Benefits and limits of anticholinergic use in schizophrenia: Focusing on its effect on cognitive function

Authors


Abstract

All currently available antipsychotic drugs are the dopamine D2 receptor antagonists and are capable of producing extrapyramidal side-effects (EPS). Anticholinergic drugs are primarily used to treat EPS or prevent EPS induced by antipsychotics in the treatment of psychosis and schizophrenia. However, they can cause a variety of distressing peripheral side-effects (e.g. dry mouth, urinary disturbances, and constipation) and central adverse effects (e.g. cognitive impairment, worsening of tardive dyskinesia, and delirium). Disturbances in cognitive abilities are cardinal features of schizophrenia from its earliest phases and account for much of the functional disability associated with the illness. It is likely that long-term concomitant administration of anticholinergics exacerbates the underlying cognitive impairment in patients with schizophrenia and subsequently affects patients' quality of life. Thus, current treatment guidelines for schizophrenia generally do not recommend the prophylactic and long-term use of anticholinergics. However, the high use of long-term anticholinergic drugs with antipsychotics has been identified as an important issue in the treatment of schizophrenia in several countries. To assess the benefits and limits of anticholinergic use in psychosis and schizophrenia, this article will provide a brief review of the pharmacology and clinical profiles of anticholinergic drugs and will focus on their effects on cognitive function in schizophrenia, particularly during the course of the early phase of the illness. In addition, we will address the effects of discontinuation of anticholinergics on cognitive function in patients with schizophrenia and provide a strategy for adjunctive anticholinergic use in patients treated with long-acting injectable antipsychotics.

SCHIZOPHRENIA IS A chronic and debilitating psychiatric illness with a worldwide prevalence of approximately 1%.[1] It is characterized by positive, negative, cognitive, and affective symptoms. Since the introduction of chlorpromazine in 1952, antipsychotic drugs represent the mainstay of the pharmacologic treatment for psychosis and schizophrenia.[2, 3] The exact pathophysiological mechanisms underlying schizophrenia are unknown but consistent evidence points to an increased subcortical presynaptic dopamine neurotransmission.[4, 5] On this neurochemical basis, all antipsychotics are dopamine D2 receptor antagonists. By blocking dopaminergic neurotransmission in subcortical areas, they are capable of producing extrapyramidal side-effects (EPS), such as parkinsonism (tremor, akinesia, and rigidity), akathisia, dystonia, and tardive dyskinesia (TD), occurring acutely or during chronic treatment.[3] In general, this propensity is more pronounced with the first-generation antipsychotics (FGA) than with the second-generation antipsychotics (SGA).[6] Over the past 2 decades, SGA replaced FGA as the standard treatments for schizophrenia,[2] although there is recent evidence indicating no differences in effectiveness.[3, 6]

Anticholinergic drugs have been used in the treatment of symptoms of Parkinson's disease for over a century and they are still in use today.[7, 8] For patients with psychosis and schizophrenia, anticholinergics are primarily used to treat EPS or prevent EPS induced by antipsychotics.[3] However, they can cause distressing peripheral side-effects (e.g. dry mouth and constipation) and central adverse effects (e.g. cognitive impairment, worsening of tardive dyskinesia, and delirium).[9-13] It is notable that disturbances in cognitive abilities are cardinal features of schizophrenia and account for much of the functional disability associated with the illness.[14-16] Thus, current treatment guidelines for schizophrenia generally do not recommend the prophylactic and chronic use of anticholinergics.[17, 18] However, the high use of long-term anticholinergic drugs with antipsychotics has been identified as an important issue in the treatment of schizophrenia in several countries.[19-23]

To assess the benefits and limits of anticholinergic use in psychosis and schizophrenia, this article will provide a brief review of the pharmacology and clinical profiles of anticholinergic drugs and will focus on their effects on cognitive function in schizophrenia, particularly during the course of the early phase of the illness.

