Second-Generation Antipsychotics and Extrapyramidal Adverse Effects

Antipsychotic-induced extrapyramidal adverse effects are well recognized in the context of first-generation antipsychotic drugs. However, the introduction of second-generation antipsychotics, with atypical mechanism of action, especially lower dopamine receptors affinity, was met with great expectations among clinicians regarding their potentially lower propensity to cause extrapyramidal syndrome. This review gives a brief summary of the recent literature relevant to second-generation antipsychotics and extrapyramidal syndrome. Numerous studies have examined the incidence and severity of extrapyramidal syndrome with firstand second-generation antipsychotics. The majority of these studies clearly indicate that extrapyramidal syndrome does occur with second-generation agents, though in lower rates in comparison with first generation. Risk factors are the choice of a particular second-generation agent (with clozapine carrying the lowest risk and risperidone the highest), high doses, history of previous extrapyramidal symptoms, and comorbidity. Also, in comparative studies, the choice of a first-generation comparator significantly influences the results. Extrapyramidal syndrome remains clinically important even in the era of second-generation antipsychotics. The incidence and severity of extrapyramidal syndrome differ amongst these antipsychotics, but the fact is that these drugs have not lived up to the expectation regarding their tolerability. Background Antipsychotic drugs are the cornerstone of the pharmacological treatment of schizophrenia. The introduction of the first antipsychotic chlorpromazine in 1952 marked the new era in psychopharmacology Clozapine was the first antipsychotic that proved to be efficacious in treatment-refractory schizophrenia Clozapine, as the first SGA, actually discredited the theory that EPS are an unavoidable accompaniment of antipsychotic efficacy. Previously, EPS were considered as an essential component of antipsychotic "neuroleptic" effect. The association of antidopaminergic (D2) potency, antipsychotic effect, and EPS (due to loss of dopamine in the extrapyramidal part of the central nervous system) was the foundation for the dopamine hypothesis of schizophrenia All antipsychotic agents have some degree of antagonistic affinity for dopaminergic D2 receptors. It was shown that first-generation antipsychotics, though known to block other receptors, not only exert their antipsychotic, but also their extrapyramidal effects, primarily by binding to D2 receptors in the central nervous system. First-generation antipsychotics produce their therapeutic (antipsychotic) effect at 60-80% of D2 occupancy, while the 75-80% of D2 receptor occupancy leads to the acute EPS The efficacy of a pharmacological treatment cannot be interpreted independently from its adverse effects profile. Better tolerability of SGAs was considered as one of their major advantages as a class Extrapyramidal Symptoms EPS include acute dystonias, akathisia, Parkinsonism, and tardive dyskinesia (TD). EPS are serious, sometimes debilitating and stigmatizing adverse effects, and require additional pharmacotherapy. EPS develop into two phases. Early, acute EPS most often develop upon the beginning of treatment with antipsychotics or when the dose is increased. The later-onset EPS usually occur after prolonged treatment and present as tardive dyskinesia (TD). The motor manifestations include akathisia (restlessness and pacing), acute dystonia (sustained abnormal postures and muscle spasms, especially of the head or neck), and Parkinsonism (tremor, skeletal muscle rigidity, and/or bradykinesia) Acute EPS usually respond to dose reduction of the antipsychotic agent or require additional pharmacological treatment. Acute dystonia occurs within first few days after the initiation of the antipsychotic treatment and can be effectively prevented or reversed with anticholinergic drugs such as biperiden Akathisia is very common (about one half of all cases of EPS), poorly understood, and difficult to treat. It occurs mostly within the first three months of treatment. Akathisia does not respond to anticholinergic medication, but antipsychotic dose reduction, liposoluble beta adrenergic blockers, and benzodiazepines have proved effective Parkinsonism induced by antipsychotics occurs between few days and up to several months after the initiation of the treatment. Risk factors for this type of Parkinsonism are age (elderly), gender (females), cognitive deficit, and early onset EPS In CATIE study, the results regarding Parkinsonism were also conflicting. CATIE study includes patients with previous tardive dyskinesia, who at baseline were excluded from perphenazine branch. This could lead to potential bias, meaning that patients with previous vulnerability to EPS were allocated exclusively to SGA branch. In order to avoid this potential bias, only patients without previous TD were included in comparisons for Parkinsonism. The proportion of patients showing no evidence of Parkinsonism at baseline who met at least one of the three criteria for Parkinsonism during the subsequent follow-up period revealed no substantial differences between treatment groups. At the 12-month followup, covariate-adjusted rates of Parkinsonism were 37%-44% for SGAs and 37% for perphenazine Tardive dyskinesia occurs after months or years of antipsychotic therapy. The risk of TD development is highest in the first five years of treatment with FGAs Recent studies on the propensity of FGAs and SGAs to cause EPS yielded conflicting results EPS remain the most serious problem among patients affected with schizophrenia, even in the era of new antipsychotics with less affinity towards D2 receptors. Upon the introduction of second-generation antipsychotics, these agents were defined as atypical based on their mechanism of action. Atypical antipsychotics expressed less affinity for striatal D2 receptors than typical, FGAs, and different levels of 5-HT2A antagonism, alpha-1 antagonism, or cholinergic antagonism. However, all SGAs still affect D2 receptors to some degree, with clozapine having the least affinity Conclusion SGAs have not completely fulfilled the expectation of being EPS-free antipsychotic drugs. Though recommended by current guidelines as the first-line therapy in the treatment of schizophrenia The likelihood of causing EPS with an SGA exists and depends on many factors. The patient's characteristics (age, gender, and concomitant conditions), history of the disease, previous treatment, the choice of a particular antipsychotic, its dose, and duration of treatment and adjuvant therapy should be taken into consideration in the order to minimize the risk of EPS and provide the best quality of care. At this moment, the trial-and-error approach is recommended, since the therapeutic outcome and adverse effects are not easily predictable. Hopefully, the recent, promising advances in pharmacogenomics and neurobiology could provide predictive markers of antipsychotic response and adverse effects and lead towards personalized therap

