Incidence Of Extrapyramidal Side Effects Research Articles

Artesunate prevents rats from the clozapine-induced hepatic steatosis and elevation in plasma triglycerides

Clozapine is an atypical antipsychotic with therapeutic efficacy in treatment-resistant schizophrenia patients and low incidence of extrapyramidal side effects. However, the use of clozapine has been limited by its adverse effects on metabolism. Artesunate is a semisynthetic derivative of artemisinin and was shown to decrease the plasma cholesterol and triglyceride in rabbits and rats in recent studies. The aim of this study was to examine possible effects of artesunate on the clozapine-induced metabolic alterations in rats given saline, clozapine, artesunate, or clozapine plus artesunate for 6 weeks. The clozapine group showed significantly high plasma levels of triglyceride, hepatic steatosis, and fibrosis along with high levels of C-reactive protein, alanine aminotransferase, and aspartate aminotransferase compared to the saline group. But the treatment had no effect on weight gain and caused no hyperglycemia, hyperinsulinemia, and behavioral changes in the rats. More significantly, these clozapine-induced changes were not seen in rats coadministered with clozapine plus artesunate. These results added evidence supporting psychiatrists to try add-on treatment of artesunate in schizophrenia patients to ameliorate clozapine-induced adverse metabolic effects.

Extrapyramidal symptoms after exposure to calcium channel blocker-flunarizine or cinnarizine

PurposeFlunarizine (fz) and cinnarizine (cz) have well-known extrapyramidal side effects (EPSEs). The aim of this study was to evaluate the incidence and occurrence time of cz- and fz-related EPSEs.MethodPatients who took fz or cz for more than 1 month were identified from the longitudinal health insurance database 2005 and 2010. Excluded were patients with any of the underlying diseases that may cause parkinsonism. Drug-induced EPSEs were defined as the new diagnosis of parkinsonism, dyskinesia, or secondary dystonia during drug use or within 3 months after discontinuing the medication. Age- and sex-matched controls were included in this study.ResultsRecruited for analysis were individuals who took fz (n = 26,133) and cz (n = 7186). The incidence rates of fz- and cz-induced EPSEs were 21.03 and 10.3 per 10,000 person-months, respectively. The hazard ratios (HRs) of EPSEs among fz and cz subjects were 8.03 (95% CI 6.55–9.84) and 3.41 (95% CI 2.50–4.63) when compared with the control individuals. Both fz and cz patients had a higher cumulative incidence of EPSEs than their control individuals (p < 0.001). Among subjects who took fz, the incidence of EPSEs was higher in the second than first year of drug exposure (45.59 vs 21.03 per 10,000 person-months).ConclusionsFz and cz significantly increased the risk of parkinsonism, dyskinesia, and dystonia. Potential benefits and risks should be weighed when considering long-term use of these drugs especially fz.

The Relationship Between Early Haloperidol Response and Associated Extrapyramidal Side Effects.

Early response to antipsychotic medication within 2 weeks of initiating treatment can predict psychiatric outcomes. However, it is unclear whether early response is also predictive of extrapyramidal side effects (EPSs) associated with antipsychotic medications. In this study, we investigated 136 consecutive antipsychotic-naive, first-episode psychosis patients naturalistically treated with haloperidol. Patients were assessed at baseline and weekly after treatment initiation using the Brief Psychiatric Rating Scale, Hamilton Depression Rating Scale, and Hamilton Anxiety Rating Scale. Dystonia, parkinsonism, akathisia, and dyskinesia were also assessed weekly using standardized rating scales. Regression analyses were used to determine whether early response at week 2 of treatment predicted the incidence of EPS at any point during hospitalization. A secondary analysis was conducted to determine whether early response continued to predict EPS in patients who experienced no EPS within the first 2 weeks of treatment. The analyses demonstrated that greater Brief Psychiatric Rating Scale percent improvement at week 2 predicted a decreased risk of EPSs (P = 0.004), even in patients who did not show any EPSs within the first 2 weeks of treatment (P = 0.005). For specific EPS, early response predicted decreased incidences of parkinsonism (P = 0.028) and dyskinesia (P = 0.025), but not akathisia or dystonia. Hamilton Depression Rating Scale and Hamilton Anxiety Rating Scale improvement at week 2 did not predict EPSs. In addition, EPSs were not predicted by the maximum antipsychotic dose received during hospitalization. These results indicate that early antipsychotic response is valuable not only for predicting psychiatric outcomes, but also for predicting the risk of EPSs.