Pharmacology of Anticholinergics

The neurotransmitter acetylcholine (ACh) participates in a number of physiological functions in the peripheral and the central nervous system (CNS).[24] ACh binds to two types of cholinergic receptors: the ionotropic family of nicotinic ACh receptors and the metabotropic family of muscarinic ACh receptors (mAChR), overlapping in a wide variety of peripheral tissues and brain regions.[25, 26] Muscarinic AChR consist of five subtypes termed M1–M5 receptors. M1, M3, and M5 receptors couple to Gq and activate phospholipase C, whereas M2 and M4 receptors couple to Gi/o and associated effecter systems, such as ion channels and adenylyl cyclase.[24, 25, 27]

Dopamine, an inhibitory neurotransmitter in the caudate nucleus of the basal ganglia, is known to be in balance with cholinergic excitatory neurons in the same pathway.[7] Antipsychotic drugs can reduce dopaminergic activity through the blockade of dopamine D2 receptors and alter this balance, thereby producing EPS.[28] Currently available antiparkinsonian anticholinergic drugs (e.g. benztropine, biperiden, and trihexyphenidyl) can block excitatory cholinergic pathways in the basal ganglia and restore the dopamine/Ach balance.[7] The antimuscarinic, rather than antinicotinic, properties of anticholinergics are thought to be responsible for their efficacy in treating EPS. Antiparkinsonian anticholinergics generally block all subtypes of mAChR, but most of them show the highest affinity for M1 receptors.[29] The difference in optimal-dose level between the different anticholinergics appears to be associated with their relative potency in binding to mAChR.[8]

Anticholinergic drugs also act as potent indirect dopamine agonists by blocking the presynaptic uptake of dopamine and causing its release from presynaptic terminals.[7, 30] In addition, they strongly inhibit the presynaptic reuptake of norepinephrine and weakly inhibit the reuptake of serotonin.

Most anticholinergic drugs are given orally for routine use and administered as the hydrochloric acid salt with the exception of benztropine, which is given as the mesylate salt.[8] The time to maximal plasma concentrations is generally less than 2.5 h. Oral bioavailability is variable between the different agents, ranging from 30% to over 70%.[8] All of the anticholinergics appear to be extensively metabolized, primarily to N-dealkylated and hydroxylated metabolites. The clearance of the anticholinergics is low in relation to hepatic blood flow. Thus, a high hepatic first-pass effect would not be expected after oral administration.[8] Elimination of parent anticholinergics and their metabolites is via the urine and bile.

Effect of Anticholinergic Use on the Peripheral Nervous System

In the peripheral nervous system, ACh acts as a neurotransmitter in the autonomic ganglia and the neuromuscular junction.[26] The mAChR are located in the eye, secretory glands, heart, lungs, gastrointestinal tract, genitourinary tract, and skin.[10] Ach is involved in various peripheral functions, such as heart rate, blood flow, gastrointestinal tract motility, sweat production, and smooth muscle activity. Thus, targeting pharmacological treatments to the CNS without affecting the peripheral ACh functions has been a difficult challenge.[26]

Anticholinergic drugs can cause uncomfortable peripheral side-effects, such as blurred vision, constipation, dry mouth, urinary disturbances, and tachycardia.[7, 12] Elderly patients can be especially sensitive to the anticholinergic action of these drugs due to physiological and pathophysiological changes that often accompany the aging process.[10] Among the currently available antiparkinson anticholinergics, benztropine has the highest affinities for mAChR.[29] Biperiden has higher affinity than does trihexyphenidyl for all subtypes of mAChR. However, the peripheral side-effect profile of biperiden was not significantly different from that of trihexyphenidyl in healthy volunteers.[31]

Effect of Anticholinergic Use on the Central Nervous System

Cholinergic neurotransmission plays a critical role in various CNS functions, including sensory perception, motor control, cognitive processing, learning and memory, arousal, attention, regulation of sleep–wake cycles, nociception, motivation, reward, mood, and psychosis.[24, 26] The cholinergic projections originating in the medial septum and the diagonal band of Broca make synaptic contact with widespread but highly specific targets in a variety of forebrain regions, including the basal ganglia, cortex, and hippocampus.[24] The striatum is the main input structure of the basal ganglia that subserves motor and cognitive function. Drugs that decrease cholinergic transmission can impair storage of new information into long-term memory, whereas immediate memory seems not to be affected.[32]

It has been reported that anticholinergic drugs can cause cognitive dysfunction in healthy subjects[32-35] and, at higher doses, can induce delirium as well as vivid hallucinations in healthy controls.[26, 36] In addition, they can impair memory function in patients treated for Parkinson's disease.[37, 38] These drug-related phenomena are generally attributed to the antimuscarinic properties of these agents. Kurlan and Como[39] previously called this memory dysfunction ‘drug-induced alzheimerism’.