Pharmacotherapy of Rare Diseases in Serbia: The Current State of Art

Rare diseases affect less than 1 in 2000 or 5 in 10,000 people by definition. Most of those diseases have genetic basis (80% of cases) and first symptoms appear in early childhood (50% of cases). Most of these diseases are chronic and degenerative and pharmacotherapy is not available for many of them. Until today, there are more than 7000 rare diseases. In Serbia, the problem of diagnosis and pharmacotherapy of rare diseases is currently under public scrutiny. Patients who suffer from rare diseases in Serbia face many challenges in terms of awareness, timely diagnosis, and adequate treatment. These people are often misdiagnosed or the diagnosis is delayed due to several problems: lack of awareness among medical professionals, lack of expertise, unavailability and/or high costs of diagnostic tests, etc. According to the National Organization of Patients with Rare Diseases in Serbia (NORBS), many diagnostic procedures have to be conducted abroad and the process comprises many difficulties: high costs, travel expenses, or transportation of biological material. Although national legislation ensures the availability of drugs for those diseases, pharmacotherapy is faced with many problems. In this work, we aim to show that improvement of the knowledge regarding rare diseases among both professionals and patients represents a crucial step for enhancement of perspectives for those patients in our community

Synthesis, Characterization and Biological Studies of Organoselenium trans-Palladium(II) Complexes