COMT gene polymorphisms and response to treatment and the incidence of extrapyramidal side effects in schizophrenic patients

COMT gene polymorphisms and response to treatment and the incidence of extrapyramidal side effects in schizophrenic patients

Severe Diabetic Ketoacidosis and Acute Pancreatitis Precipitated by Olanzapine in a Nondiabetic Patient

Olanzapine, a second generation or atypical antipsychotic, is one of the commonly prescribed antipsychotics and has lower incidence of extrapyramidal side effects, sedation and anticholinergic side effects. Atypical antipsychotics like olanzapine are now widely prescribed for treatment of schizophrenia as well as for schizoaffective disorder, bipolar affective disorder, depression and dementia. Olanzapine, has been reported to cause metabolic dysregulation like weight gain, type II diabetes mellitus and hyperlipidemia as compared to conventional antipsychotics. Sometimes patient taking olanzapine may present in acute deterioration like diabetic ketoacidosis complicated with acute pancreatitis. Hereby we are reporting a young patient who presented with life threatening severe diabetic ketoacidosis complicated with acute pancreatitis and acute kidney injury which resolved after withdrawal of olanzapine and with supportive care and Insulin. Combination of diabetic ketoacidosis, acute pancreatitis and acute kidney injury induced by olanzapine is very rarely reported.

Paliperidone protects SK-N-SH cells against glutamate toxicity via Akt1/GSK3β signaling pathway

Schizophrenia is a heterogeneous psychotic illness and its etiology remains poorly understood. Recent studies have suggested that neurodegeneration is a component of schizophrenia pathology and some atypical antipsychotics appear to slow progressive morphological brain changes. In addition, the atypical antipsychotics were reported to have a superior therapeutic efficacy in treating schizophrenia and have a low incidence of extrapyramidal side effects (EPS) compared to typical antipsychotics. However, the mechanisms of atypical antipsychotics in treating schizophrenia and the basis for differences in their clinical effects were still totally unknown. In the present study, we investigated whether paliperidone shows protective effects on SK-N-SH cells from cell toxicity induced by exposure to glutamate. We examined the effects of the drugs on cell viability (measured by MTT metabolism assay and lactate dehydrogenase (LDH) activity assay), apoptosis rate, ROS levels and gene expression and phosphorylation of Akt1 and GSK3β. The results showed that paliperidone significantly increases the cell viability by MTT and LDH assays (p<0.05), in contrast to the typical antipsychotic (haloperidol), which had little neuroprotective activity. Moreover, paliperidone retarded the glutamate-mediated promotion of ROS and the rate of apoptosis (p<0.05). In addition, paliperidone also effectively reversed glutamate-induced decreases of gene expression and phosphorylation of Akt1 and GSK3β (both p<0.05). Our results demonstrated that paliperidone could effectively protect SK-N-SH cells from glutamate-induced damages via Akt1/GSK3β signaling pathway.

Pericyazine for schizophrenia.

