% adopted an addiction conceptualization, 9% adopted an impulse control conceptualization, and 2% an obsessive compulsive spectrum conceptualization. Alternative or blended conceptualizations were utilized by 27% and 16% did not specify a particular conceptualization. The findings were also broken down by excessive behaviour. Almost half of the articles were review articles (49%), 34% were empirical articles, and the remaining 17% were commentaries.

There was a general lack of agreement regarding conceptualization and a lack of consistency in nomenclature, definitions, and use of language. The addiction conceptualization was most prevalent consistent with the common use of the term behavioural addiction, and in line with proposed changes to the DSM-5.

Neurological Disorders of Purine and Pyrimidine Metabolism

Purines and pyrimidines, regarded for a long time only as building blocks for nucleic acid synthesis and intermediates in the transfer of metabolic energy, gained increasing attention since genetically determined aberrations in their metabolism were associated clinically with various degrees of mental retardation and/or unexpected and often devastating neurological dysfunction. In most instances the molecular mechanisms underlying neurological symptoms remain undefined. This suggests that nucleotides and nucleosides play fundamental but still unknown roles in the development and function of several organs, in particular central nervous system. Alterations of purine and pyrimidine metabolism affecting brain function are spread along both synthesis (PRPS, ADSL, ATIC, HPRT, UMPS, dGK, TK), and breakdown pathways (5NT, ADA, PNP, GCH, DPD, DHPA, TP, UP), sometimes also involving pyridine metabolism. Explanations for the pathogenesis of disorders may include both cellular and mitochondrial damage: e.g. deficiency of the purine salvage enzymes hypoxanthine-guanine phosphoribosyltransferase and deoxyguanosine kinase are associated to the most severe pathologies, the former due to an unexplained adverse effect exerted on the development and/or differentiation of dopaminergic neurons, the latter due to impairment of mitochondrial functions. This review gathers the presently known inborn errors of purine and pyrimidine metabolism that manifest neurological syndromes, reporting and commenting on the available hypothesis on the possible link between specific enzymatic alterations and brain damage. Such connection is often not obvious, and though investigated for many years, the molecular basis of most dysfunctions of central nervous system associated to purine and pyrimidine metabolism disorders are still unexplained.

Role of Nitric Oxide in Motor Control: Implications for Parkinsons Disease Pathophysiology and Treatment

According to classical thinking about Parkinsons disease, loss of dopaminergic input from the substantia nigra pars compacta leads to overactivity and underactivity of the indirect and direct output pathways, respectively, in the basal ganglia. Administration of the dopamine precursor L-DOPA (l-3, 4-dihydroxyphenylalanine) is proposed to induce changes in the opposite directions. L-DOPA is the most used drug to treat Parkinsons disease symptoms. After repeated treatment with this compound, however, disabling secondary effects such as the abnormal involuntary movements usually appear. Nitric oxide is a free radical that can also acts as an atypical neurotransmitter and influences dopamine-mediated neurotransmission. In this paper we will briefly review the role of nitric oxide on motor control and in Parkinsons disease, particularly a possible role of nitric oxide in L-DOPA induced dyskinesia in rodents. Recent results show that nitric oxide synthase inhibition reduces L-DOPA-induced dyskinesia in rats and mice. The effect is dose-dependent, does not suffer tolerance nor interferes with L-DOPA positive motor effects. These preclinical findings suggest that nitric oxide is a promising therapeutic target for the reduction of L-DOPA-induced dyskinesia.

The Role of PGC-1α in the Pathogenesis of Neurodegenerative Disorders

Mitochondrial dysfunction is a common hallmark of ageing-related diseases involving neurodegeneration. Huntingtons disease (HD) is one of the most common monogenetic forms of neurodegenerative disorders and shares many salient features with the major sporadic disease of neurodegeneration, such as amyotrophic lateral sclerosis (ALS), Alzheimers disease (AD) and Parkinsons disease (PD). Recent evidence from the study of transgenic and knockout animal models of HD has stimulated new perspectives on mitochondrial dysfunction in HD and possibly other neurodegenerative diseases. The transcriptional co-activator PGC-1a, originally described as a metabolic master regulator in peripheral tissues such as brown adipose tissue (BAT) and muscle, has emerged as a molecular link between transcriptional dysregulation and mitochondrial dysfunction in the brain. PGC-1α knockout mice display many phenotypic similarities to transgenic mouse models of HD and the gene-expression analysis of tissues from HD patients revealed a disruption of the PGC-1α regulatory pathway. Hence, mitochondrial and transcriptional dysregulation in HD – previously thought to be unrelated mechanisms of neurodegeneration – appear to be directly linked at the molecular level. The clinical and therapeutic potential of targeting the PGC-1α in HD is further highlighted by the finding that common genetic variations in the PGC-1α gene significantly modify the disease onset, delaying the onset of motor symptoms by several years. The present review provides an overview of the advances in the understanding of the role of the PGC-1a system in HD pathogenesis and explores the implications for ALS, AD and PD.