As already mentioned, anticholinergic drugs also have dopaminergic- and noradrenergic-agonist activity in the CNS.[7, 30] The activity may play a role in producing the behavioral agitation, mood elevation, central stimulating effects, stereotypy, drug dependence, and exacerbation of psychosis, which have been infrequently reported with anticholinergics in both healthy and psychiatric populations.

Effect of Anticholinergic Use on Cognitive Function in Schizophrenia

Patients with schizophrenia have all domains of cognitive impairments, including attention, processing speed, executive function, verbal fluency, verbal learning and memory, and working memory.[14, 40] The pattern of cognitive deficits may vary widely among individuals with schizophrenia and the mean deficit in these domains may be 1–3 standard deviations below normal, although about 15% of patients with schizophrenia test within the normal range in all domains.[41] Cognitive impairment relates directly to sociovocational functioning,[15] and exerts a greater influence on functional outcome than the presence or severity of the positive or negative symptoms of schizophrenia.[42, 43] Moreover, these cognitive deficits are associated with poor quality of life (QOL) in patients with schizophrenia.[44, 45]

Many authors have reported that the use of anticholinergics in schizophrenia is associated with decreases in cognitive function, including memory, learning, attention, and executive function.[9, 11, 13, 46, 47] For example, Silver and Geraisy[11] compared the effects of biperiden and a dopaminergic antiparkinsonian agent, amantadine, on memory function in 26 chronic schizophrenic patients and found that biperiden caused poorer memory performance than did amantadine, particularly on visual memory task. Several studies found that serum anticholinergic drug activity levels in stabilized patients with schizophrenia showed a significant inverse correlation with the patients' performances on tests of verbal learning and memory.[9, 48, 49] McEvoy and Freter[50] demonstrated that memory impairment increased as the dose of anticholinergic drugs was increased to the upper boundary of the clinically acceptable dosage range. Additionally, in the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) study conducted in the USA,[51] anticholinergics impaired several domains of cognitive functioning, including attention, declarative memory, verbal memory, and spatial working memory.[47] It is likely that long-term concomitant administration of anticholinergics exacerbates the underlying cognitive impairment in patients with schizophrenia and subsequently affects patients' QOL.[47]

It should be noted that anticholinergics can exacerbate psychosis but modestly improve negative symptoms of schizophrenia.[26, 52, 53] These effects could be associated with an increased release of dopamine induced by anticholinergics.[26, 54] In accordance with these findings, patients with schizophrenia often report an activating effect of higher doses of anticholinergics, which sometimes results in an abuse of them.[26, 55]

Effect of Discontinuation of Long-Term Anticholinergic Use on Cognitive Function in Schizophrenia

To date, four studies have addressed the effects of discontinuation of anticholinergics on cognitive function in schizophrenia.[56-59] Baker et al.[56] reported that discontinuation of benztropine mesylate improved attention and concentration in patients with chronic schizophrenia. However, long-term memory, delayed verbal recall, and learning of new information were not affected by the withdrawal of the anticholinergic drug. In contrast, Mori et al.[57] demonstrated significant improvements in immediate memory and verbal working memory after withdrawal from anticholinergics, including biperiden, trihexyphenidyl, and mazaticol. Drimer et al.[58] reported that discontinuation of long-term biperiden use induced significant improvements in the Alzheimer's Disease Assessment Scale-Cognitive total score as well as in the ideational praxis and orientation subscales in elderly patients with chronic schizophrenia.

The use of long-term anticholinergics with antipsychotics is still highly prevalent in Japan.[21-23] Yoshio et al.[22] reported that adjunctive anticholinergics were prescribed in 56–75% of chronic inpatients with schizophrenia who were taking SGA in 2006. One meta-analysis and other quantitative reviews showed a significant advantage for SGA over FGA in several cognitive domains in schizophrenia.[43, 60, 61] Thus, it is possible that some benefits of SGA, particularly on cognitive function, are offset by chronic use of anticholinergics.