Pericyazine is a 3-cyano-10 (3-4'-hydroxypiperidinopropyl) phenothiazine. It is overall pharmacologically similar with chlorpromazine, though particularly sedating. Dopamine receptor subtype analysis has not been performed for pericyazine, but the drug appears to induce greater noradrenergic than dopaminergic blockade. Compared to chlorpromazine, pericyazine reportedly has more potent antiemetic, antiserotonin, and anticholinergic activity. To evaluate the clinical effects and safety of pericyazine in comparison with placebo, typical and atypical antipsychotic agents and standard care for people with schizophrenia. We searched the Cochrane Schizophrenia Group Trials Register (February 2013) which is based on regular searches of CINAHL, EMBASE, MEDLINE and PsycINFO. We inspected references of all identified studies for further trials. All relevant randomised controlled trials focusing on pericyazine for schizophrenia and other types of schizophrenia-like psychoses (schizophreniform and schizoaffective disorders). We excluded quasi-randomised trials. Data were extracted independently from included papers by at least two review authors. Risk ratios (RR) and 95% confidence intervals (CI) of homogeneous dichotomous data were calculated. We assessed risk of bias for included studies and used GRADE to judge quality of evidence. We could only include five studies conducted between 1965 and 1980. Most of the included studies did not report details of randomisation, allocation concealment, details of blinding and we could not assess the impact of attrition due to poor reporting.For the primary outcome of Global state - not improved, the confidence interval was compatible with a small benefit and increased risk of not improving with pericyazine compared with typical antipsychotics (2 RCTs, n = 122, RR 1.24 CI 0.93 to 1.66, very low quality of evidence) or atypical antipsychotics (1 RCT, n = 93, RR 0.97 CI 0.67 to 1.42, very low quality of evidence).When compared with typical antipsychotics relapse was only experienced by one person taking pericyazine (1 RCT, n = 80, RR 2.59 CI 0.11 to 61.75, very low quality of evidence).Pericyazine was associated with more extrapyramidal side effects than typical antipsychotics (3 RCTs, n = 163, RR 0.52 CI 0.34 to 0.80, very low quality of evidence) and atypical antipsychotics (1 RCT, n = 93, RR 2.69 CI 1.35 to 5.36, very low quality of evidence).The estimated risk of leaving the study early for specific reasons was imprecise for the comparisons of pericyazine with typical antipsychotics (2 RCTs, n = 71, RR 0.46 CI 0.11 to 1.90, very low quality of evidence), and with atypical antipsychotics (1 RCT, n = 93, RR 0.13 CI 0.01 to 2.42, very low quality of evidence). On the basis of very low quality evidence we are unable to determine the effects of pericyazine in comparison with typical or atypical antipsychotics for the treatment of schizophrenia. However, there is some evidence that pericyazine may be associated with a higher incidence of extrapyramidal side effects than other antipsychotics, and again this was judged to be very low quality evidence. Large, robust studies are still needed before any firm conclusions can be drawn.

Role of α1 adrenergic antagonism in the mechanism of action of iloperidone: reducing extrapyramidal symptoms

The low incidence of extrapyramidal side effects associated with the atypical antipsychotic iloperidone may be linked to its unique binding profile of high affinity antagonism of both α1 adrenergic receptors and serotonin 2A receptors.

Comparing tolerability profile of quetiapine, risperidone, aripiprazole and ziprasidone in schizophrenia and affective disorders: a meta-analysis

Objective: Second-generation antipsychotics (SGAs) are extensively prescribed for psychiatric disorders. Based on clinical observations, schizophrenia (SCZ) and affective disorder (AD) patients can experience different SGA side effects. The expanded use of SGAs in psychiatry suggests a need to investigate whether there is a difference in the incidence and severity of side effects related to diagnosis.Methods: A comprehensive literature search was conducted to identify studies reporting side effects of four common prescribed SGAs (aripiprazole, quetiapine, risperidone and ziprasidone) in the treatment of SCZ or AD. Randomized controlled trials were included in this study if they administered oral SGAs as a monotherapy, in adult patients. The metabolic and extrapyramidal side effects were collected separately for each group, and then were combined in a meta-analysis.Results: 80 studies were included in the analysis (N = 14,319). Quetiapine treatment induced significantly higher low-density lipoprotein (LDL) and total blood cholesterol mean change in the SCZ group, relative to the AD group. Based on the results, the incidence of extrapyramidal side effects was more frequent in the AD group. Aripiprazole treatment led to significantly more akathisia incidence in the AD group, compared with the SCZ group.Conclusion: The results suggest that SCZ patients may be more vulnerable to some SGA-induced metabolic disturbances, in which lifestyle risk factors and possible inherent genetic vulnerabilities may play a role. Most of the studied SGAs caused more movement disorders in AD patients than SCZ. It might be that an antipsychotic induces severity of side effect according to the phenotype.

Dose-related effects of clozapine and risperidone on the pattern of brain regional serotonin and dopamine metabolism and on tests related to extrapyramidal functions in rats

