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Association Between Serum Anticholinergic Activity and Psychiatric Symptoms of Chronic Schizophrenia

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Association Between Serum Anticholinergic Activity and Psychiatric Symptoms of Chronic Schizophrenia Showa Univ J Med Sci 27（4）, 251～260, December 2015 Original Association Between Serum Anticholinergic Activity and Psychiatric Symptoms of Chronic Schizophrenia 1 1 1 Norihisa AKASHI＊ ）, Masayuki TANI ）, Takahiro TOKUMASU ）, 2 3 4 Misa HOSOI ）, Kimiko KONISHI ）, Mitsugu HACHISU ）, 1 1 2 Nobumasa KATO ）, Akira IWANAMI ） and Koji HORI ） Abstract : The cholinergic system in schizophrenia has been associated with treat- ments, adverse effects, and pathophysiological processes. Although the role of the cholinergic system in schizophrenia has been thoroughly investigated, few studies have examined the dynamics of human cholinergic systems in vivo. We compared serum anticholinergic activity （SAA） in patients with schizophrenia to that in healthy controls and investigated correlations between anticholinergic activity and various domains of psychiatric symptoms. Fifteen chronically medicated patients with schizophrenia and 10 healthy controls participated in the study. We measured SAA using a receptor-binding assay （［3H］-QNB）. We also measured extrapyrami- dal motor symptoms and psychiatric symptoms, and assessed cognitive functioning with subscales of the Wechsler Memory Scale. Elevated levels of SAA （＞ 1.95 pmol / ml） were signicantly more common among patients with schizophrenia than among healthy controls （P＜0.001）. There was a signicant negative correla- tion between SAA and extrapyramidal motor symptoms in patients with schizo- phrenia （P＝0.043）. We found no signicant association between SAA and other psychiatric symptoms and cognitive functions. These results indicate that SAA is greater among patients with schizophrenia than healthy controls, and that the anticholinergic effects might reduce extrapyramidal motor symptoms but exacerbate thought disorders. Further studies are warranted to conrm this nding in a larger cohort of non-medicated patients. Key words : thought disorder, schizophrenia, acetylcholine, neurotransmitters, motor symptoms Introduction Schizophrenia is a severe chronic mental illness that affects about 1％ of the population 1）. Despite numerous studies over the past century, the etiology and pathophysiology of schizo- 1）Department of Psychiatry, Showa University Karasuyama Hospital, 6-11-1 Kita-Karasuyama, Setagaya-ku, Tokyo 157-0061, Japan. 2）Department of Psychiatry, Showa University Northern Yokohama Hospital. 3）Department of Pharmacy, Tokyo Metropolitan Tobu Medical Center for Persons with Developmental / Multiple Dis- abilities. 4）Division of Clinical Pharmacy, Department of Pharmaceutical Tharapeutics, Showa University School of Pharmacy. ＊ To whom corresponding should be addressed. 252 Norihisa AKASHI, et al phrenia are poorly understood and the available treatments are only modestly effective 1）. Over recent decades, neuropsychopharmacological research has focused on identifying the role of neurotransmitter systems in schizophrenia. The disorder has been associated with deterioration of dopamine signaling and changes relating to other neurotransmitters, including glutamate, gamma - aminobutyric acid, serotonin, norepinephrine, and acetylcholine（ ACh）2）. ACh was the first neurotransmitter to be discovered. It operates in the central nervous system （CNS） and the peripheral nervous system （PNS）. In the PNS, it acts in the parasym- pathetic nervous system, where it is involved in ganglionic neurotransmission and neuroeffector junctions, modulating various autonomic functions. It also acts in the somatic branch of the PNS, where it is involved in skeletal muscle activation. In the CNS, there are cholinergic inter- neurons and cholinergic projection neurons, mainly distributed in the frontal cortex, modulating motor function and cognitive abilities such as memory, executive function, and attention 3）. Antipsychotic agents used to treat schizophrenia, particularly first-generation antipsychotics, frequently cause extrapyramidal motor side effects such as tremor, akinesia, impairment of the postural reex, akathisia, dyskinesia, and dystonia. Because these side effects lead to only mod- est impairments in activities of daily living, they are often treated with adjunctive anticholinergic agents to promote treatment adherence 4）. However, long-term use of anticholinergic agents can cause cognitive decline, delirium, and a worsening of psychiatric symptoms that is referred to as “antimuscarinic syndrome” 5）, and thus, the use of anticholinergic agents has declined. Further- more, second-generation antipsychotics that have reduced extrapyramidal side effects have been developed. Recently, dysregulation of the cholinergic system in schizophrenia has been thoroughly