In this context, we sought to evaluate the effects of discontinuation of long-term biperiden use on cognitive function in patients with chronic schizophrenia receiving an SGA.[59] We assessed cognitive function by using the Japanese-language version of the Brief Assessment of Cognition in Schizophrenia (BACS-J),[62] which has established reliability and validity, and is designed to measure cognitive function in schizophrenia.[62, 63] We found that discontinuation of biperiden significantly improved attention and processing speed and the composite score, as measured by BACS-J without practice effects (Fig. 1).[59] Furthermore, discontinuing biperiden use significantly improved subjective QOL and psychiatric symptoms without significant adverse effects. It has been reported that withdrawal symptoms of EPS and those of cholinergic rebound may reach their peak within 2 weeks after abrupt discontinuation of anticholinergics.[64, 65] In our study, biperiden was reduced at a rate of 1 mg/2–4 weeks, which may be a safe strategy for discontinuation of long-term biperiden use in schizophrenia. It also appears to be important to taper biperiden over at least 4 weeks.[59]

Figure 1.

Biperiden was gradually tapered and discontinued at a rate of 1 mg/2–4 weeks in 24 patients with chronic schizophrenia who had received a second-generation antipsychotic with concomitant biperiden for at least 3 months. Before and 4 weeks after discontinuation of biperiden, the Japanese-language version of the Brief Assessment of Cognition in Schizophrenia (BACS-J) was administered. Within-group improvements in cognitive performance over time were evaluated using paired t-tests. The data were based on the study by Ogino et al.[59] *P < 0.05; **P < 0.01. image, Baseline; image, End-point.

Cognitive Function in the Early Stages of Psychosis

A meta-analysis of cognitive findings from 47 studies of 2204 patients experiencing a first-episode psychosis demonstrated moderate to large effect size (−0.64 to −1.20) across all cognitive domains, and the magnitude and pattern of these impairments approximate those documented in more chronic samples.[66] Accumulating evidence also suggests that for most schizophrenic patients, cognitive deficit is only slowly progressive after the first episode and some components of the deficit are already present during childhood and early adolescence, but usually in a mild form.[41] It is thus possible that an extensive decline in cognitive function may develop during the pre-psychotic phases period, the first episode, or both. Recent advancements in the past years have allowed clinicians to address this issue by investigating individuals at clinical high risk (CHR) for psychosis.[67] This putatively prodromal psychotic phase is associated with an enhanced probability of developing the illness, mostly schizophrenia spectrum disorders,[68] as compared to the general population (1%), ranging from 18% after 6 months up to 36% after 3 years.[69] Interest in this area has exponentially grown to the extent that a new diagnostic category is being discussed in the DSM-5,[70] although ‘attenuated psychosis syndrome’ is included in the manual's proposed criteria sets. Accumulating neurobiological evidence suggests the CHR state for psychosis is characterized by abnormalities in the structure,[71-73] function,[74-76] connectivity,[77] and neurochemistry[5, 78, 79] of the brain, resembling those observed in established psychosis.[80] These alterations represent the neural correlate of the neurocognitive impairments usually observed in these subjects.

To clarify this notion, Pukrop et al.[81] cross-sectionally compared cognitive profiles in 179 healthy controls, 38 CHR subjects in an early initial prodromal state (EIPS), 90 CHR subjects in a late initial prodromal state (LIPS), 86 first-episode patients with schizophrenia, and 88 multiple-episode patients. They found that IPS subjects were substantially impaired in verbal memory and verbal executive functions. Compared to EIPS subjects, LIPS subjects showed additional attentional deficits. CHR subjects were superior to first-episode patients who showed a generalized cognitive deficit profile, and to multiple-episode patients who presented evidence for further decline. These results suggest a clear tendency towards a continuous generalized cognitive decline across the course of the illness.[81]

Niendam et al.[82] evaluated the pattern of cognitive deficits in 45 CHR individuals and found that they showed significant deficits in speed of processing, verbal learning and memory, and motor speed. Poorer verbal learning and memory performance was significantly associated with poorer social functioning. Keefe et al.[83] compared the cognitive performance of 37 CHR subjects to that of 47 healthy subjects and 59 subjects with first-episode psychosis. The CHR subjects performed more poorly than healthy subjects, but better than first-episode patients. They were particularly impaired on measures of vigilance and processing speed. The cognitive performance of CHR subjects who progressed to psychosis was similar to that of first-episode subjects and worse than that of healthy controls. The CHR subjects who did not develop psychosis were not significantly different from the healthy controls, but performed better than the first-episode subjects. The authors also suggest that the combination of poor vigilance and high processing speed may be an early risk predictor for subsequent development of psychosis.