The present study was designed to evaluate the behavioral and neurochemical profiles of clozapine and risperidone in rats in a dose-dependent manner. Animals injected intraperitoneally (i.p.) with clozapine (2.5, 5.0 and 10.0 mg kg-1) or risperidone (1.0, 2.5 and 5.0 mg kg-1) were sacrificed 1 h later to collect brain samples. Hypolocomotive effects (home cage activity and catalepsy) were successively monitored in each animal after the drug or saline administration. Both drugs significantly (p < 0.01) decreased locomotor activity at high doses and in a dose-dependent manner. Maximum (100%) cataleptic potential was achieved at a high dose (5.0 mg kg-1) of risperidone. Neurochemical estimations were carried out by HPLC with electrochemical detection. Both drugs, at all doses, significantly (p < 0.01) increased the concentration of homovanillic acid (HVA), a metabolite of dopamine (DA), in the striatum. Dihydroxyphenylacetic acid (DOPAC) levels increased in the striatum and decreased in the rest of the brain, particularly in clozapine-injected rats. 5-Hydroxyindoleacetic acid (5-HIAA), the predominant metabolite of serotonin, significantly (p < 0.01) decreased in the striatum. 5-Hydroxytryptamine (5-HT) was significantly (p < 0.01) increased by risperidone and decreased by clozapine in the rest of the brain. Striatal tryptophan (TRP) was significantly (p < 0.01) decreased by risperidone and increased in the rest of the brain. The striatal HVA/DA ratio increased and the 5-HT turnover rate remained unchanged in the rest of the brain. Results suggest that the affinity of the two drugs towards D2/5-HT1A receptors interaction is involved in lower incidence of extrapyramidal side effects. Role of 5-HT1A receptors in the treatment of schizophrenia is discussed.

Fluvoxamine for blonanserin-associated akathisia in patients with schizophrenia: report of five cases

BackgroundAtypical antipsychotic drugs have been reported to cause fewer incidences of extrapyramidal side effects (EPS) than typical antipsychotic drugs, but adverse events such as akathisia have been observed even with atypical antipsychotic drugs. Although understanding of the pathophysiology of akathisia remains limited, it seems that a complex interaction of several neurotransmitter systems plays a role in its pathophysiology. The endoplasmic reticulum protein sigma-1 receptors have been shown to regulate a number of neurotransmitter systems in the brain.MethodsWe report on five cases in which monotherapy of the selective serotonin reuptake inhibitor and sigma-1 receptor agonist fluvoxamine was effective in ameliorating the akathisia of patients with schizophrenia treated with the new atypical antipsychotic drug blonanserin.ResultsThe global score on the Barnes Akathisia Scale in five patients with schizophrenia treated with blonanserin rapidly decreased after fluvoxamine treatment.ConclusionDoctors should consider that fluvoxamine may be an alternative approach in treating akathisia associated with atypical antipsychotic drugs.

Fluvoxamine for aripiprazole-associated akathisia in patients with schizophrenia: a potential role of sigma-1 receptors

BackgroundSecond-generation antipsychotic drugs have been reported to cause fewer incidences of extrapyramidal side effects (EPSs) than typical antipsychotic drugs, but adverse events such as akathisia have been observed even with atypical antipsychotic drugs. Although understanding of the pathophysiology of akathisia remains limited, it seems that a complex interplay of several neurotransmitter systems might play a role in its pathophysiology. The endoplasmic reticulum protein sigma-1 receptors are shown to regulate a number of neurotransmitter systems in the brain.MethodsWe report on two cases in which monotherapy of the selective serotonin reuptake inhibitor and sigma-1 receptor agonist fluvoxamine was effective in ameliorating the akathisia of patients with schizophrenia treated with the antipsychotic drug aripiprazole.ResultsThe global score on the Barnes Akathisia Scale in the two patients with schizophrenia treated with aripiprazole decreased after fluvoxamine monotherapy.ConclusionDoctors may wish to consider fluvoxamine as an alternative approach in treating akathisia associated with antipsychotic drugs such as aripiprazole.

Pharmacovigilance on olanzapine

Pharmacovigilance on olanzapine

Acute Administration of Clozapine and Risperidone Altered Dopamine Metabolism More in Rat Caudate than in Nucleus Accumbens: A Dose-Response Relationship