Background: Over the years, transition metal complexes have exhibited significant antimicrobial and antitumor activity. It all started with cisplatin discovery, but due to the large number of side effects it shows, there is a growing need to find a new metal-based compound with higher selectivity and activity on more tumors. Objectives: Two novel trans-palladium(II) complexes with organoselenium compounds as ligands, [Pd(L1)2Cl2] (L1 = 5-(phenylselanylmethyl)-dihydrofuran-2(3H)-one) and [Pd(L2)2Cl2] (L2 = 2- methyl-5-(phenylselanylmethyl)- tetrahydrofuran) were synthesized, in the text referred to as Pd-Se1 and Pd-Se2. Also, a structurally similar trans-palladium(II) complex, [Pd(L3)2Cl2] (L3= 2,2- dimethyl-3-(phenylselanylmethyl)-tetrahydro-2H-pyran ) was synthesized according to an already published work and is referred to as Pd-Se3. The interaction of synthesized complexes with DNA and bovine serum albumin was observed. Also, antimicrobial activity and in vitro testing, cell viability, and cytotoxic effects of synthesized ligands and complexes on human epithelial colorectal cancer cell line HCT-116 were studied. Molecular docking simulations were performed to understand better the binding modes of the complexes reported in this paper with DNA and BSA, as well as to comprehend their antimicrobial activity. Methods: The interactions of the synthesized complexes with DNA and bovine serum albumin were done using UV-Vis and emission spectral studies as well as docking studies. Antimicrobial activity was tested by determining the minimum inhibitory concentrations (MIC) and minimum microbicidal concentration (MMC) using the resazurin microdilution plate method. Cytotoxic activity on cancer cells was studied by MTT test. Results: The Pd(II) complexes showed a significant binding affinity for calf thymus DNA and bovine serum albumin by UV-Vis and emission spectral studies. The intensity of antimicrobial activity varied with the complexes Pd-Se1 and Pd-Se3, showing significantly higher activity than the corresponding ligand. The most significant activity was shown on Pseudomonas aeruginosa. Under standardized laboratory conditions for in vitro testing, cell viability and cytotoxic effects of synthesized ligands and complexes were studied on human epithelial colorectal cancer cell line HCT-116, where Pd-Se2 showed some significant cytotoxic effects. Conclusion: The newly synthesized complexes have the potential to be further investigated as metallodrugs.Publishe

Confocal Synaptology: Synaptic Rearrangements in Neurodegenerative Disorders and upon Nervous System Injury

The nervous system is a notable exception to the rule that the cell is the structural and functional unit of tissue systems and organs. The functional unit of the nervous system is the synapse, the contact between two nerve cells. As such, synapses are the foci of investigations of nervous system organization and function, as well as a potential readout for the progression of various disorders of the nervous system. In the past decade the development of antibodies specific to presynaptic terminals has enabled us to assess, at the optical, laser scanning microscopy level, these subcellular structures, and has provided a simple method for the quantification of various synapses. Indeed, excitatory (glutamatergic) and inhibitory synapses can be visualized using antibodies against the respective vesicular transporters, and choline-acetyl transferase (ChAT) immunoreactivity identifies cholinergic synapses throughout the central nervous system. Here we review the results of several studies in which these methods were used to estimate synaptic numbers as the structural equivalent of functional outcome measures in spinal cord and femoral nerve injuries, as well as in genetic mouse models of neurodegeneration, including Alzheimer's disease (AD). The results implicate disease-and brain region-specific changes in specific types of synapses, which correlate well with the degree of functional deficit caused by the disease process. Additionally, results are reproducible between various studies and experimental paradigms, supporting the reliability of the method. To conclude, this quantitative approach enables fast and reliable estimation of the degree of the progression of neurodegenerative changes and can be used as a parameter of recovery in experimental models

Second-Generation Antipsychotics and Extrapyramidal Adverse Effects

Antipsychotic-induced extrapyramidal adverse effects are well recognized in the context of first-generation antipsychotic drugs. However, the introduction of second-generation antipsychotics, with atypical mechanism of action, especially lower dopamine receptors affinity, was met with great expectations among clinicians regarding their potentially lower propensity to cause extrapyramidal syndrome. This review gives a brief summary of the recent literature relevant to second-generation antipsychotics and extrapyramidal syndrome. Numerous studies have examined the incidence and severity of extrapyramidal syndrome with first- and second-generation antipsychotics. The majority of these studies clearly indicate that extrapyramidal syndrome does occur with second-generation agents, though in lower rates in comparison with first generation. Risk factors are the choice of a particular second-generation agent (with clozapine carrying the lowest risk and risperidone the highest), high doses, history of previous extrapyramidal symptoms, and comorbidity. Also, in comparative studies, the choice of a first-generation comparator significantly influences the results. Extrapyramidal syndrome remains clinically important even in the era of second-generation antipsychotics. The incidence and severity of extrapyramidal syndrome differ amongst these antipsychotics, but the fact is that these drugs have not lived up to the expectation regarding their tolerability