The study by Pflueger and colleagues[84] provides data showing that CHR subjects demonstrate deficiencies in intelligence, executive functions, working memory, and attention compared to those of healthy controls. They also suggested that verbal intelligence, executive functions, and, in particular, working memory may be useful for distinguishing CHR subjects from healthy individuals. Simon et al.[85] found that the CHR group demonstrated intermediate cognitive performance between the first-episode group and the subjects who met basic symptoms at risk. Auditory working memory, verbal fluency/processing speed, and declarative verbal memory were mostly impaired in the CHR group. However, the above findings were not consistent across the individual studies. To address this issue at a quantitative level, Fusar-Poli et al. recently conducted a meta-analysis of cognitive functioning in CHR subjects.[86] Nineteen studies met their inclusion criteria, comprising a total of 1188 CHR subjects and of 1029 controls. At a meta-analytical level, CHR subjects were impaired relative to controls on tests of general intelligence, executive functions, verbal/visual memory, verbal fluency, attention and working memory, and social cognition.[86] Processing speed was also slower but the difference was not statistically significant. Later transition to psychosis was associated with even more marked deficits in the verbal fluency and memory domains. The authors concluded that the CHR state for psychosis is associated with robust and widespread impairments in neurocognitive functioning and social cognition and that subsequent transition to psychosis is particularly associated with deficits in verbal fluency and memory functioning.

These findings suggest that in the near future, performance on tests of cognition may serve as a predictor for the development of psychosis.[83] Early intervention to prevent the further progression of cognitive impairments at the early stage of psychosis is warranted.

Benefits and Limits of Anticholinergic Use in Early Psychosis

It has been suggested that patients with first-episode psychosis are more responsive and sensitive to treatment with an antipsychotic drug in terms of efficacy and side-effects than patients with recurrent episodes.[87, 88] Young, severely ill patients in their first psychotic episode who have never been treated with antipsychotics appear to be at higher risk to develop acute dystonia.[89] Acute dystonia is a painful and distressing side-effect for patients and usually occurs within the first few days of starting treatment with antipsychotics. Kopala[90] suggested that patients' experience of EPS during their first exposure to antipsychotic medication can have lasting effects on their attitudes to medication and adherence. Supporting this notion, Robinson et al.[91] demonstrated that EPS are associated with antipsychotic discontinuation by first-episode subjects even when present at low levels of severity.

Acute dystonia is rapidly and effectively treated with an anticholinergic agent, particularly when administered parenterally.[92] Moreover, short-term prophylaxis with anticholinergic medication is likely to be effective. Kopala[90] reported that approximately 60% of drug-naïve first-episode patients with schizophrenia relapsed in the first year after resolution of an acute psychotic episode, but prophylactic anticholinergic medication with FGA reduced the relapse rate to less than 20% per year.

Because of the frequency with which acute EPS occur, particularly with high-potency antipsychotic agents, clinicians may wish to consider the prophylactic use of anticholinergic drugs. However, they are generally less effective for acute akathisia[92] and their long-term use may predispose to the development of TD,[93] although there is no evidence that chronic use of anticholinergics causes damage to the basal ganglia.[7] Moreover, as already mentioned, they may cause a variety of unpleasant side-effects in the peripheral and central nervous system.

To date, no study has examined the effects of adjunctive use of anticholinergics with antipsychotics on cognitive function in early psychosis. Robinson et al.[91] reported that better executive functioning can decrease the likelihood of medication discontinuation by patients with first-episode schizophrenia, suggesting that efforts to improve cognitive deficits in early schizophrenia may enhance adherence and subsequently improve long-term outcomes.

On the basis of these considerations, we do not recommend the prophylactic use of anticholinergics in patients with early psychosis. If EPS appear, clinicians should consider lowering the antipsychotic dosage, or switching to an SGA with a lower risk of EPS. The risk–benefit ratio of anticholinergics may be optimized when it is used at the lowest effective dose, and with those patients at highest risk for EPS.[3] Further prospective study is needed to develop knowledge about the potential risks and benefits of short-term anticholinergic use in patients with early psychosis, particularly on cognition.