The present study compares the extrapyramidal and neurochemical effects of clozapine and risperidone in rat caudate (corpus striatum) and nucleus accumbens (ventral striatum) dose-dependently. Animals injected with clozapine (2.5, 5.0 and 10.0 mg/kg IP) or risperidone (1.0, 2.5 and 5.0 mg/kg IP) in acute were sacrificed 1 h later to collect brain samples. Extrapyramidal side effects (EPS) in terms of locomotor activity and catalepsy were monitored in each animal after the drug or vehicle administration. Maximum cataleptic potentials were found only at high doses of clozapine (10.0 mg/kg; 60%) and risperidone (5.0 mg/kg; 100%). Neurochemical estimations were carried out by HPLC-EC. Both drugs at all doses significantly (p<0.01) increased the concentration of homovanillic acid (HVA), a metabolite of DA, in the caudate nucleus and decreased in nucleus accumbens. Levels of Dihydroxyphenylacetic acid (DOPAC) significantly (p<0.01) increased in the caudate by clozapine administration and decreased in the nucleus accumbens by the administration of both drugs in a dose-dependent manner. 5-Hydroxyindoleacetic acid (5-HIAA), the predominant metabolite of serotonin significantly decreased in the caudate and nucleus accumbens in a similar fashion. Levels of tryptophan (TRP) were remained insignificant in caudate and nucleus accumbens by the injections of two drugs. In caudate, clozapine and risperidone administrations significantly (p<0.01) decreased HVA/DA ratio and increased DOPAC/DA ratio in nucleus accumbens at all doses. The findings suggest the evidence for DA/5-HT receptor interaction as an important link in the lower incidence of EPS. The possible role of serotonin1A receptors in the pathophysiology of schizophrenia is also discussed.

Atypical antipsychotic drugs: Part 1.

This is the second of two columns on atypical antipsychotic drugs. Part II discusses olanzapine, quetiapine, and ziprasidone. Olanzapine (Zyprexa) Since evidence continues to accrue implicating numerous neurotransmitter pathways, antipsychotics with broader effects are sought. Olanzapine appears to affect the glutamate system and can prevent the schizophrenic signs and symptoms typically induced by N-methyl-D-aspartate (NMDA) receptor antagonists PCP or ketamine (Tollefson, 1997). Olanzapine is similar to clozapine in receptor affinity, antagonizing 5[HT.sub.2], [D.sub.2], [D.sub.1], and [D.sub.4] receptors significantly. It is thought to target mesolimbic and mesocortical systems over the nigrostriatal system (Allan, Sison, Alpert, Connolly, & Crichton, 1998). Olanzapine has affinity for muscarinic, [H.sub.1] and alpha-1 receptors, accounting for moderate anticholinergic effects, significant sedation, and weight gain (Ganguli, 1999; Sussman & Ginsberg, 1999; Wirshing et al., 1999), and mild levels of orthostasis. Other side effects include nausea, lightheadedness, dizziness, headache, and akathisia (Bever & Perry, 1998; Tran et al., 1997). It causes few extrapyramidal side effects (EPSEs) and is not thought to produce tardive dyskinesia. Though transient increased levels of prolactin have been reported, those levels are not long lasting (Jibson & Tandon, 1998). Unlike clozapine, olanzapine is not a significant risk for agranulocytosis, though anecdotal reports confirm some instances of this disorder. A number of studies support the overall effectiveness of olanzapine in treating schizophrenia, and it often is the drug used when patients have treatment-ending reductions in WBCs related to clozapine (Breier & Hamilton, 1999; Conley et al., 1998; Tollefson et al., 1997). Further, olanzapine has proven effective for treating acute mania (Tohen et al., 1999) and is the only atypical drug FDA approved for monotherapy for bipolar disorder. In a large study (N = 1,996) at multiple sites, when compared to haloperidol, olanzapine was significantly more effective for negative symptoms, had fewer EPSEs and other side effects, was safer, and did not cause significant elevations of prolactin (Tollefson et al.). Further, these individuals continued to manifest a positive clinical effect during a 1-year study extension. These patients demonstrated a statistically higher score on a quality-of-life scale than did patients treated with haloperidol. Pharmacokinetically, olanzapine is conducive to compliance due to its relatively long half-life of 21-54 hours and is suitable for one-per-day dosing. It can be used across gender, ethnicity, and age groups (Tollefson, 1997). Though metabolized by the CYP-450 isoenzymes 1A, 2D6, and 2C, olanzapine has few significant interactions. Typical dosage is 5-40 mg/day, and an intramuscular formulation is anticipated. Quetiapine (Seroquel) Quetiapine was developed as an answer to the clozapine dilemma (i.e., clozapine is an effective drug with a life-threatening side effect). Quetiapine is similar to clozapine pharmacodynamically but does not cause agranulocytosis (Green, 1999; Hustey, 1999; Peuskens & Link, 1997). Several studies indicate quetiapine has a greater affinity for 5[HT.sub.2] receptors (58%-72% occupancy) than for dopamine [D.sub.2] receptors (27%-44% occupancy), at about the same occupancy ratio as clozapine (Borison et al., 1996; Green, 1999; McManus et al., 1999; Parsa & Bastani, 1998; Small et al., 1997). As with other atypicals, this occupancy ratio is thought to be instrumental in the low incidence of EPSEs for quetiapine. For example, Green found a 44% occupancy of striatal [D.sub.2] receptors (threshold occupancy for EPSEs ~80%). These and other studies have shown quetiapine to significantly antagonize alpha-1 adrenoreceptors with a less significant blockade of alpha-2 and muscarinic receptors (Hustey, 1999; Peuskens & Link, 1997, Saller & Salama, 1993). …