Shoulder Manifestations of Diabetes Mellitus

The musculoskeletal system can be affected by diabetes in a number of ways. The shoulder is one of the frequently affected sites. One of the rheumatic conditions caused by diabetes is frozen shoulder (adhesive capsulitis), which is characterized by pain and severe limited active and passive range of motion of the glenohumeral joint, particularly external rotation. This disorder has a clinical diagnosis and the treatment is based on physiotherapy, non-steroidal antiinflammatory drugs (NSAIDs), corticosteroid injections and, in refractory cases, surgical resolution. As with adhesive capsulitis, calcific periarthritis of the shoulder causes pain and limited joint mobility, although usually it has a better prognosis than frozen shoulder. Reflex sympathetic dystrophy, also known as shoulder-hand syndrome, is a painful syndrome associated with vasomotor and sudomotor changes in the affected member. Diabetic amyotrophy usually affects the peripheral nerves of lower limbs. However, when symptoms involve the shoulder girdle, it must be considered in the differential diagnosis of shoulder painful conditions. Osteoarthritis is the most common rheumatic condition. There are many risk factors for shoulder osteoarthritis including age, genetics, sex, weight, joint infection, history of shoulder dislocation, and previous injury, in older age patients, diabetes is a risk factor for shoulder OA. Treatment options include acetaminophen, NSAIDs, short term opiate, glucosamine and chondroitin. Corticosteroid injections and/or injections of hyaluronans could also be considered. Patients with continued disabling pain that is not responsive to conservative measures may require surgical referral.

The present review will focus on practice points of view about shoulder manifestations in patients with diabetes.

Safety Considerations of the Use of Second Generation Antipsychotics in the Treatment of Major Depression: Extrapyramidal and Metabolic Side Effects

Second generation antipsychotics (SGAs) are increasingly employed in the treatment of depression. Adjunctive aripiprizole and olanzapine/fluoxetine combination (OFC) have been approved in the US in the treatment of depression. Quetiapine also appears to be poised for an FDA approval as an adjunctive treatment for resistant depression. Historically, first generation antipsychotics were thought to carry an enhanced risk of certain side effects in the treatment of mood disorders, including an enhanced risk of extrapyramidal symptoms (EPS). The second generation antipsychotics are also known to be associated with a variety of metabolic side effects. The use of SGA in a depressed population may pose risks that differ from use in other conditions such as bipolar disorder and schizophrenia. In this paper, the risk of extrapyramidal and metabolic side effects is reviewed in depressed patients treated with second generation antipsychotics.

Stem Cells: An Overview of the Current Status of Therapies for Central and Peripheral Nervous System Diseases

In regenerative medicine, stem cells are currently considered ideal candidates for the treatment of diseases and injuries of the nervous system, for which, at present, there are no effective treatments. Promising results have been shown by clinical trials for neurodegenerative diseases such as Parkinsons diseases, but also for demyelinising disorders and traumatic lesions of the brain and spinal cord. The proof-of-principle is that the replacement of damaged cells and the restoration of function can be accomplished by the transplantation of embryonic or adult stem cells. Advancements in stem cell biology were recently propelled by the ability to generate induced pluripotent stem (iPS) cells from fibroblasts of several neurodegenerative diseases (e.g. Parkinsons and Huntingtons diseases, Amyotrophic Lateral Sclerosis and Spinal Muscular Atrophy). In this review, we discuss the molecular basis of stem cell therapy and the advancement of research on regenerative medicine for diseases and injuries of the nervous system.

