Safety of antipsychotic drugs: focus on therapeutic and adverse effects.

Review

Safety of antipsychotic drugs: focus on therapeutic and adverse effects 1.

Introduction

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Effects of second-generation and recently admitted

Expert Opin. Drug Saf. Downloaded from informahealthcare.com by University of Laval on 07/03/14 For personal use only.

antipsychotic drugs 3.

Safety evaluation of SGAs

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Conclusion

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Expert opinion

Felix-Martin Werner† & Rafael Covenãs †

University of Salamanca, Institute of Neurosciences of Castilla y Leoń (INCYL), Laboratory of Neuroanatomy of the Peptidergic Systems (Lab. 14), Salamanca, Spain

Introduction: Schizophrenia is a chronic psychiatric disease, which is treated by antipsychotic drugs. These drugs are mostly D2 and 5-HT2A antagonists and have extrapyramidal side effects depending on the D2 antagonistic effect. Recently admitted antipsychotic drugs also have systemic side effects. Clozapine, which has the strongest antipsychotic effect, can cause neutropenia. A problem in the treatment of schizophrenia is poor patient compliance leading to the recurrence of psychotic symptoms. Areas covered: A search was carried out in Medline using the following terms: antipsychotic drugs, antipsychotic effect, risperidone, olanzapine, clozapine, ziprasidone, aripiprazol, asenapine, questiapine, cariprazine, lurasidone, arrythmia, diabetes mellitus, weight gain, epileptic activity, extrapyramidal symptoms, sexual activity, clinical trials and tolerability. Expert opinion: Most clinical trials describe a good antipsychotic effect of the currently used antipsychotic drugs. The efficacy and safety of the antipsychotic drugs also depend on the form of schizophrenia, for example, the chronic recurrent form of schizophrenia. Clozapine and olanzapine have the safest therapeutic effect, while the side effect of neutropenia must be controlled by 3 weekly blood controls. If schizophrenia has remitted and if patients show a good compliance, the adverse effects can be controlled. The pharmacological treatment should be combined with social therapies and psychoeducation in order to reach a good therapeutic outcome. Keywords: aripiprazole, asenapine, cariprazine, clinical trial, clozapine, lurasidone, olanzapine, paliperidone, quetiapine, risperidone, side effects, tolerability, ziprasidone Expert Opin. Drug Saf. [Early Online]

1.

Introduction

Antipsychotic drugs, above all atypical antipsychotic drugs are prescribed for the treatment of chronic schizophrenia. After treatment of an acute psychosis, which becomes manifest with positive symptoms such as paranoia and hallucinations, a permanent medication with atypical antipsychotic drugs is necessary in most cases in order to prevent recurrence of psychotic symptoms [1]. In schizophrenia, dopamine hyperactivity via D2 receptors and serotonin hyperactivity via 5-HT2A receptors occur in the mesolimbic system and the hippocampus. In schizophrenia, some susceptibility genes, for example, neuregulin-1, dysbindin-1, glutamate decarboxylase 67, catechyl-O-methyl-transferase (COMT) and monoamine oxidase A/B have been reported [2]. It has not yet been examined in experimental or clinical studies whether there is or not an interaction between the altered neurotransmitters; this might be due to the risk genes. Dopamine hyperactivity could be due to a reduced function of enzymes degrading dopamine, for example, COMT or monoamine oxidase A/B [2].

10.1517/14740338.2014.935761 © 2014 Informa UK, Ltd. ISSN 1474-0338, e-ISSN 1744-764X All rights reserved: reproduction in whole or in part not permitted

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F.-M. Werner & R. Covenãs

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This paper reviews the safe antipsychotic effect and adverse effects, for example, extrapyramidal symptoms (EPS), metabolic side effects, changes of the prolactin levels and changes of the blood cell counts of conventional second-generation antipsychotic drugs. Risperidone which has a similar mechanism of action like typical neuroleptics has a safe antipsychotic effect and produces less EPS than haloperidol. Olanzapine has a superior antipsychotic effect than other second-generation antipsychotic drugs, above all on negative schizophrenic symptoms, although it has more severe metabolic side effects and produces more weight gain. Clozapine has the strongest antipsychotic effect, but neutropenia which occurs in 3% of the patients must be excluded through 3 weekly blood cell counts. The antipsychotic drugs such as lurasidone, asenapine and cariprazine have a safe antipsychotic effect and a promising adverse effect profile, but the effect in long-term treatments should still be investigated. The effect of the recently admitted antipsychotic drugs to improve cognitive function should be investigated in long-term treatments. It should be examined whether patients treated with two combined antipsychotic drugs, administered as an injectable depot form, show a lower tendency to discontinue the treatment and a better outcome.

This box summarizes key points contained in the article.

The treatment of a chronic schizophrenia has been performed with an injectable application of first-generation antipsychotic drugs, for example, haloperidol and fluphenazine which have a high affinity for the D2 receptor, but they do not interfere with the 5-HT2A receptor. Extrapyramidal symptoms (EPS) often occurred as a consequence of the strong D2 antagonistic effect [3]. Haloperidol and fluphenazine interfere also with adrenergic, cholinergic and histaminergic receptors, but the main antipsychotic effect is achieved through a D2 receptor blockade [2]. The commonly used second-generation antipsychotic drugs (SGAs) are risperidone, olanzapine and quetiapine [3]. Risperidone is a D2 and 5-HT2A antagonist, although it shows a higher affinity for the D2 receptor. Risperidone has fewer extrapyramidal side effects than the first-generation antipsychotic drugs, which are D2 antagonists and show no affinity for the 5-HT2A receptor [3]. Olanzapine and quetiapine, which are often administered, have a slightly different mechanism of action but have other side effects, for example, an increased insulin resistance [2]. If psychotic symptoms have not remitted, the antipsychotic drug clozapine is selected exerting an antipsychotic effect which is superior to that of other antipsychotic drugs [4]. Because clozapine can cause neutropenia in 3% of patients, a question must be addressed: how to deal with this side effect [4]. Clinical trials about the safety of other antipsychotic drugs such as ziprasidone and 2

aripiprazole and about the recently admitted antipsychotic drugs are discussed here. Among these antipsychotic drugs, cariprazine and lurasidone are worth mentioning because, due to a different mechanism of action, these drugs improve cognitive function [2,4].

Effects of second-generation and recently admitted antipsychotic drugs

2.

