Antipsychotic-Induced Extrapyramidal Side Effects in Bipolar Disorder and Schizophrenia

Department of Psychiatry, Bipolar Disorder Research Center at the Mood Disorders Program, University Hospitals Case Medical Center/Case Western Reserve University, School of Medicine, Cleveland, OH, USA.
Journal of Clinical Psychopharmacology (Impact Factor: 3.24). 05/2008; 28(2):203-9. DOI: 10.1097/JCP.0b013e318166c4d5
Source: PubMed


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.

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Available from: Keming Gao, Sep 30, 2015
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    • "Mood stabilizers may be protective for brain structure and function (Emsell and McDonald, 2009; Benedetti et al., 2011), but whether saccade accuracy is restored with mood stabilizer treatment requires further investigation. Higher rates of extrapyramidal effects of antipsychotic medication have been noted in bipolar disorder compared with schizophrenia (Gao et al., 2008). Our data may be consistent with this in that prior to treatment, BDP patients showed a motor system disturbance that schizophrenia patients did not. "
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    ABSTRACT: Neurocognitive deficits are associated with most psychotic disorders, but may differ across diagnosis and by treatment status. This ambiguity is partly addressed in longitudinal pre/post treatment studies with first episode patients. Antipsychotic-naïve first-episode schizophrenia patients have shown intact performance on a predictive saccade task that assesses simple motor learning, spatial abilities, and response planning. After antipsychotic treatment, however, schizophrenia patients performing this task show a selective impairment in the accuracy of anticipatory responses, generated from learned internal representations of the task stimulus. This finding is in line with other observations of antipsychotic medication effects on frontostriatal systems, particularly dorsolateral prefrontal cortex. We sought to replicate this provocative finding with an independent sample of antipsychotic-naïve first-episode schizophrenia patients and extend it by including a group of patients with first episode bipolar disorder with psychosis (BDP). Matched healthy controls were also studied in parallel. Schizophrenia patients demonstrated intact performance pretreatment followed by impairment post-treatment for accuracy of anticipatory responses, and worse accuracy was associated with higher antipsychotic dose. BDP patients displayed saccade accuracy deficits before and after treatment and had no correlation of performance and antipsychotic dose. The findings suggest different neural alterations early in the course of each psychotic disorder, and different vulnerabilities to antipsychotic treatment effects between schizophrenia and BDP.
    Schizophrenia Research 08/2014; 159(1). DOI:10.1016/j.schres.2014.07.028 · 3.92 Impact Factor
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    • "A highly significant increase in responsiveness to haloperidol was found in the Kv10.1−/− group in the haloperidol-induced catalepsy test, which has been suggested as an experimental model of parkinsonism (44), irrespective of whether or not there had been AMPH sensitization. Haloperidol blocks dopaminergic receptors, especially D2 receptors, in the mesocortex and the limbic system of the brain and is effective in the treatment of acute psychotic states (45); however, by blocking the dopaminergic action in the nigrostriatal pathways, haloperidol induces extrapyramidal-motoric side effects such as dystonias, akathisia and pseudoparkinsonism (46). The hyperresponsivity to cataleptic effects of haloperidol that we have now observed in Kv10.1−/− mice may suggest a decreased density/number of somatodendritic D2 receptors in these mice (47,48). "
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    ABSTRACT: Kv10.1 (Eag1), member of the Kv10 family of voltage-gated potassium channels, is preferentially expressed in adult brain. The aim of the present study was to unravel the functional role of Kv10.1 in the brain by generating knockout mice, where the voltage sensor and pore region of Kv10.1 were removed to render non-functional proteins through deletion of exon 7 of the KCNH1 gene using the '3 Lox P strategy'. Kv10.1-deficient mice show no obvious alterations during embryogenesis and develop normally to adulthood; cortex, hippocampus and cerebellum appear anatomically normal. Other tests, including general health screen, sensorimotor functioning and gating, anxiety, social behaviour, learning and memory did not show any functional aberrations in Kv10.1 null mice. Kv10.1 null mice display mild hyperactivity and longer-lasting haloperidol-induced catalepsy, but there was no difference between genotypes in amphetamine sensitization and withdrawal, reactivity to apomorphine and haloperidol in the prepulse inhibition tests or to antidepressants in the haloperidol-induced catalepsy. Furthermore, electrical properties of Kv10.1 in cerebellar Purkinje cells did not show any difference between genotypes. Bearing in mind that Kv10.1 is overexpressed in over 70% of all human tumours and that its inhibition leads to a reduced tumour cell proliferation, the fact that deletion of Kv10.1 does not show a marked phenotype is a prerequisite for utilizing Kv10.1 blocking and/or reduction techniques, such as siRNA, to treat cancer.
    Human Molecular Genetics 02/2013; 22(11). DOI:10.1093/hmg/ddt076 · 6.39 Impact Factor
    • "Despite some authors telling us about a possible vulnerability of patients with affective symptoms to present EPS (Gao et al., 2008), there is no result suggesting that the relationship between D2RO and EPS in patients with affective disorders could be different from that observed in psychotic patients (Attarbaschi et al., 2007). Otherwise some researchers have argued that spontaneous abnormal movements, such as spontaneous parkinsonism, could be part of a neurodysfunction intrinsic to the pathogenesis of schizophrenia and may occur in up to 17% of patients (Pappa and Dazzan, 2009). "
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    ABSTRACT: Levels above 75% of striatal dopamine 2 receptor occupancy (D2RO) have been associated with extrapyramidal symptoms (EPS). The aim of the present study is to investigate the relationship between D2RO and EPS in a sample of psychotic patients in current treatment with both typical and atypical antipsychotics. Brain iodine-123-iodobenzamide single photon emission computed tomography ((123)I-IBZM SPECT) was performed in 81 patients taking stable doses of haloperidol, risperidone, olanzapine, quetiapine, clozapine or ziprasidone. First, the degree of D2RO and Positive and Negative Syndrome Scale (PANSS) scores was compared between the group of patients who presented EPS and the group free of EPS. Afterwards, these variables were compared among the different antipsychotic medications. The group with EPS presented means of D2RO significantly higher than the group free of EPS. Significant differences in D2RO were found in clozapine, quetiapine and ziprasidone groups compared with the haloperidol group. No differences were observed between either olanzapine or risperidone and haloperidol. No quetiapine- or clozapine-treated patients developed EPS. Haloperidol and risperidone demonstrated a relationship between striatal D2RO and EPS. The findings suggest that higher D2RO is related to appearance of EPS. Occupancy in the group with EPS was in agreement with previous studies that suggested a high degree of D2RO is necessary for the occurrence of EPS.
    Psychiatry Research 01/2012; 201(1):73-7. DOI:10.1016/j.pscychresns.2011.02.004 · 2.47 Impact Factor
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