Mechanisms of Action of Antipsychotic Drugs of Different Classes, Refractoriness to Therapeutic Effects of Classical Neuroleptics, and Individual Variation in Sensitivity to their Actions: PART II

Rapid-onset psychotic rebound is uncommon on discontinuation of most antipsychotic drugs, as might be expected for antipsychotic drugs with (hypothetically) indirect actions at their final target receptors. Rapid-onset psychosis is more common on withdrawal of clozapine, which might be expected if its action is direct. Drugs other than clozapine (notably thioridazine) may have hitherto unrecognised similarities to clozapine (but without danger of agranulocytosis), and may be useful in treatment of refractory psychosis. Quetiapine fulfils only some criteria for a clozapine-like drug. Clinical response to neuroleptics varies widely at any given plasma level. Haases “neuroleptic threshold” concept suggests that the dose producing the slightest motor side effects produces most or all of the therapeutic benefit, but analyses presented here suggest that antipsychotic actions are not subject to a sharp “all-or-none” threshold but increase over a small dose range. This concept could provide a method for quantitative determination of individualized optimal doses.

Current Clinical Applications of Botulinum Toxin

Botulinum toxin has long been known for its paralytic effects on the human voluntary musculature via inhibition of acetylcholine release at neuromuscular junctions. Its original clinical use for the treatment of strabismus has expanded significantly to include neurological conditions related to muscle hyperactivity and/or spasticity (e.g., dystonia, spasticity, tics, tremor, dysphonia). Recently, botulinum toxin has been shown to impact autonomic disorders by acting at acceptors on glands and smooth muscle, and consequently it has been used in the management of a number of other conditions including hypersecretory disorders, pain syndromes, detrusor sphinchter dyssenergia or overactivity and gastointestinal smooth muscle/sphincter spasm; it may also reduce pain in patients for whom it is used to treat these and other primary conditions. This article will review the pharmacology and formulations of botulinum toxins as well as data from clinical trials demonstrating their efficacy for numerous conditions based on their effects on cholinergic synapses outside the motor nervous system.

Body Dysmorphic Disorder: A Review of Current Nosological Issues and Associated Cognitive Deficits

Recent study into body dysmorphic disorder (BDD) has raised questions about the validity of its current diagnostic classification as well as categorical division into ‘psychotic’ and ‘non-psychotic’ variants. Furthermore, though individuals with the disorder are believed to experience cognitive difficulties, the precise nature of these deficits remains unclear. This paper aims to provide a comprehensive review of existing knowledge of BDD in terms of its nosology and cognitive deficits. We evaluate arguments in relation to its inclusion within the obsessive-compulsive spectrum disorders (OCSDs), consider how delusionality is coded in BDD, and also examine recent studies suggesting which specific cognitive deficits may underpin the disorder. There appears to be a sound rationale for considering BDD as part of the OCSDs, though current findings indicate that it is not simply a subtype of obsessive-compulsive disorder (OCD). Evidence also suggests that the degree of delusional beliefs in BDD would be more appropriately theorised on a dimensional basis. In terms of cognitive deficits, research to date has implied that attentional biases and/or abnormalities in basic visual processing may be especially important. Further research is needed to elucidate an inclusive profile of the underlying cognitive deficits in BDD. In turn, these insights could help to clarify current nosological debates surrounding the disorder.

1-Cyclohexylpiperazine and 3,3-Dimethylpiperidine Derivatives as Sigma-1 (σ1) and Sigma-2 (σ2) Receptor Ligands: A Review

Herein the evolution in the development of new sigma (??) receptor ligands since the middle & 90s by our research group is reported. In the effort to contribute to the identification of the structural features for high-affinity ligands selective versus serotonin, dopamine and other CNS-related receptors, two general classes of (naphthalene)alkylamine compounds were prepared and explored, with the aim of addressing the affinities toward the two recognized σ receptor subtypes. The common template of these compounds was mainly an unsubstituted or methoxy-substituted naphthalene or tetralin nucleus, linked by an alkyl spacer to a substituted piperazine or piperidine ring. The design of new ligands was thought keeping in mind their possible application as PET diagnostic tools and fluorescence tools. High-affinity σ2 receptor ligands were found among N-cyclohexylpiperazine derivatives, such as 1-cyclohexyl-4-[3-(5-methoxy-1,2,3,4- tetrahydronaphthalen-1-yl)propyl]piperazine (3) (PB 28), when they were assayed in radioligand binding with [3H]-DTG in rat liver. Unfortunately, these ligands were all devoid of a significant selectivity relative to σ1 receptor whose binding was assayed with (+)-[3H]-pentazocine in guinea pig brain. Nevertheless, compound 3 had previously shown to be 40-fold selective with a slightly different binding method in animals tissues. Moreover, it demonstrated 46-fold and 59-fold σ2 versus σ1 receptor binding selectivity in MCF7 and MCF7 ADR tumor cell lines respectively. In the class of piperazines, also high-affinity σ1 receptor ligands were found, possibly due to the presence of a double N-atom and an additional reverse mode of binding. Piperidine derivatives were investigated as high-affinity and selective σ1 receptor ligands leading to some 3,3-dimethylpiperidines such as 3,3-dimethyl-1-[3-(6-methoxynaphthalen-1-yl)propyl]piperidine (69) which resulted to be highly selective relative to the σ2 receptor. For the best ligands, functional assays were conducted in order to investigate agonist/antagonist activity. The effect of chirality in the intermediate methyl-alkyl chain was explored for a class of 4-methylpiperidines linked to some (4-chlorophenoxy)alkyl moieties, and compound ( – )-(S)-92 emerged as the most selective σ1 relative to σ2 receptor ligand.