In the treatment of chronic schizophrenia, the most frequently used SGAs are risperidone, olanzapine and quetiapine [4]. Risperidone causes extrapyramidal side effects to a smaller extent than the first-generation antipsychotic drugs, which are D2 antagonists without interfering with serotonergic subreceptors [3]. Risperidone can be used for the treatment of chronic schizophrenia, autism, obsessive-compulsive disorder and against agitation in dementia [5]. Olanzapine blocks D2 and 5-HT2A receptors and has a lower ratio of the D2/5-HT2A receptors occupancy than risperidone and causes less often extrapyramidal side effects than risperidone. Olanzapine is prescribed for the long-term treatment of schizophrenia and for dementia, major depression and bipolar depression [5]. Quetiapine has an even lower affinity for the D2 receptor and a higher affinity for the 5-HT2A receptor than olanzapine and seldom causes EPS. Quetiapine is administered in patients suffering chronic schizophrenia or major depression and exerts a therapeutic effect in generalized anxiety disorders [4,5]. Clozapine, which exerts a D3, D4 and 5-HT2A antagonistic effect, has a stronger antipsychotic effect than other SGAs [4]. Clozapine is administered when psychotic symptoms have not remitted after treatment with other antipsychotic drugs. Extrapyramidal side effects occur very seldom [2]. Ziprasidone is a D2 and 5-HT2A antagonist with a preference for the D2 receptor; it exerts a 5-HT1A agonistic effect and has therefore good antipsychotic and antidepressant effects. Aripiprazole with a different mechanism of action has a D2 partial agonism and a strong 5-HT2A antagonistic effect. Therefore, aripiprazole has antipsychotic and antidepressant properties and can be administered in patients with dementia [2,5]. Aripiprazole often causes gait disturbances, for example, akathisia [5]. Among the recently admitted antipsychotic drugs, details about their mechanisms of action and their therapeutic effects are presented here for asenapine, lurasidone and cariprazine. Asenapine is a drug with a D2 and 5-HT2A antagonistic effect and has comparable antipsychotic effects like olanzapine [6]. Apart from the antipsychotic effect, it improves cognitive function [6]. Lurasidone is an antipsychotic drug, which has a D2 and 5-HT2A antagonistic effect, a 5-HT1A agonistic effect and a 5-HT7 antagonistic effect [7]. Lurasidone, as a consequence of its mechanism of action, has a good antipsychotic and antidepressant effect and improves cognitive function. Clinical trials have been carried out to investigate whether lurasidone has comparable therapeutic effects and a good tolerability compared with conventional antipsychotic drugs [8].

Expert Opin. Drug Saf. (2014) 13(8)

Safety of antipsychotic drugs

Besides, it is worth mentioning that the recently admitted antipsychotic drug cariprazine shows a 5-HT1A agonism and a partial agonism at D2 and D3 receptors. Clinical trials have been undertaken in order to know whether it exerts comparable antipsychotic effects and a good tolerability like other antipsychotic drugs. Because of its mechanism of action, cariprazine can be used to treat major depression and bipolar disorders [2,9].


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Safety evaluation of SGAs

The safety of the SGAs, such as risperidone, olanzapine and quetiapine and recently admitted antipsychotic drugs, has been investigated in clinical trials [3,5]. In these trials, the question is addressed whether these antipsychotic drugs have a significant therapeutic effect in the treatment of an acute psychosis and whether they can be applied for a maintenance treatment in order to prevent recurrence of psychotic symptoms [10]. In this sense, it has been examined if long-acting injectable applications of the antipsychotic drugs are available and if they enable a safe maintenance treatment [11]. This application is important because the often lacking patients’ compliance can lead to a recurrence of psychotic symptoms. Besides, it must be considered which effects the antipsychotic drugs have on the cognitive function and whether they cause sedation [9]. A question will be answered, whether the antipsychotic drugs cariprazine and lurasidone have a positive effect on cognitive function [9,10]. Disabling side effects of the antipsychotic drugs are EPS, above all akathisia. The occurrence of this side effect can be explained through the mechanism of action indicated above. A question will be answered, whether its frequency can be reduced by the recently developed antipsychotic drugs [3]. Although clozapine has an antipsychotic effect, which is higher than other antipsychotic drugs, its application is limited by the neutropenia, induced in 3% of the patients. Clinical trials about the safety of clozapine will be mentioned. The SGAs have other disturbing side effects, such as liver and kidney damage, cardiac side effects, insulin resistance and weight gain [4]. Another important issue will be addressed if pharmacotherapy combined with psychoeducation has a positive influence on the outcome of the disease [12]. Second-generation antipsychotic drugs Decrease of positive and negative syndrome total score

3.1

3.1.1

Risperidone is a drug which exerts its antipsychotic effect mainly via the D2 receptor [2]. In order to assess the antipsychotic effect of antipsychotic drugs, the Positive and Negative Syndrome Scale (PANSS) total score was performed in some clinical studies [13]. The PANSS total score was found to be 91.6 before treatment with haloperidol and 91.1, when the antispychotic drugs risperidone, olanzapine, ziprasidone and paliperidone were administered. The Emax of risperidone was 0.23 compared to olanzapine, 0.39. The effective dose