Benefits and Limits of Anticholinergic Use in Long-Acting Antipsychotic Medications

Several FGA and SGA are available in long-acting injectable (LAI) formulations. LAI formulations are especially advantageous in patients with poor adherence and those with a history of severe relapse upon medication discontinuation.[3, 94] A recent systematic review of 10 randomized long-term studies comparing LAI with oral antipsychotics in schizophrenia demonstrated that LAI antipsychotics significantly reduced relapse rates from an average of 33.2% to 21.5%.[95] LAI formulations may be particularly helpful in the maintenance phase of treatment.[3] However, several studies suggest that the use of LAI medication is also feasible in first-episode schizophrenia and may have distinct advantages.[96-99] Nonetheless, due to a number of methodological problems, the quality of this evidence is subject to possible bias.[95]

Another advantage of LAI antipsychotics is that they eliminate bioavailability problems related to absorption and first-pass metabolism and give a stable plasma concentration.[94] In addition, LAI antipsychotics assure better and safer possibilities to use the lowest effective dose strategy. These factors may contribute to reducing the frequency of side-effects, such as akathisia.[94] In fact, several studies suggest that the use of LAI SGA is generally associated with a reduced risk of developing EPS compared with LAI FGA.[100-102] Moreover, Kim and colleagues[103] reported that switching from oral SGA (mainly risperidone) to LAI risperidone significantly improved cognitive function, including vigilance, verbal learning and memory, executive function, sustained attention, and visuomotor speed in patients with chronic schizophrenia. LAI risperidone also significantly improved EPS and adjunctive use of anticholinergics was reduced after switching. In contrast, a recent large-scale long-term randomized controlled trial demonstrated that LAI risperidone was not superior to oral antipsychotic treatment in terms of time to hospitalization, symptoms, or QOL, and it was associated with more adverse events at the injection site and more EPS.[104]

To date, no study has examined the effects of concomitant anticholinergics with LAI antipsychotics on cognitive function and safety in patients with schizophrenia. Moreover, existing guidelines for the use of LAI formulations in schizophrenia do not mention how to use the adjunctive anticholinergics.[98] Pullen et al.[105] previously described that if long-term anticholinergic treatment for EPS is indicated in patients on regular depot antipsychotic medication, it may be possible to limit the administration of the anticholinergic to 7–10 days after injection. However, this notion is merely based on empirical evidence and data to support it are lacking.

Considering the potential undesirable peripheral and central side-effects of anticholinergics as described in this article, we would like to propose that anticholinergics should be restricted to those patients with EPS that cannot be controlled by lowering the dose of LAI antipsychotics. They should then be stopped later to allow the need for continued use to be assessed. The prophylactic use of anticholinergics is not recommended. These strategies might enhance the potential benefits of LAI antipsychotics on cognition, subjective experience, and adherence. Prospective studies of anticholinergics are necessary to confirm our proposal in patients with schizophrenia treated with LAI antipsychotics.

Table 1 summarizes the key clinical studies reviewed in this article. We also present key learning points in Table 2.