Confocal Synaptology: Synaptic Rearrangements in Neurodegenerative Disorders and upon Nervous System Injury

The nervous system is a notable exception to the rule that the cell is the structural and functional unit of tissue systems and organs. The functional unit of the nervous system is the synapse, the contact between two nerve cells. As such, synapses are the foci of investigations of nervous system organization and function, as well as a potential readout for the progression of various disorders of the nervous system. In the past decade the development of antibodies specific to presynaptic terminals has enabled us to assess, at the optical, laser scanning microscopy level, these subcellular structures, and has provided a simple method for the quantification of various synapses. Indeed, excitatory (glutamatergic) and inhibitory synapses can be visualized using antibodies against the respective vesicular transporters, and choline-acetyl transferase (ChAT) immunoreactivity identifies cholinergic synapses throughout the central nervous system. Here we review the results of several studies in which these methods were used to estimate synaptic numbers as the structural equivalent of functional outcome measures in spinal cord and femoral nerve injuries, as well as in genetic mouse models of neurodegeneration, including Alzheimer’s disease (AD). The results implicate disease- and brain region-specific changes in specific types of synapses, which correlate well with the degree of functional deficit caused by the disease process. Additionally, results are reproducible between various studies and experimental paradigms, supporting the reliability of the method. To conclude, this quantitative approach enables fast and reliable estimation of the degree of the progression of neurodegenerative changes and can be used as a parameter of recovery in experimental models

Prenatal diagnosis of lissencephaly: A case report

Introduction. Lissencephaly (“smooth brain”) forms a major group of brain malformations due to abnormal neuronal migration. It can cause severe intellectual and motor disability and epilepsy in children. The prenatal diagnosis of this malformation is rare. Case report. We presented a case of the prenatal diagnosis of lissencephaly. A 30-year old pregnant woman was reffered to the hospital at the week 35 of gestation for magnetic resonance imaging (MRI) after an ultrasound examination demonstrated fetal cerebral ventriculomegaly. Fetal MRI of the brain showed “smooth”, agyrya cortex. The female infant was born at term with birth weight of 2,500 g and Apgar score 8, showing global developmental delay. Postnatal ultrasound and MRI confirmed classical lissencephaly. She is now 8 years old and has spastic quadriparesis, mental retardation and epilepsy. Conclusion. Confirmation of the ultrasound diagnosis with MRI is desirable for the prenatal diagnosis of lissencephaly

The Efficacy and Safety of Antipsychotic Medications in the Treatment of Psychosis in Patients with Parkinson’s Disease

Psychotic symptoms are present in up to 50% of patients with Parkinson’s disease. These symptoms have detrimental effects on patients’ and caregivers’ quality of life and may predict mortality. The pathogenesis of psychotic symptoms in Parkinson’s disease is complex, but the use of dopaminergic medications is one of the risk factors. The treatment of psychotic symptoms in Parkinson’s disease is complicated due to the ability of antipsychotic medications to worsen motor symptoms. The efficacy of clozapine in the treatment of psychosis in patients with Parkinson’s disease has been confirmed in several clinical trials; however, the adverse effects and the necessity of blood count monitoring are the reasons why the use of this drug is challenging. The studies on safety and efficacy of other antipsychotics conflicting results. The use of antipsychotics in these patients is also associated with increased mortality. Psychotic symptoms in Parkinson’s disease per se are also proven predictors of mortality. Thus it is necessary to treat psychotic symptoms but the choice of an antipsychotic should be based on careful risk/benefit assessment. Pimavanserin as a novel therapeutic option with more favorable adverse effects profile is now available for this indication, but careful postmarketing monitoring is necessary to establish the true picture of this drug’s long-term safety and efficacy