No regional difference in dopamine D2 receptor occupancy by the second-generation antipsychotic drug risperidone in humans: a positron emission tomography study

The effects of antipsychotic drugs have generally been considered to be mediated by blockade of dopamine D2 receptors. The concept of limbic and cortical selectivity of second-generation antipsychotics, i.e. higher dopamine D2 receptor occupancy in the cerebral cortices than in the striatum, has been suggested to explain their clinical efficacy with lower incidence of extrapyramidal side-effects. In this study, regional distribution of dopamine D2 receptor occupancy by risperidone was determined in order to elucidate the limbic and cortical selectivity of second-generation antipsychotics. Striatal and extrastriatal dopamine D2 receptor binding at baseline and after oral administration of 2 mg risperidone were measured in ten healthy men by positron emission tomography (PET) using different tracers with different affinity for the receptors, [11C]raclopride and [11C]FLB 457, respectively. Striatal and extrastriatal occupancies of dopamine D2 receptors were calculated for each brain region. Occupancies of dopamine D2 receptors were about 70% and 60% in the striatum and extrastriatum, respectively. A simulation study showed that non-negligible specific binding in the reference region (cerebellum), could cause systemic underestimation of occupancy in [11C]FLB 457 PET studies, indicating that occupancies in both the striatum and extrastriatum may not have differed. Among the extrastriatal regions including limbic and neocortical regions, no significant regional differences in dopamine D2 receptor occupancy were observed. Thus, limbic and cortical selectivity was not observed by one of the second-generation antipsychotics, risperidone.

Antipsychotic-induced extrapyramidal side effects in bipolar disorder and schizophrenia: a systematic review.

Newer atypical antipsychotics have been reported to cause a lower incidence of extrapyramidal side effects (EPS) than conventional agents. This review is to compare antipsychotic-induced EPS relative to placebo in bipolar disorder (BPD) and schizophrenia. English-language literature cited in Medline was searched with terms antipsychotics, placebo-controlled trial, and bipolar disorder or schizophrenia and then with antipsychotic (generic/brand name), safety, akathisia, EPS, or anticholinergic use, bipolar mania/depression, BPD, or schizophrenia, and randomized clinical trial. Randomized, double-blind, placebo-controlled, monotherapy studies with comparable doses in both BPD and schizophrenia were included. Absolute risk increase and number needed to treat to harm (NNTH) for akathisia, overall EPS, and anticholinergic use relative to placebo were estimated. Eleven trials in mania, 4 in bipolar depression, and 8 in schizophrenia were included. Haloperidol significantly increased the risk for akathisia, overall EPS, and anticholinergic use in both mania and schizophrenia, with a larger magnitude in mania, an NNTH for akathisia of 4 versus 7, EPS of 3 versus 5, and anticholinergic use of 2 versus 4, respectively Among atypical antipsychotics, only ziprasidone significantly increased the risk for overall EPS and anticholinergic use in both mania and schizophrenia, again with larger differences in mania, an NNTH for overall EPS of 11 versus 19, and anticholinergic use of 5 versus 9. In addition, risks were significantly increased for overall EPS (NNTH = 5) and anticholinergic use (NNTH = 5) in risperidone-treated mania, akathisia in aripiprazole-treated mania (NNTH = 9) and bipolar depression (NNTH = 5), and overall EPS (NNTH = 19) in quetiapine-treated bipolar depression. Bipolar patients, especially in depression, were more vulnerable to having acute antipsychotic-induced movement disorders than those with schizophrenia.