of risperidone was 0.8 mg/day with a 30% decrease of the PANSS total score compared with baseline and with an effective concentration of 5.2 ng/ml, that is, the minimal serum level to achieve a therapeutic effect [13]. If the changes of the PANSS total score in the pharmacokinetic-pharmacodynamic model of the antipsychotic drugs haloperidol, risperidone and olanzapine are compared, the following findings are worth to be mentioned: olanzapine leads to a stronger decrease in the PANSS total score than haloperidol and risperidone. Risperidone has a comparable effect upon positive schizophrenic symptoms like haloperidol and has a weaker therapeutic effect upon negative schizophrenic symptoms than olanzapine [14]. A decrease in 20% of negative symptoms can be found with a concentration of 42.1 ng/ml of risperidone in comparison to olanzapine (4.9 ng/ml) [14]. This could be explained by the fact that risperidone has a higher ratio of the D2/5-HT2A receptor occupancy than olanzapine and that olanzapine has a faster dissociation from D2 and 5-HT2A receptors [14]. Paliperidone was approved as a monotherapy for the treatment of schizophrenia and for the treatment of schizoaffective disorder and as an adjunctive therapy with mood stabilizers and/or antidepressants [15]. Paliperidone is the active metabolite of risperidone and is available as an oral extended-release form or as a long-acting injectable form, the paliperidone palmitate [15]. The recommended daily dose of paliperidone extended-release is 6 mg/day and can be increased to 12 mg/day; by increasing the dosage, an additional therapeutic effect can be obtained, but dose-related adverse effects can also increase. The terminal half-life is ~ 23 h. The main elimination is by renal excretion, and it is quite different from that of risperidone; so that, paliperidone is recommended in patients with a liver disease [15]. Paliperidone exerts the antipsychotic effect through the same mechanism of action like risperidone, because it is the active metabolite of risperidone. Administering these doses of paliperidone, a comparable decrease in the PANSS score is achieved, like administering risperidone [14]. Paliperidone has a comparable effect upon positive schizophrenic symptoms like risperidone; however, it has a weaker therapeutic effect upon negative schizophrenic symptoms than olanzapine [14]. Paliperidone needs a plasma concentration of 9.8 ng/ml to achieve a 30% decrease in the PANSS total score in comparison to risperidone, which requires 5.3 ng/ml. A decrease in 20% of negative symptoms can be found with a concentration of 30.0 ng/ml of paliperidone in comparison to risperidone (42.1 ng/ml) and to olanzapine (4.9 ng/ml) [14]. Olanzapine is a SGA which exerts an antipsychotic effect and shows a lower affinity for the D2 receptor and a higher affinity for the 5-HT2A receptor than risperidone [2]. The effect of olanzapine on positive and negative schizophrenic symptoms has been examined in a meta-analysis [13,14]. The effective concentration required to obtain a 30% decrease of the PANSS score compared to baseline is 13.8 ng/ml, and the effective dose per day is 7.3 mg in comparison to


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risperidone with 0.8 mg/day [13]. The maximum drug effect, that is, the Emax of olanzapine on the PANSS-positive subscale is 0.43 compared to risperidone, 0.32, and the Emax of the PANSS negative subscale is 0.33 compared to risperidone, 0.14. The Emax of olanzapine in the PANSS general subscale is 0.34 compared to other antipsychotic drugs like haloperidol (0.27), risperidone (0.19), ziprasidone (0.12) and paliperidone (0.24) [14]. Consequently, olanzapine has a stronger antipsychotic effect compared to other antipsychotic drugs and exerts a stronger therapeutic effect on negative schizophrenic symptoms as a consequence of its high affinity for the 5-HT2A receptor [2]. Quetiapine is a SGA with an even lower affinity for the D2 receptor and a higher affinity for the 5-HT2A receptor than olanzapine [2]. It has been examined in a randomized clinical trial of 156 patients suffering from first-episode schizophrenia. Seventy-eight patients were daily administered with 705 mg of quetiapine and the other 78 patients were daily administered with 14 mg of haloperidol [16]. In the course of the treatment, the authors examined the PANSS score and the Global Assessment of Functioning (GAF) scale for overall psychosocial functioning [16]. Quetiapine had significant better PANSS positive and negative scores than haloperidol; however, both antipsychotic drugs showed no differences in the total PANSS score and in the GAF score [16]. Ziprasidone is an antipsychotic drug which mechanism of action has been described above. It has antipsychotic and antidepressant properties [2]. The effective concentration to achieve a 20% decrease in the total PANSS score is 15.6 ng/ml in comparison to olanzapine with 4.89 ng/ml. A 20% decrease in the PANSS-positive subscale can be obtained at an effective concentration of 8.70 ng/ml, and a 20% decrease in the PANSSnegative subscale can be achieved at an effective concentration of 82.8 ng/ml [14]. The therapeutic effect of ziprasidone on negative schizophrenic symptoms is weaker than that of olanzapine. The antipsychotic effect of ziprasidone on the PANSS score is comparable to that of risperidone [14]. Clozapine is an antipsychotic drug which can be administered if other antipsychotic drugs did not exert a sufficient antipsychotic effect [2,4]. Among the treatment-resistant schizophrenic patients, 30% of them respond after 6 weeks to clozapine administration, another 20% after 3 months and another 10 -- 20% after 6 months. The side effects, for example, neutropenia which occurs in 3% of patients and agranulocytosis which occurs in 0.8% of patients can be managed by reducing the daily dosage [4]. It has been reported in a meta-analysis carried out in a Chinese population suffering schizophrenia that clozapine achieved a 55.4% decrease in the total PANSS score with half of the Emax., for example, 296 mg/day [17]. The antipsychotic effect of clozapine which is superior to that of other SGAs can be explained by its mechanism of action. Clozapine has a high affinity for the 5-HT2A receptor and it interferes with other dopaminergic subreceptor than the D2 receptor, namely with the D3 and D4 receptors [4]. The blockade of D4 receptors stabilizes D2 dopaminergic 4

neurons in the hippocampus, because in this region D4 dopaminergic neurons exert a postsynaptic excitatory impulse upon D2 dopaminergic neurons [2]. Aripiprazole is a SGA with a different mechanism of action, which it has been pointed out in a previous section. It has a good antipsychotic effect through the 5-HT2A antagonistic effect, which is not weakened by the D2 partial agonism. Besides, it exerts antidepressant properties through the 5-HT1A agonistic effect [2]. It has been performed a meta-analysis about the safety and tolerability of aripiprazole in schizophrenic patients in comparison to other SGAs such as clozapine, quetiapine, risperidone, ziprasidone and olanzapine, and it has been reported that aripiprazole led to a comparable decrease in the PANSS total score like the other antipsychotic drugs but that patients obtaining aripiprazole had a better quality of life [18]. In a clinical trial with 59 patients suffering a first-episode schizophrenia, aripiprazole achieved an at least 20% decrease in the PANSS total score after 3 weeks [19]. Lurasidone is a drug with an additional antagonistic effect at the 5-HT7 receptor. It exerts a good antipsychotic and antidepressant effect and improves cognitive functions as a consequence of the blockade of 5-HT7 receptors in the hippocampus [2]. It has been performed a clinical study with 198 schizophrenic or schizoaffective out-patients treated with lurasidone [20]. From the 198 out-patients, 98 patients obtained the study medication. It was found that the most frequent adverse effects were insomnia, nausea, akathisia and anxiety [20]. The dosage of lurasidone was 40, 80 or 120 mg/day. According to this study, adverse effects such as weight gain, glucose or cholesterol increases or hyperprolactinemia were not observed. No meaningful disorders were seen in schizophrenic patients [20]. The PANSS, Clinical Global Impressions-Severity and the calgary depression scale for schizophrenia decreased in all participating patients compared to baseline scores. These results demonstrate that lurasidone exerts a good antipsychotic and antidepressant effect [20]. Asenapine is a recently admitted antipsychotic drug, which in addition to its antipsychotic effect, improves cognitive functions [2]. It has been performed a pooled, post-hoc analysis with schizophrenic patients treated with asenapine, olanzapine, risperidone, haloperidol or placebo. The PANSS score was defined at weeks 2 and 6 [21]. It was found that all antipsychotic drugs, except olanzapine which had a higher effect, had a decrease in 20% in the PANSS score in the second week of treatment and caused a remission of psychotic symptoms in the sixth week with a further decrease in the PANSS score [21]. In another study, it was compared the effect of asenapine and olanzapine on negative schizophrenic symptoms on evaluating two 26-week core studies and extensions and found that there were no differences between asenapine and olanzapine in reducing persistent negative symptoms, but that asenapine had a superior effect compared to olanzapine in improving negative schizophrenic symptoms in the extension study [22]. In a pooled meta-analysis about the treatment of acute