Substance Abuse and Movement Disorders

The complex relation between movement disorders and substance abuse is reviewed. First, we discuss the wide variety of movement disorders that occur as a direct consequence of acute use or withdrawal of drugs of abuse, such as alcohol, cocaine, heroin, amphetamine and methcathinone. Second, we describe the recent advances in the comorbid relationship between alcoholism and two movement disorders: essential tremor and myoclonus-dystonia. Lastly, we discuss the abuse potential of the dopaminergic agents, apomorphine and levodopa, in patients with Parkinsons disease.

New Molecular Avenues in Parkinson ’ s Disease Therapy

Idiopathic Parkinsons Disease (PD) is a progressive neurodegenerative disease characterized by dopaminergic neuronal loss within the substantia nigra. The degeneration of dopamine and other neuronal populations in PD lead to both chronic motor and non-motor disabilities but the mechanisms remain unclear. Molecular genetic studies in familial forms of the disease identified key proteins involved in PD pathogenesis, supporting a major role for (i) protein aggregation and neurotoxic α-synuclein oligomeric species due to an altered protein quality control, (ii) parkin-driven deregulation of the ubiquitin-proteasome system, (iii) oxidative stress and mithocondrial dysfunction, and, finally, (iv) disturbed kinase activity. The elucidation of these new molecular pathways has increased our knowledge of PD pathophysiology, but it remains an open question whether alterations of these pathways lead to different entities of PD or whether they finally converge at a point that is the common pathogenetic denominator of PD. However, the knowledge of validated targets is in its infancy, and thus, traditional target-based drug discovery strategies are of limited use. Alternative approaches are needed, and early attempts were aimed at identifying molecules inhibiting the aggregation of α-synuclein fragments, interfering with the ubiquitin proteasome pathway and reducing oxidative stress. Such discovery strategies have an impact on the configuration of screening cascades for effective translation of drug candidates toward clinical trials. This review examines how these genetic findings provided us with suitable animal models and how the gained insights will contribute to better therapies for PD.

Monoaminergic Neurotransmission: The History of the Discovery of Antidepressants from 1950s Until Today

The 1950s saw the clinical introduction of the first two specifically antidepressant drugs: iproniazid, a monoamine- oxidase inhibitor that had been used in the treatment of tuberculosis, and imipramine, the first drug in the tricyclic antidepressant family. Iproniazid and imipramine made two fundamental contributions to the development of psychiatry: one of a social-health nature, consisting in an authentic change in the psychiatric care of depressive patients; and the other of a purely pharmacological nature, since these agents have constituted an indispensable research tool for neurobiology and psychopharmacology, permitting, among other things, the postulation of the first aetiopathogenic hypotheses of depressive disorders. The clinical introduction of fluoxetine, a selective serotonin reuptake inhibitor, in the late 1980s, once again revolutionized therapy for depression, opening the way for new families of antidepressants. The present work reviews, from a historical perspective, the entire process that led to the discovery of these drugs, as well as their contribution to the development of the neuroscientific disciplines. However, all of these antidepressants, like the rest of those currently available for clinical practice, share the same action mechanism, which involves the modulation of monoaminergic neurotransmission at a synaptic level, so that the future of antidepressant therapy would seem to revolve around the search for extraneuronal non-aminergic mechanisms or mechanisms that modulate the intraneuronal biochemical pathways.