Dr. Mamo Replies

Back to table of contents Previous article Next article Letters to the EditorFull AccessDr. Mamo RepliesDAVID C. MAMO M.D., M.Sc.,DAVID C. MAMO M.D., M.Sc.Search for more papers by this author,Published Online:1 Mar 2008https://doi.org/10.1176/appi.ajp.2007.07091513rAboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack Citations ShareShare onFacebookTwitterLinked InEmail To The Editor: We thank Dr. Poyurovsky et al. for their thoughtful comments regarding our observation of restlessness in subjects switched to aripiprazole as well as their discussion of the pathophysiological mechanisms involved. We agree that understanding these mechanisms has important implications given the association between akathisia and adverse clinical outcome. Dr. Poyurovsky et al. highlight our suggestion that aripiprazole’s relative freedom from extrapyramidal side effects may be related to the drug’s partial agonism at D 2 receptors and that the high rate of restlessness noted in our positron emission tomography study may have been an expression of akathisia. In our study, two subjects experienced clear evidence of extrapyramidal side effects (increased tone in upper extremities and acute dystonia responsive to benztropine), and five subjects reported some degree of restlessness. For the two subjects with extrapyramidal side effects, a combination of individual pharmacokinetic variability or decreased D 2 receptor reserve may be the more plausible explanation for their vulnerability to these side effects. Dr. Poyurovsky et al. further suggest that while aripiprazole’s partial agonism at the D 2 and 5-HT 1A receptors may have contributed to the low incidence of extrapyramidal side effects, this pharmacological profile does not prevent akathisia. They argue that protection from drug-induced akathisia is likely related to high 5-HT 2 binding relative to D 2 binding. While the effect of 5-HT 2 antagonism on extrapyramidal side effects remains formally untested in the literature, the antipsychotic drugs with the highest 5-HT 2 :D 2 binding ratio (risperidone and paliperidone) are actually associated with high rates of extrapyramidal side effects and akathisia, arguing against a simple 5-HT 2 protective effect. Moreover, many drugs with a variety of mechanisms have been used to manage akathisia, such as beta blockers, antihistaminics, and benzodiazepines, arguing against a pure 5-HT 2 effect. Finally, not all restlessness is akathisia. Restlessness is associated with a number of psychotropic drugs, including antipsychotics, preoperative sedatives, and antidepressants, and responds to drugs with different pharmacological profiles. The restlessness reported by patients receiving aripiprazole is often described qualitatively in more positive terms, including a feeling of increased energy and interest in a more active lifestyle. It is therefore possible that the restlessness noted in some, if not the majority, of the patients receiving aripiprazole may not be true “akathisia” but rather a state of activation induced by a central dopamine agonist effect. Given the high prevalence of this outcome as well as the potential clinical and mechanistic significance as discussed by Dr. Poyurovsky et al., restlessness occurring in the context of aripiprazole treatment deserves closer scrutiny in future studies at both the phenomenological and mechanistic levels.Toronto, Ontario, CanadaDr. Mamo’s disclosures accompany the original article.This letter (doi: 10.1176/appi.ajp.2007.07091513r) was accepted for publication in November 2007. FiguresReferencesCited byDetailsCited ByNone Volume 165Issue 3 March, 2008Pages 398-399THE AMERICAN JOURNAL OF PSYCHIATRY March 2008 Volume 165 Number 3 Metrics PDF download History Published online 1 March 2008 Published in print 1 March 2008

