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

Different Functions of Recombinantly Expressed Domains of Tenascin-C in Glial Scar Formation

Extracellular matrix glycoprotein tenascin-C (TnC) is highly expressed in vertebrates during embryonic development and thereafter transiently in tissue niches undergoing extensive remodeling during regeneration after injury. TnC's different functions can be attributed to its multimodular structure represented by distinct domains and alternatively spliced isoforms. Upon central nervous system injury, TnC is upregulated and secreted into the extracellular matrix mainly by astrocytes. The goal of the present study was to elucidate the role of different TnC domains in events that take place after spinal cord injury (SCI). Astrocyte cultures prepared from TnC-deficient (TnC-/-) and wild-type (TnC+/+) mice were scratched and treated with different recombinantly generated TnC fragments. Gap closure, cell proliferation and expression of GFAP and cytokines were determined in these cultures. Gap closure in vitro was found to be delayed by TnC fragments, an effect mainly mediated by decreasing proliferation of astrocytes. The most potent effects were observed with fragments FnD, FnA and their combination. TnC-/- astrocyte cultures exhibited higher GFAP protein and mRNA expression levels, regardless of the type of fragment used for treatment. Application of TnC fragments induced also pro-inflammatory cytokine production by astrocytes in vitro. In vivo, however, the addition of FnD or Fn(D+A) led to a difference between the two genotypes, with higher levels of GFAP expression in TnC+/+ mice. FnD treatment of injured TnC-/- mice increased the density of activated microglia/macrophages in the injury region, while overall cell proliferation in the injury site was not affected. We suggest that altogether these results may explain how the reaction of astrocytes is delayed while their localization is restricted to the border of the injury site to allow microglia/macrophages to form a lesion core during the first stages of glial scar formation, as mediated by TnC and, in particular, the alternatively spliced FnD domain

Tenascin-C fibronectin D domain is involved in the fine-tuning of glial response to CNS injury in vitro

Understanding processes that occur after injuries to the central nervous system is essential in order to gain insight into how the restoration of function can be improved. Extracellular glycoprotein tenascin-C (TnC) has numerous functions in wound healing process depending on the expression time, location, isoform and binding partners which makes it interesting to study in this context. We used an in vitro injury model, the mixed culture of cortical astrocytes and microglia, and observed that without TnC microglial cells tend to populate gap area in greater numbers and proliferate more, whereas astrocytes build up in the border region to promote faster gap closure. Alternatively spliced domain of TnC, fibronectin type III-like repeat D (FnD) strongly affected physiological properties and morphology of both astrocytes and microglia in this injury model. The rate of microglial proliferation in the injury region decreased significantly with the addition of FnD. Additionally, density of microglia also decreased, in part due to reduced proliferation, and possibly due to reduced migration and increased contact inhibition between enlarged FnD-treated cells. Overall morphology of FnD-treated microglia resembled the activated pro-inflammatory cells, and elevated expression of iNOS was in accordance with this phenotype. The effect of FnD on astrocytes was different, as it did not affect their proliferation, but stimulated migration of reactivated astrocytes into the scratched area 48 h after the lesion. Elevated expression and secretion of TNF-alpha and IL-1 beta upon FnD treatment indicated the onset of inflammation. Furthermore, on Western blots we observed increased intensity of precursor bands of beta 1 integrin and appearance of monomeric bands of P2Y12R after FnD treatment which substantiates and clarifies its role in cellular shape and motility changes. Our results show versatile functions of TnC and in particular FnD after injury, mostly contributing to ongoing inflammation in the injury region. Based on our findings, FnD might be instrumental in limiting immune cell infiltration, and promoting astrocyte migration within the injury region, thus influencing spaciotemporal organization of the wound and surrounding area

Oligodendrocyte Development and the Onset of Myelination in the Human Fetal Brain

Oligodendrocytes are cells that myelinate axons, providing saltatory conduction of action potentials and proper function of the central nervous system. Myelination begins prenatally in the human, and the sequence of oligodendrocyte development and the onset of myelination are not thoroughly investigated. This knowledge is important to better understand human diseases, such as periventricular leukomalacia, one of the leading causes of motor deficit in premature babies, and demyelinating disorders such as multiple sclerosis (MS). In this review we discuss the spatial and temporal progression of oligodendrocyte lineage characterized by the expression of specific markers and transcription factors in the human fetal brain from the early embryonic period (5 gestational weeks, gw) until midgestation (24 gw). Our in vitro evidence indicated that a subpopulation of human oligodendrocytes may have dorsal origin, from cortical radial glia cells, in addition to their ventral telencephalic origin. Furthermore, we demonstrated that the regulation of myelination in the human fetal brain includes positive and negative regulators. Chemokines, such as CXCL1, abundant in proliferative zones during brain development and in regions of remyelination in adult, are discussed in the view of their potential roles in stimulating oligodendrocyte development. Other signals are inhibitory and may include, but are not limited to, polysialic acid modification of the neural cell adhesion molecule on axons. Overall, important differences in temporal and spatial distribution and regulatory signals for oligodendrocyte differentiation exist between human and rodent brains. Those differences may underlie the unique susceptibility of humans to demyelinating diseases, such as MS

The complexity of the calretinin-expressing progenitors in the human cerebral cortex