schizophrenia, it has been compared the effect of asenapine and other SGAs on the PANSS score. Asenapine had a superior effect compared to placebo, had a greater decrease in the PANSS score than ziprasidone, but exerted a smaller effect than olanzapine [23]. Moreover, it has been found in two randomized, controlled trials of asenapine monotherapy that asenapine had a decrease in the negative symptom assessment-16 total score comparable to olanzapine [24]. Cariprazine is a new antipsychotic drug with a partial agonism at D2 and D3 receptors, although shows a preference for the D3 receptor [25]. Doses of more than 1.5 mg/day achieve a D2/D3 receptor occupancy of at least 75%, as it was measured by positron emission tomography [25]. Besides, cariprazine has a 5-HT1A agonism and exerts an antidepressant effect in addition to the antipsychotic effect [2]. Four Phase II and III clinical trials were performed, and cariprazine achieved a superior effect than placebo and led to decrease in the PANSS total score at doses of 1.5, 3.0, 4.5, 6.0 and 9.0 mg/day [26]. It has been performed a double-blind, randomized, placebo- and active-controlled clinical trial in patients with exacerbation of schizophrenia [27]. The patients obtained 1.5, 3.0 or 4.5 mg of cariprazine per day, 4.0 mg risperidone per day or placebo for 6 weeks and a safe dose of an effective antipsychotic drug for 2 weeks. Of the 732 included patients, 64% completed the study. In this period, the decrease in the PANSS score was measured. During the 6 weeks, the PANSS score improvement for patients obtaining 1.5 cariprazine per day, 3.0 cariprazine per day and 4.5 cariprazine per day was -7.6, -8.8 and -10.4, respectively, p < 0.001, whereas this value in the patients treated with 4.0 mg risperidone per day was at 15.1, p < 0.001 [27]. The observed adverse effects were identical to those reported by other authors [25,26]. In sum, among the antipsychotic drugs, olanzapine shows a higher effect than other SGAs, above all upon negative schizophrenic symptoms. Asenapine is a recently admitted antipsychotic drug which has a comparable antipsychotic effect like olanzapine. Risperidone, quetiapine and ziprasidone have similar antipsychotic properties. Aripiprazole has a good antipsychotic effect and offers a good quality of life. Clozapine can be used in treatment-resistant schizophrenia; however, the adverse effects must be considered. The long-term effect of lurasidone and cariprazine should still be examined.

ameliorated in the course of the treatment by decreasing the dose [2,3]. Because paliperidone has a comparable mechanism of action like risperidone, it can cause EPS to the same extent like risperidone [2]. Because olanzapine has a weaker affinity for the D2 receptor than risperidone and paliperidone, it causes EPS less seldom and to a smaller extent than these antipsychotic drugs [2,3]. It is worth mentioning as well that quetiapine had less seldom and fewer extrapyramidal side effects than haloperidol as a consequence of its preference for the 5-HT2A receptor, which counteracts the D2 antagonistic effect that takes place in the putamen [16]. Ziprasidone can cause extrapyramidal side effects, but to a smaller extent than risperidone. Clozapine very seldom and to a small extent causes extrapyramidal side effects, because it does not block D2 receptors in the extrapyramidal system [4,28]. Patients treated with aripiprazole achieved a better Brief Psychiatric Rating Scale score and had fewer EPS than risperidone [18]. This reduced side effect can be explained by the partial D2 agonism [2]. The two most commonly observed side effects of lurasidone were akathisia in 13% of the patients and insomnia in 11% of them [29]. The adverse effects such as EPS, hyperprolactinemia, weight gain and increases of glucose and lipid levels were found to be low [24]. It has been examined 67 articles about the safety of asenapine, and it was found that asenapine had comparable antipsychotic effects like other antipsychotic drugs in the treatment of schizophrenia and bipolar disorder [30]. The most common adverse effects were found to be somnolence in 13 -- 24% of patients, EPS in 7 -- 12% of patients and dizziness in 11% of them [30]. In clinical trials, cariprazine was revealed to have a superior therapeutic effect in schizophrenia and bipolar mania and caused the following side effects: insomnia, EPS, akathisia, sedation, nausea, dizziness and constipation [25]. In sum, among the SGAs, risperidone and paliperidone cause EPS to a high extent. However, antipsychotic drugs like olanzapine, quetiapine, ziprasidone and aripiprazole have extrapyramidal side effects to a smaller extent. Clozapine has few EPS. Lurasidone and cariprazine lead to akathisia in 11% of patients.