The Therapeutic Potential of Melatonin in Neurological Disorders

Melatonin (N-acetyl-5- methoxytryptamine) is a pineal gland hormone, synthesized from amino acid Ltryptophan. Other tissues including retina, skin, and gastrointestinal tract also synthesize it. It is secreted into the cerebrospinal fluid and circulatory system in a circadian pattern. Its production is light:dark dependent and its levels are low during the day and maximal during the hours of darkness. It plays an important role in different physiological and pathophysiological processes in the brain, which includes regulation of biological rhythms and seasonal reproduction. Its biological activity is associated with its action on melatonin receptors - ML-1 and ML-2. It has antioxidant and neuroprotective propertities and potential therapeutic role in different neurological disorders. Melatonin has been used as a sleep-promoting agent; more recently it has also been used in headache, movement disorders, neuropathic pain, and seizure disorders. In this review, some recent patents also discussed.

Pharmacology and Therapeutic Potential of Sigma1 Receptor Ligands

Sigma () receptors, initially described as a subtype of opioid receptors, are now considered unique receptors. Pharmacological studies have distinguished two types of receptors, termed 1 and 2. Of these two subtypes, the 1 receptor has been cloned in humans and rodents, and its amino acid sequence shows no homology with other mammalian proteins. Several psychoactive drugs show high to moderate affinity for 1 receptors, including the antipsychotic haloperidol, the antidepressant drugs fluvoxamine and sertraline, and the psychostimulants cocaine and methamphetamine; in addition, the anticonvulsant drug phenytoin allosterically modulates 1 receptors. Certain neurosteroids are known to interact with 1 receptors, and have been proposed to be their endogenous ligands. These receptors are located in the plasma membrane and in subcellular membranes, particularly in the endoplasmic reticulum, where they play a modulatory role in intracellular Ca2+ signaling. Sigma1 receptors also play a modulatory role in the activity of some ion channels and in several neurotransmitter systems, mainly in glutamatergic neurotransmission. In accordance with their widespread modulatory role, 1 receptor ligands have been proposed to be useful in several therapeutic fields such as amnesic and cognitive deficits, depression and anxiety, schizophrenia, analgesia, and against some effects of drugs of abuse (such as cocaine and methamphetamine). In this review we provide an overview of the present knowledge of 1 receptors, focussing on 1 ligand neuropharmacology and the role of 1 receptors in behavioral animal studies, which have contributed greatly to the potential therapeutic applications of 1 ligands.

Challenge and Therapeutic Studies Using Alpha-Methyl-para-Tyrosine (AMPT) in Neuropsychiatric Disorders: A Review

Alpha-methyl-para-tyrosine (AMPT) temporarily inhibits tyrosine hydroxylase, the rate limiting step in the dopamine biosynthesis cascade. AMPT has been approved for clinical use in phaeochromocytoma in 1979. Recently however, AMPT has been increasingly employed as a pharmacological challenge in acute dopamine depletion studies including neuroimaging studies. The use of this exciting challenge technique allows us to increase our understanding of dopaminergic neurotransmission in the brain. In addition, there have been clinical reports that AMPT may be useful to treat movement disorders like dystonia, dyskinesia and Huntingtons chorea, psychiatric disorders like mania, psychosis, obsessive compulsive disorder and substance abuse as well as behavioral problems in 22q11 deletion syndrome. In this review we will discuss the effects of AMPT in challenge studies that have been reported in humans. Furthermore we will review all studies reporting therapeutic effects of AMPT in neuropsychiatric disorders and adverse effects associated with AMPT use reported in both challenge and therapeutic research.

Schizophrenia and Idiopathic Unconjugated Hyperbilirubinemia (Gilberts Syndrome)

Idiopathic unconjugated hyperbilirubinemia (Gilberts syndrome, GS) is a relatively common congenital hyperbilirubinemia occurring in 3-7% of the world population. It has been recognized as a benign familial condition in which hyperbilirubinemia occurs in the absence of structural liver disease or hemolysis, and the plasma concentration of conjugated bilirubin is normal. Recently, it was reported that uncojugated bilirubin had neurotoxicity in the developing nervous system. The ‘neurodevelopmental hypothesis’ of schizophrenia was proposes that a yet-unidentified event occurring in utero or early postnatal life. We have observed that patients suffering from schizophrenia frequently present an increased unconjugated bilirubin plasma concentration when admitted to the hospital. Therefore, we had notice the relation between unconjugated bilirubin and the etiology and vulnerability of schizophrenia. Our reported findings suggest that there are significant biological and clinical character differences between schizophrenic patients with GS and without GS. From the viewpoint of heterogeneity of schizophrenia, there may be poor outcome for the subtype of schizophrenia with GS.