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

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