Extrapyramidal symptoms Because risperidone exerts a strong D2 antagonistic effect, it can cause EPS if the D2 receptor occupancy exceeds 80% [2]. Risperidone has a lower risk for EPS than first-generation antipsychotic drugs, such as haloperidol, because risperidone has a faster dissociation from the D2 receptor and because it interferes with the 5-HT2A receptor, but it has a higher risk for EPS than olanzapine [3]. However, risperidone has stronger extrapyramidal side effects than other SGAs as a consequence of its high affinity for the D2 receptor. As some patients need an antipsychotic drug exerting this antidopaminergic effect, the extrapyramidal side effect could be

3.1.3

3.1.2

Metabolic and cardiac side effects The question whether risperidone can cause cardiovascular adverse effects was studied in a post-hoc analysis [31]. Thus, observed symptoms were syncope through the a1 noradrenergic antagonistic effect, tachycardia, palpitations, peripheral edema and transient ischemic attack, while the incidence of death related to a cardiovascular disease was comparable to that found in the control group [31]. Rummel-Kluge et al. [32] included 48 studies about the metabolic side effects of the SGAs and performed a metaanalysis. The side effects to be examined were as follows: weight gain, hyperlipidemia and glucose increase [32]. These


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authors found that risperidone produces weight gain, less severely than clozapine, olanzapine and quetiapine but more severely than ziprasidone and aripiprazole [32]. Risperidone can cause an increase in glucose, but less severely than aripirazole, clozapine and olanzapine, and to the same extent than quetiapine; in this aspect, only ziprasidone has a more favorable effect [32]. Regarding the metabolic side effects, paliperidone can cause weight gain, but less severely than clozapine, olanzapine and quetiapine [32]. Paliperidone can cause an increase in glucose and cholesterol to the same extent like risperidone [32]. It has been examined a Swedish cohort of 809 schizophrenic patients treated with 10 different antipsychotic drugs and studied metabolic parameters such as hyperglycemia, hypertriglyceridemia, high-density lipoprotein (HDL) levels, hypertension and waist circumference [33]. According to these examinations, a metabolic syndrome occurred in 17% of patients taking olanzapine and risperidone, in 9% of patients taking clozapine and in 3% of patients taking ziprasidone [33]. Among the patients taking antipsychotic drugs, 34% of patients suffered from hyperglycemia, 40% from hyperlipidemia and 61% of patients had an elevated blood pressure [33]. Consequently, schizophrenic patients treated with olanzapine showed increased cardiovascular risk factors, because they also have a significantly reduced HDL level [33]. According to the meta-analysis conducted by Rummel-Kluge et al. [32], olanzapine leads to weight gain in the same extent like clozapine, but stronger than other antipsychotic drugs like risperidone, aripiprazole, quetiapine or ziprasidone. Olanzapine causes a stronger increase in cholesterol than the above-mentioned antipsychotic drugs. Besides, olanzapine causes a stronger increase in glucose than the above-mentioned antipsychotic drugs, except clozapine [32]. Although olanzapine exerts a strong antipsychotic effect, it causes metabolic side effect that must be considered by the physician [32,33]. Due to the metabolic side effects, quetiapine causes weight gain and produces an increase in glucose to the same extent than risperidone, ziprasidone and clozapine and significantly less severely than olanzapine. There are no differences in the increase of cholesterol between quetiapine and risperidone as well as between quetiapine and ziprasidone. The increase of cholesterol due to olanzapine is significantly higher than that of quetiapine [32]. According to a meta-analysis, a metabolic syndrome occurs in only 39% of the patients treated with quetiapine [33]. Regarding to the metabolic side effects of ziprasidone, a metabolic side effect occurred in 43% of the treated patients in comparison to olanzapine (54%) [33]. Ziprasidone causes less weight gain than olanzapine; no differences in this aspect were seen between ziprasidone and quetiapine or risperidone [32]. Ziprasidone produces a smaller increase in cholesterol than risperidone, olanzapine and quetiapine [32]. The increase in glucose of ziprasidone is smaller than in the treatment with olanzapine, no difference in this metabolic side effect was observed in the treatment with ziprasidone compared to that of risperidone and quetiapine [32]. 6

Clozapine causes metabolic side effects in 45% of the treated patients [33]. Clozapine leads to weight gain to the same extent like olanzapine; however, this side effect is more severe compared with the treatment with risperidone and quetiapine [32]. Clozapine causes a larger increase in cholesterol than risperidone; no differences in this side effect were seen in comparison to the treatment with olanzapine [32]. The increase in glucose is more severe than in the treatment with olanzapine and risperidone [32]. Like olanzapine, clozapine can lead to an insulin resistance [2,32]. According to the metabolic side effects, aripiprazole causes weight gain to a smaller extent than olanzapine and risperidone [32]. The increase in cholesterol and glucose levels in patients treated with aripiprazole are smaller than those reported in patients treated with olanzapine [32]. It has been performed a 6-week, double-blind, placebocontrolled study with lurasidone at a dose of 40 or 120 mg once daily or olanzapine at a dose of 15 mg once daily in schizophrenic patients, which was extended to a 6-month, open-label extension study [29]. Of 254 patients, 133 (44.5%) performed the whole study. During this trial, patients receiving lurasidone experienced decreases in weight and in lipid levels (total cholesterol: - 6.5 mg/100 ml; triglycerides: - 8.5 mg/100 ml), and patients treated with olanzapine had a smaller decrease of weight and lipid levels, whereas patients who were treated with lurasidone in the 6-week, double-blind study and during its continuation, as well in the 6-month extension study had minimal changes in these parameters [29]. It has also been examined 17 asenapine trials and it was studied the effect of asenapine on metabolic parameters and the weight in comparison with placebo and olanzapine groups [34]. The authors found that in the treatment of schizophrenia and bipolar disorder, asenapine produced weight gain and an increase in glucose and total cholesterol, which was greater than in the placebo group, but smaller than in the olanzapine group. Metabolic side effects, an increase in prolactin or an increased QT interval in the electrocardiogram were not observed [26]. Metabolic and cardiac side effects occur during the treatment with antipsychotic drugs. The SGAs risperidone, paliperidone, quetiapine and ziprasidone cause an increase in glucose and cholesterol to the same extent. The metabolic side effects found during the treatment with olanzapine and clozapine were more severe than those found during the treatment with other antipsychotic drugs. Lurasidone and asenapine had more favorable results in this regard than olanzapine. Blood pressure was seen to be elevated, as well as cardiac side effects (e.g., a ST segment prolongation was observed). Hyperprolactinemia Hyperprolactinemia is a side effect which occurs during the treatment with some SGAs; however, some SGAs are prolactin-sparing antipsychotic drugs. This dysfunction is also due to the D2 antidopaminergic effect exerted, above all 3.1.4