The complex structure and function of the cerebral cortex critically depend on the balance of excitation and inhibition provided by the pyramidal projection neurons and GABAergic interneurons, respectively.The calretinin-expressing (CalR+) cell is a subtype of GABAergic cortical interneurons that is more prevalent in humans than in rodents. In rodents, CalR+ interneurons originate in the caudal ganglionic eminence (CGE) from Gsx2+ progenitors, but in humans it has been suggested that a subpopulation of CalR+ cells can also be generated in the cortical ventricular/subventricular zone (VZ/SVZ). The progenitors for cortically generated CalR+ subpopulation in primates are not yet characterized. Hence, the aim of this study was to identify patterns of expression of the transcription factors (TFs) that commit cortical stem cells to the CalR fate, with a focus on Gsx2. First, we studied the expression of Gsx2 and its downstream effectors, Ascl1 and Sp8 in the cortical regions of the fetal human forebrain at midgestation. Next, we established that a subpopulation of cells expressing these TFs are proliferating in the cortical SVZ, and can be co-labeled with CalR. The presence and proliferation of Gsx2+ cells, not only in the ventral telencephalon (GE) as previously reported, but also in the cerebral cortex suggests cortical origin of a subpopulation of CalR+ neurons in humans. In vitro treatment of human cortical progenitors with Sonic hedgehog (Shh), an important morphogen in the specification of interneurons, decreased levels of Ascl1 and Sp8 proteins, but did not affect Gsx2 levels. Taken together, our ex-vivo and in vitro results on human fetal brain suggest complex endogenous and exogenous regulation of TFs implied in the specification of different subtypes of CalR+ cortical interneurons

Diversity of Cortical Interneurons in Primates: The Role of the Dorsal Proliferative Niche

Summary Evolutionary elaboration of tissues starts with changes in the genome and location of the stem cells. For example, GABAergic interneurons of the mammalian neocortex are generated in the ventral telencephalon and migrate tangentially to the neocortex, in contrast to the projection neurons originating in the ventricular/subventricular zone (VZ/SVZ) of the dorsal telencephalon. In human and nonhuman primates, evidence suggests that an additional subset of neocortical GABAergic interneurons is generated in the cortical VZ and a proliferative niche, the outer SVZ. The origin, magnitude, and significance of this species-specific difference are not known. We use a battery of assays applicable to the human, monkey, and mouse organotypic cultures and supravital tissue to identify neuronal progenitors in the cortical VZ/SVZ niche that produce a subset of GABAergic interneurons. Our findings suggest that these progenitors constitute an evolutionary novelty contributing to the elaboration of higher cognitive functions in primates

The long-term effects of maternal deprivation on the number and size of inhibitory interneurons in the rat amygdala and nucleus accumbens

IntroductionThere is an increasing evidence supporting the hypothesis that traumatic experiences during early developmental periods might be associated with psychopathology later in life. Maternal deprivation (MD) in rodents has been proposed as an animal model for certain aspects of neuropsychiatric disorders.MethodsTo determine whether early-life stress leads to changes in GABAergic, inhibitory interneurons in the limbic system structures, specifically the amygdala and nucleus accumbens, 9-day-old Wistar rats were exposed to a 24 h MD. On postnatal day 60 (P60), the rats were sacrificed for morphometric analysis and their brains were compared to the control group.ResultsResults show that MD affect GABAergic interneurons, leading to the decrease in density and size of the calcium-binding proteins parvalbumin-, calbindin-, and calretinin-expressing interneurons in the amygdala and nucleus accumbens.DiscussionThis study indicates that early stress in life leads to changes in the number and morphology of the GABAergic, inhibitory interneurons in the amygdala and nucleus accumbens, most probably due to the loss of neurons during postnatal development and it further contributes to understanding the effects of maternal deprivation on brain development

Embryonic Stem Cell-Derived L1 Overexpressing Neural Aggregates Enhance Recovery after Spinal Cord Injury in Mice

An obstacle to early stem cell transplantation into the acutely injured spinal cord is poor survival of transplanted cells. Transplantation of embryonic stem cells as substrate adherent embryonic stem cell-derived neural aggregates (SENAs) consisting mainly of neurons and radial glial cells has been shown to enhance survival of grafted cells in the injured mouse brain. In the attempt to promote the beneficial function of these SENAs, murine embryonic stem cells constitutively overexpressing the neural cell adhesion molecule L1 which favors axonal growth and survival of grafted and imperiled cells in the inhibitory environment of the adult mammalian central nervous system were differentiated into SENAs and transplanted into the spinal cord three days after compression lesion. Mice transplanted with L1 overexpressing SENAs showed improved locomotor function when compared to mice injected with wild-type SENAs. L1 overexpressing SENAs showed an increased number of surviving cells, enhanced neuronal differentiation and reduced glial differentiation after transplantation when compared to SENAs not engineered to overexpress L1. Furthermore, L1 overexpressing SENAs rescued imperiled host motoneurons and parvalbumin-positive interneurons and increased numbers of catecholaminergic nerve fibers distal to the lesion. In addition to encouraging the use of embryonic stem cells for early therapy after spinal cord injury L1 overexpression in the microenvironment of the lesioned spinal cord is a novel finding in its functions that would make it more attractive for pre-clinical studies in spinal cord regeneration and most likely other diseases of the nervous system