Aripiprazole’s Receptor Pharmacology and Extrapyramidal Side Effects

Back to table of contents Previous article Next article Letters to the EditorFull AccessAripiprazole’s Receptor Pharmacology and Extrapyramidal Side EffectsMICHAEL POYUROVSKY M.D.RONIT WEIZMAN M.D.ABRAHAM WEIZMAN M.D.,MICHAEL POYUROVSKY M.D.Search for more papers by this authorRONIT WEIZMAN M.D.Search for more papers by this authorABRAHAM WEIZMAN M.D.Search for more papers by this author,Published Online:1 Mar 2008https://doi.org/10.1176/appi.ajp.2007.07091513AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack Citations ShareShare onFacebookTwitterLinked InEmail To The Editor: In the September 2007 issue of the Journal , David Mamo, M.D., M.Sc., et al. (1) reported that at clinically effective doses (10–30 mg/day) aripiprazole exerts more than 80% striatal dopamine D 2 receptor occupancy in patients with schizophrenia. Correspondingly, higher striatal D 2 occupancy (>90%) was associated with the development of extrapyramidal side effects (dystonia, parkinsonism). Aripiprazole was distinguished by a low serotonin 5-HT 2 :D 2 affinity ratio (52% [SD=18%] versus 87% [SD=4%], respectively) and a low 5-HT 1A receptor occupancy (mean=16%) (1) . The authors implied that aripiprazole’s partial D 2 agonist properties accounted for a low propensity for extrapyramidal side effects. In several controlled trials, the rate of aripiprazole-induced extrapyramidal side effects was reported similar to placebo; however, it was the rate of aripiprazole-induced akathisia reported as being significantly higher (approximately 20%) in patients with schizophrenia and bipolar mania (2 , 3) . The estimated rate of aripiprazole-induced akathisia in naturalistic settings has been shown to be even higher (4) . The pathophysiological mechanisms and treatment of akathisia differ from that of other extrapyramidal side effects. Anticholinergic agents that are efficacious in treating dystonia and parkinsonism are apparently ineffective in treating akathisia. In contrast, a robust anti-akathisia effect of mianserin and mirtazapine (both with marked 5-HT 2A antagonism), comparable with propranolol (the drug of choice for treating akathisia), has consistently been shown in patients treated with first-generation antipsychotic agents, underscoring the role of 5-HT 2A receptor antagonism in the pathophysiology and treatment of akathisia (5) . Preliminary evidence indicating an anti-akathisia effect of the selective 5-HT 2A inverse agonist ACP-3 (6) supports this assumption. Notably, the 5-HT 1A agonist buspirone was ineffective as an anti-akathisia agent (7) . We suggest that aripiprazole’s partial agonism at the D 2 and 5-HT 1A receptors accounts for the low incidence of extrapyramidal side effects but does not “protect” against akathisia. Noteworthy, five (42%) of 12 participants in the study developed restlessness (1) , which may well have been an expression of akathisia. A sufficient degree of the 5-HT 2A antagonism and a high 5-HT 2A :D 2 occupancy ratio are essential to prevent or ameliorate drug-induced akathisia. Elucidation of pathophysiological mechanisms and efficacious treatment of akathisia are imperative because of akathisia’s association with non-compliance and suicidal and violent behavior. Tirat Carmel, IsraelThe authors report no competing interests.This letter (doi: 10.1176/appi.ajp.2007.07091513) was accepted for publication in November 2007.

Affinity of cyamemazine metabolites for serotonin, histamine and dopamine receptor subtypes

Animal and human pharmacological studies indicate that the antipsychotic action of cyamemazine results from blockade of dopamine D 2 receptors, its anxiolytic properties from serotonin 5-HT 2C receptor antagonism and the low incidence of extrapyramidal side effects from a potent 5-HT 2A receptor antagonistic action. Cyamemazine is metabolized in monodesmethyl cyamemazine and cyamemazine sulfoxide, which are not known for their affinities for serotonin, dopamine and other brain receptor types considered to mediate central nervous systems effects of drugs. Hence, metabolite affinities were determined in human recombinant receptors expressed in CHO cells ( hD 2 and hD4.4 receptors, h5-HT 1A, h5-HT 2A, h5-HT 2C and h5-HT 7 receptors and hM 1, hM 2 and hM 3 receptors) and HEK-293 cells ( h5-HT 3 receptors) or natively present in rat cerebral cortex (non-specific α 1- and α 2-adrenoceptors, GABA A and GABA B receptors) and guinea pig cerebellum (H 1 central histamine receptors) membranes. Monodesmethyl cyamemazine showed a neurotransmitter receptor profile similar to that of its parent compound cyamemazine, i.e.: high affinity for h5-HT 2A receptors ( K i = 1.5 nM), h5-HT 2C receptors ( K i = 12 nM) and hD 2 receptors ( K i = 12 nM). Cyamemazine sulfoxide showed high affinity for h5-HT 2A receptors ( K i = 39 nM) and histamine H 1 receptors ( K i = 15 nM) and a reduced affinity for D 2 and 5-HT 2C receptors. Therefore, monodesmethyl cyamemazine can contribute to enhance and prolong the therapeutic actions of cyamemazine. Further investigation is required to see if the high affinities of cyamemazine sulfoxide for H 1 and 5-HT 2A receptors are of therapeutic benefit against sleep onset insomnia and/or sleep maintenance insomnia respectively.