of risperidone [35]. Prolactin is synthesized in the lactotroph cells of the anterior pituitary gland and its synthesis is controlled by D2 receptors. A blockade of these receptors removes the dopaminergic inhibition of prolactin synthesis and leads to increased prolactin levels [36]. In a cohort of 617 Chinese psychiatric patients with four different diagnoses, hyperprolactinemia was found in 59.6% of schizophrenic patients [35]. Hyperprolactinemia was less often found in schizophrenic patients treated with clozapine and aripirprazole [35]. As a consequence of the strong D2 antagonistic effect, paliperidone can as well lead to hyperprolactinemia, which can be found in 59.6% of the schizophrenic patients [25]. Hyperprolactinemia is an adverse effect in schizophrenic patients treated with antipsychotic drugs which is often neglected. Eighteen per cent of men and 47% of women treated with an antipsychotic drug showed prolactin levels above the normal range [36]. However, it seems that the faster the antipsychotic-drug dissociates from D2 receptors, the lesser an increase in prolactin and hence a less severe hyperprolactinemia appears [36]. Olanzapine belongs to the prolactin-sparing antipsychotic drugs. Thus, the treating physician must examine symptoms like sexual dysfunction, gynecomestia and infertility in men and amenorrhea and galactorrhea in women [36]. It is impossible to treat hyperprolactinemia using a D2 agonist, because this treatment would worsen the mental illness [36]. Among the SGAs, quetiapine is a prolactin-sparing antipsychotic drug, that is, it does not raise prolactin levels as a consequence of the weak D2 antagonistic effect. In a double-blind, 12-week trial, treatment-resistant schizophrenic patients were treated with either risperidone, quetiapine or fluphenazine. The patients taking quetiapine were the only group showing normal levels of prolactin and had the greatest benefit among these drugs regarding sexual functioning [37]. In contrast to the antipsychotic treatment with risperidone, patients administered with clozapine have a low serum level of prolactin. These patients have a significant lower incidence of sexual dysfunction compared to patients treated with haloperidol or risperidone [35]. Because clozapine does not block D2 receptors, the dopaminergic effect inhibiting prolactin release is not decreased [35]. As ziprasidone is a prolactin-sparing antipsychotic drug, hyperprolactinemia occurs but only in a small number of treated patients [19]. Aripiprazole is a prolactin-sparing antipsychotic drug, and as a consequence of its partial D2 agonism, prolactin levels are not increased [35]. Patients administered with lurasidone had minimal changes in prolactin levels. Metabolic side effects, an increase in prolactin or an increased QT interval in the electrocardiogram were not observed [26]. Asenapine and cariprazine are as well prolactin-sparing antipsychotic drugs [36]. In sum, hyperprolactinemia occurs in about half of the patients treated with antipsychotic drugs. Risperidone and paliperidone raise prolactin levels, but clozapine and aripiprazole do not raise these levels. The SGAs olanzapine, quetiapine, ziprasidone and the recently admitted SGAs lurasidone,

asenapine and cariprazine only increase prolactin concentrations to a small extent and in a small number of patients. Liver and kidney damage Risperidone can cause liver damage. A disturbed liver function was found in 10% of the schizophrenic patients receiving a risperidone long-acting injectable depot [38]. Compared to other antipsychotic drugs such as olanzapine, quetiapine and ziprasidone, risperidone has less metabolic side effects than olanzapine and quetiapine and causes less often weight gain than olanzapine. The administration of paliperidone should be preferred rather than that of risperidone, if patients suffer from a liver disease [15]. Olanzapine has a liver metabolism and when liver function is impaired the concentration of olanzapine is unchanged [39]. The main excretion of olanzapine is through the kidneys. If the renal function is impaired, the renal clearance would be reduced. In this case, the dose of olanzapine should be reduced taking into consideration that schizophrenic symptoms do not worsen [39]. Quetiapine has a liver metabolism and is excreted through the kidney [39]. A liver impairment does not alter the serum level of quetiapine; however, a renal impairment augments quetiapine serum concentration so that the dosage must be reduced [39]. 3.1.5

Neutropenia and agranulocytosis Neutropenia and agranulocytosis is a serious side effect in the treatment of schizophrenic patients with clozapine. The administration of clozapine should be restricted to patients with a treatment-resistant form of schizophrenia. In order to find out neutropenia in these patients, a 3 weekly white cell count should be performed. In the case of clozapine discontinuation, the psychotic symptoms can get worse again. It has been reviewed patients’ histories showing that a clozapine continuation can be achieved after administration of granulocyte colony-stimulating factors, which increases the number of matured granulocytes within the bone marrow [40]. On controlling the white cell count, the physician can use clozapine in treatment-resistant schizophrenic patients, because clozapine exerts a higher antipsychotic effect than other SGAs and because it shows significantly fewer EPS [2,4,40]. Agranulocytosis can occur as an adverse effect in the treatment with other antipsychotic drugs than clozapine. In a population-based cohort study in Sweden from 2006 till 2009, agranulocytosis was observed only in 23 patients [41]. 3.1.6

Summary of the safe and adverse effects of antipsychotic drugs

3.1.7

Risperidone is available as a long-acting injectable antipsychotic, namely risperidone microspheres [11]. Risperidone has a good safety and tolerability, and the post-injection delirium/ sedation syndrome only occurs with a frequency of 5 -- 7%, in the treated patients, versus 3% of the patients receiving placebo [11]. Outpatient medication compliance is enhanced during treatment with long-acting injectable risperidone