inves- tigated. Some researchers have suggested that the cholinergic system, especially muscarinic signaling, plays a key role in the pathogenesis of schizophrenia 6）. Although the role of the cholinergic system in schizophrenia has been suggested by pharmacological, physiological, and neuroimaging studies, few studies have examined the dynamics of human cholinergic systems in vivo. It is difcult to directly study cholinergic neurotransmission in the brain. However, it has been suggested that levels of serum anticholinergic activity （SAA） adequately reect central anticholinergic activity 7）. There are few published studies of SAA measurement in patients with schizophrenia as a means of evaluating the effects of antipsychotic agents on motor symptoms or the effects of antimuscarinic agents on cognitive dysfunction. Furthermore, the association between SAA and motor symptoms has relied on the DiMascio Extrapyramidal Symptoms Scale 8）, which does not provide a sufcient rating of extrapyramidal motor symptoms. Moreover, despite detailed investigations of various cognitive functions ― for example, Measurement and Treatment Research to Improve Cognition in Schizophrenia （MATRICS）9） ― detailed examina- tion of clinical symptoms in neuropsychiatric and behavioral domains has not been conducted. Notably, levels of SAA and its association with physical and cognitive symptoms have not been directly compared between patients with schizophrenia and healthy controls. In this study, we compared levels of SAA in older age patients with chronic schizophrenia with levels of SAA in healthy controls. We examined the association between SAA and various SAA and Psychiatric Symptoms of Schizophrenia 253 domains of extrapyramidal motor symptoms and psychiatric and behavioral symptoms including affective symptoms, thought disorder, delirium, and decit syndrome. We hypothesized that SAA would be negatively correlated with the severity of extrapyramidal motor symptoms, depres- sive symptoms, and negative symptoms, and would be positively correlated with the severity of thought disorder, delirium-related symptoms, and cognitive impairments. Materials and methods Participants Fifteen chronic schizophrenia patients （six men and nine women） and 10 healthy controls （ve men and ve women） participated in the study. The two groups were matched for age. The participants with schizophrenia were either outpatients or inpatients at Showa University Karasuyama Hospital in Tokyo, Japan, and were diagnosed with schizophrenia according to the Diagnostic and statistical manual of mental disorders, text revision, 4th edition 10）. All participants were aged 60 years or older （mean ± SD : 65.5 ± 3.4 years ; range : 60–77 years）. All those who had schizophrenia had an illness duration of more than 20 years（ mean ± SD : 43.6 ± 7.49 years）. No participant had any other signicant neurological illness, or signicant physical illness, history of drug misuse, other comorbidities, or comorbid personality disorders. The healthy controls were not taking any medication. Schizophrenia diagnoses and data on sociodemographic status were rechecked by two psychiatrists before the study. Participants were given the Japanese version of the National Adult Reading Test 11） to estimate their intelligence quotients（ IQs）. Procedure Serum Anticholinergic Activity（ SAA） Venous blood was obtained from participants between 7:00am and 9:00am. The blood was collected in untreated tubes and allowed to clot at room temperature for 30 min and then cen- trifuged at 2500 rpm for 10 min. Serum was removed and frozen at –80°C until it was assayed. SAA was measured according the protocol of Tune and Coyle 12）, using a receptor-binding assay at LSI Medience Corporation, Kumamoto, Japan. In this radioreceptor technique, the amount of muscarinic antagonist, ［3H］-radiolabeled quinuclidinyl benzilate （［3H］-QNB）, inhibited by the blood sample is compared with that of a known concentration of atropine and expressed as an “atropine equivalent”. The relationship between atropine concentration and ［3H］-QNB counts was linear for atropine concentrations ranging from 1.95 pmol / ml to 25 pmol / ml. Participants with SAA levels greater than 1.95 pmol / ml were dened as SAA positive 13）. Evaluation of Extrapyramidal Symptoms, Psychiatric Symptoms, and Cognitive Functioning We evaluated the severity of global extrapyramidal symptoms among patients with schizophre- nia using the Drug-Induced Extrapyramidal Symptoms Scale （DIEPSS）14） and the Abnormal Involuntary Movement Scale （AIMS）15）, and we evaluated akathisia with the Barnes Akathisia Scale（ BAS）16）. The DIEPSS has been commonly used in Japan to evaluate drug-induced extra- pyramidal symptoms since 1997 ; higher scores indicate more severe extrapyramidal symptoms. We also evaluated the severity of global psychiatric symptoms with the Brief Psychiatric 254 Norihisa AKASHI, et al Rat ing Scale
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