7



compared to orally administered risperidone [42]. Paliperidone is available as a long-injection form, namely paliperidone palmitate in order to ensure the patients’ often lacking compliance [15]. If the treating physician takes into consideration the adverse effects, olanzapine is a safe antipsychotic drug with a good therapeutic effect [2]. Quetiapine is a safe antipsychotic drug with fewer movement disturbances and metabolic side effects in comparison to other SGAs and in addition it is a prolactinsparing antipsychotic drug [2,32,37]. It can be concluded that in first-episode schizophrenia quetiapine has greater efficacy on positive and negative schizophrenia symptoms and fewer extrapyramidal side effects than haloperidol [16]. As ziprasidone is a prolactin-sparing antipsychotic drug, hyperprolactinemia occurs but only in a small number of treated patients [19]. The discontinuation in the treatment of first-episode schizophrenia with ziprasidone occurred in a lower number of patients than in those treated with quetiapine, but occurred more often than those treated with aripiprazole [43]. Aripiprazole is a safe antipsychotic drug with fewer metabolic side effects and fewer movement disturbances than risperidone and olanzapine and offers a good quality of life [18,44]. A decrease in the PANSS total score was observed at -- 8.7 in patients treated with lurasidone after a 6-month treatment [29]. From these findings, it can be concluded that lurasidone is a safe and well-tolerated antipsychotic drug which decreases the PANSS total score and shows fewer metabolic side effects than olanzapine [29]. From the abovementioned studies, it can be concluded that asenapine has a comparable antipsychotic effects like olanzapine and that it decreases the negative schizophrenic symptoms at the same extent like olanzapine, but the metabolic side effects were smaller than those observed in the olanzapine group [21-24,30,34]. Consequently, cariprazine is a safe antipsychotic drug which is effective in the treatment of schizophrenia and which has a good profile of adverse effects [25-27]. Combination of antipsychotic drugs If a patient with a first-episode of schizophrenia does not respond to the treatment with a single antipsychotic drug, the dose of the antipsychotic drug can be increased. If the treatment resistance still exists, an antipsychotic drug with another receptor-binding profile can be chosen. An alternative is to administer clozapine which shows a high antipsychotic effect. In some cases, two antipsychotic drugs showing a different affinity for dopaminergic and serotonergic subreceptors are administered, for example, risperidone and quetiapine. Both antipsychotic drugs are D2 and 5-HT2A antagonists, although risperidone has a higher affinity for the D2 receptor and quetiapine for the 5-HT2A receptor [45]. It has been carried out a nationwide study in Hungary, and it was compared the monotherapy and polypharmacy treatments in schizophrenia [46]. Two groups were formed. The patients of the first group received an antipsychotic drug and then they were switched to another antipsychotic drug after 60 days. The second group was treated with a monotherapy for 60 days and then treated 3.2

8

with two antipsychotic drugs after this period. The authors of the study examined the discontinuation rate in both groups and found in monotherapy and polypharmacy the following discontinuation median times: 192 and 100 days for aripiprazole; 222 and 86 days for olanzapine; 176 and 91 days for quetiapine; and 157 and 93 days for risperidone. Although a combination of antipsychotic drugs leads to faster discontinuation rates, it has a smaller likelihood of hospitalization and mortality and it is more efficacious against the exacerbation of the psychotic symptoms. A way to reduce the high discontinuation rate is to administer an injectable depot form of the combined antipsychotic drugs [46]. 4.

Conclusion

Among the conventional antipsychotic drugs, risperidone decreases the PANSS score like haloperidol but improves the negative schizophrenic symptoms less than olanzapine. As described above, risperidone often causes EPS and hyperprolactinemia. It causes weight gain and metabolic side effects less severely than olanzapine and clozapine. Paliperidone has similar antipsychotic and adverse effects like risperidone, but it can be administered instead of risperidone if the liver function is impaired, because it is excreted mainly through the kidneys. Olanzapine has a superior antipsychotic effect and improves better negative schizophrenic symptoms than other antipsychotic drugs. It causes less seldom EPS due to its mechanism of action. However, it causes metabolic side effects and weight gain to a larger extent than risperidone, aripiprazole, quetiapine or ziprasidone. Due to its mechanism of action, olanzapine is a prolactin-sparing antipsychotic drug. Quetiapine has a better antipsychotic effect than haloperidol as a consequence of the strong 5-HT2A antagonistic effect and seldom causes EPS. It leads to metabolic side effects and weight gain like risperidone, but less severely than olanzapine. In the treatment with quetiapine, sexual dysfunction occurs seldom. Ziprasidone is a safe antipsychotic drug and also has an antidepressant effect. It seldom has extrapyramidal side effects and causes more metabolic side effect than risperidone and olanzapine. Hyperprolactinemia is described in a small number of patients. Clozapine has the strongest antipsychotic effect among the antipsychotic drugs and very seldom causes EPS, because it blocks other dopaminergic subreceptors than D2 receptors. It increases glucose and cholesterol levels and causes weight gain like olanzapine but does not increase prolactin levels. In order to diagnose patients with neutropenia which occurs in 3% of them, blood cell count should be taken every 3 weeks. Aripiprazole has different mechanisms of action. It has a similar antipsychotic effect like other antipsychotic drugs and exerts an antidepressant effect. EPS occurs very seldom and patients do not suffer sexual dysfunction. It causes metabolic side effects and weight less than risperidone and olanzapine. Among the recently admitted antipsychotic drugs, we have mentioned lurasidone, asenapine and cariprazine.




Lurasidone has a comparable antipsychotic effect like other SGAs, exerts antidepressant properties and improves cognitive functions. The metabolic side effects and changes in the prolactin levels are minimal. Akathisia occurs in 11% of the patients. Asenapine has an antipsychotic effect, improves negative schizophrenic symptoms like olanzapine and also improves cognitive functions. Metabolic side effects, EPS and changes in the prolactin levels were found to be low. As previously mentioned, cariprazine has a different mechanism of action. It decreases the PANSS total score; however, the long-lasting antipsychotic effect should be investigated in clinical trials. Metabolic side effects, weight gain and changes in the prolactin levels were not observed. EPS occurs infrequently. When two antipsychotic drugs are combined in a firstepisode of schizophrenia, the discontinuation rate is higher than when a monotherapy treatment was chosen. However, patients treated with that medication have a lower risk of mortality and hospitalization. A question arises, whether the combined antipsychotic drugs should be administered in an injectable depot form. In order to maintain a continuous decrease in the PANSS total score, it would be favorable to continue the treatment with two antipsychotic drugs administered in an injectable depot form. In conclusion, the mentioned antipsychotic drugs are safe and tolerable drugs for long-term treatment of schizophrenia. However, clinical trials on the long-term efficacy in the treatment of schizophrenic patients with lurasidone, asenapine and above all with cariprazine should still be carried out. Clozapine and olanzapine have a superior therapeutic effect and more side effects. The side effects should be observed, and if clozapine is administered, a regular blood cell count is necessary. 5.

Expert opinion

The described antipsychotic drugs are essential for the treatment of schizophrenia. The SGAs are safe and tolerable drugs, but the followings aspects should still be considered. As most schizophrenic patients show a recurrence of positive and negative psychotic symptoms, clinical trials should be carried out for a period of some years in order to know whether psychotic symptoms are treated sufficiently or whether these symptoms appear again. The post-hoc analysis about the psychotic effect and side effects performed by Rummel-Kluge [32] merits comment because it indicates a necessary serum concentration of the antipsychotic drug administered in order to maintain a decrease in the total PANSS score. Long-term examinations are necessary. The discontinuation rate of schizophrenic patients in taking antipsychotic drugs should be considered in depth. This fact is important in many aspects. On one hand, if patients decide on their own to take no longer this treatment, it can worsen the mental illness and makes an additional treatment necessary. On the other hand, the reasons for the discontinuation of the antipsychotic treatment should be elucidated. Possible reasons could be EPS or the lacking

patients’ insight in the disease. Consequently, a long-term antipsychotic treatment combined with a social therapy and with a psychoeducation should be compared to a single pharmacotherapy. By a psychoeducation, patients should recognize disease symptoms, differentiate them from adverse effects and learn an insight in the disease. The appropriate antipsychotic drug which achieves a long-term reduction of psychotic symptoms should be put in relation to the susceptibility genes. These genes should be examined in a large cohort of schizophrenic patients in order to differentiate the patients which profit from a treatment with antipsychotic drugs such as risperidone which shows a higher affinity for the D2 receptor and those patients which can be better treated with antipsychotic drugs such as quetiapine which shows a lower ratio of the D2/5-HT2A receptor occupancy. Using these recommendations, the physician would have a technique to better choose the appropriate antipsychotic drug. EPS occurs in the administration of recently admitted antipsychotic drugs. Akathisia occurs in 11% of the patients treated with lurasidone. Therefore, a score should be developed in order to quantify the severeness of EPS, that is, parkinsonian symptoms, dyskinesia and akathisia. Besides, it should be examined the occurrence of permanent dyskinesia which appears frequently after the administration of typical antipsychotic drugs such as haloperidol. It is known that aripiprazole improves the quality of life. Examinations about different aspects of quality of life should be performed after the administration of other antipsychotic drugs. Aripiprazole and cariprazine have a partial D2 agonism and achieve a better quality of life. However, because the different mechanism of actions of aripiprazole and cariprazine does not exclude that dopamine hyperactivity occurs again, long-term examinations about the safe antipsychotic effect of such drugs are necessary. The antipsychotic drugs asenapine, lurasidone and cariprazine are found to improve cognitive functions. A question should be answered, whether patients obtaining these drugs are able to exert a profession for a constant period of time in comparison with patients treated with conventional antispychotic drugs. The long-term examinations about the safety of aripiprazole and cariprazine are very important, because basic scientists should know whether it is worth developing new antipsychotic drugs with a partial agonism at dopaminergic and serotonergic subreceptors. It should be also examined whether treatment-resistant schizophrenic patients treated with two combined antipsychotic drugs, administered as an injectable depot form, have or not a better outcome and a lower discontinuation rate. On developing new antipsychotic drugs, a question arises whether the interaction with other dopaminergic and serotonergic, nicotinic cholinergic or glutaminergic ionotropic or metabotropic subreceptors, receptors of peptides (e.g., CCKA subreceptor) or cannabinoid receptors could occur. This review is focused on the treatment of the paranoid and hallucinatory form of schizophrenia. The question arises whether auditory hallucinations can be treated sufficiently by conventional antipsychotic drugs. It should be investigated whether new antipsychotic


9


drugs such as CCKA receptor agonists or cannabinoid CB1 receptor antagonists could achieve progress in the treatment of these psychotic symptoms.

Acknowledgements The authors wish to thank Mr Nicholas Skinner (University of Salamanca) for supervising the English text and Mrs Carmen Payań (University of Salamanca) for technical assistance.


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ziprasidone and aripiprazole in a 1-year treatment of schizophrenia. 44.

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Affiliation

Felix-Martin Werner†1,2 & Rafael Covenãs2 † Author for correspondence 1 H€ohere Berufsfachschule fu¨r Altenpflege und Ergotherapie der Euro Akademie P€oneck, Carl-Gustav-Vogel-Str. 13, P€oneck 07381, Germany 2 University of Salamanca, Instituto de Neurociencias de Castilla y Leoń (INCYL), Laboratory of Neuroanatomy of the Peptidergic Systems (Lab. 14), c/Pintor Fernando Gallego, 1, 37007-Salamanca, Spain Tel: +34 923 29 44 00 ext 1856; Fax: +34 923 29 45 49; E-mail: [email protected]

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Therapeutic drug monitoring of atypical antipsychotic drugs.

Aging effects on QT interval: Implications for cardiac safety of antipsychotic drugs.

Genetics of Common Antipsychotic-Induced Adverse Effects.

Some adverse effects of drugs on nutrition.

Effects of antipsychotic drugs on memory functions of schizophrenic patients.

Minimizing cardiovascular adverse effects of atypical antipsychotic drugs in patients with schizophrenia.

Effects of antipsychotic drugs on insight in schizophrenia.

Monoclonal antibody therapy and renal transplantation: focus on adverse effects.

Antiepileptic drugs' tolerability and safety--a systematic review and meta-analysis of adverse effects in dogs.

Clinical experience with perampanel: focus on psychiatric adverse effects.

Cognitive Adverse Effects of Antiepileptic Drugs : Incidence, Mechanisms and Therapeutic Implications.

Adverse effects of nonsteroidal anti-inflammatory drugs on renal function.

[Adverse effects of anti-epileptic drugs].

Which ancillary properties of beta-adrenoceptor blocking drugs influence their therapeutic or adverse effects?: a review.

Life-threatening effects of antipsychotic drugs (1st edition).

Therapeutic hypothermia: focus on microcirculation.

Opioids and traffic safety--focus on buprenorphine.

Effects of antipsychotic drugs on 5-HT2 receptors in the medial prefrontal cortex: microiontophoretic studies.

Effects of antipsychotic drugs on cardiovascular variability in participants with bipolar disorder.

Neurological and psychiatric adverse effects of antiretroviral drugs.

Mechanisms of action of atypical antipsychotic drugs. Implications for novel therapeutic strategies for schizophrenia.

Adverse effects and safety of SGLT-2 inhibitors.

Serotonin in antipsychotic drugs action.

The influence of atypical antipsychotic drugs on sexual function.