Table 1. Key clinical studies reviewed in this article
StudyNumber of patientsSummary of resultsLimitations
  1. We selected these studies because they presented clinically meaningful results and potentially had a momentous impact on clinical practice. CHR, clinical high risk; FGA, first-generation antipsychotics; QOL, quality of life; SGA, second-generation antipsychotics.
Silver and Geraisy (1995)[11]26
  • Biperiden (4 mg/day) treatment for 2 weeks was associated with poorer memory performance than amantadine (200 mg/day) treatment, particularly with visual memory task in patients with chronic schizophrenia.
  • It is unclear whether biperiden alone induced the poorer memory performance or whether amantadine improved it in this crossover design.
Minzenberg et al. (2004)[13]106
  • Anticholinergic load was associated with lower scores on measures of auditory and visual memory and attention in clinically stable outpatients with schizophrenia.
  • This study was not designed in a prospective, randomized, or controlled manner.
McEvoy (1987)[34]90
  • Standard clinical doses of anticholinergics (benztropine or trihexyphenidyl) caused memory impairment in healthy subjects.
  • Elderly subjects were more severely impaired than were young adults.
  • Amantadine was free of effects on memory in both young adult and elderly subjects.
  • The participants were normal healthy volunteers.
  • The subjects received each medication only for 4 days in this crossover trial.
Mori et al. (2002)[57]21
  • Discontinuation of anticholinergic drugs (biperiden, trihexyphenidyl, or mazaticol) improved immediate memory, verbal working memory, and psychopathology, and increased regional cerebral blood in inpatients with chronic schizophrenia.
  • The sample size was small.
  • The mean age of the participants was high (56.1 years).
  • The participants were treated with FGA (chlorpromazine and haloperidol) or an SGA (risperidone).
Ogino et al. (2011)[59]34
  • Discontinuation of long-term biperiden use improved attention and processing speed, and global cognitive function without significant adverse effects in patients with chronic schizophrenia treated with an SGA.
  • Discontinuing biperiden use improved subjective QOL and psychiatric symptoms.
  • The sample size was small.
  • Biological measures, such as brain imaging and pharmacokinetic monitoring, were not assessed.
Pukrop et al. (2006)[81]481
  • Subjects in an initial prodromal state were substantially impaired in verbal memory and verbal executive functions.
  • Compared to subjects in an early initial prodromal state, subjects in a late initial prodromal state showed additional attentional deficits.
  • Subjects at CHR for psychosis were superior to first-episode patients who showed a generalized cognitive deficit profile, and to multiple-episode patients who presented evidence for further decline.
  • Neurocognitive performance was evaluated in a cross-sectional design, but not in a longitudinal manner.
Keefe et al. (2006)[83]143
  • The CHR subjects performed more poorly than healthy subjects, but better than first-episode patients. They were particularly impaired on measures of vigilance and processing speed.
  • The cognitive performance of CHR subjects who progressed to psychosis was similar to that of first-episode subjects and worse than that of healthy controls.
  • The CHR subjects who did not develop psychosis were not significantly different from the healthy controls, but performed better than the first-episode subjects.
  • The combination of poor vigilance and high processing speed predicted progression to psychosis.
  • The breadth of cognitive assessment in this study was limited.
  • Statistical power to determine the predictive value of neurocognitive impairments for the progression to psychosis was limited.
Pflueger et al. (2007)[84]111
  • CHR subjects demonstrated deficiencies in intelligence, executive functions, working memory, and attention compared to those of healthy controls.
  • Verbal intelligence, executive functions, and, in particular, working memory discriminated best between CHR subjects and healthy individuals.
  • This study used test versions of the Continuous Performance Test, which imposed only a moderate cognitive load. As a result, raw value distributions were skewed, and quite complex pre-processing stages had to be applied.
Simon et al. (2007)[85]185
  • CHR group demonstrated intermediate cognitive performance between the first-episode group and the subjects who met basic symptoms at risk.
  • Auditory working memory, verbal fluency/processing speed, and declarative verbal memory were mostly impaired in the CHR group.
  • Neurocognitive performance was evaluated in a cross-sectional design, but not in a longitudinal manner.
  • This study lacks adequate matching on parental socioeconomic status, sex, and age.
  • This study did not assess parental education or premorbid reading ability.
  • Some of the employed neuropsychological tests were not age scaled or were not normalized across the entire adolescent age range assessed in this study.
Robinson et al. (2002)[91]118
  • Patients with poorer premorbid cognitive functioning were more likely to discontinue antipsychotics during the first year of treatment.
  • Extrapyramidal side-effects were associated with medication non-adherence after the first relapse in patients with first-episode schizophrenia or schizoaffective disorder.
  • Better executive functioning decreased the likelihood of medication discontinuation after the first relapse.
  • The samples of this study did not include patients who were the most uncooperative.
  • This study lacked assessments of insight and patient attitudes toward medication and illness.
Table 2. Key learning points
  1. EPS, extrapyramidal side-effects; LAI, long-acting injectable.
1. Anticholinergic drugs can cause distressing peripheral and central side-effects, such as cognitive impairment.
2. Cognitive impairments are cardinal features of schizophrenia from its earliest phases and account for much of the functional disability associated with the illness.
3. Discontinuation of long-term anticholinergic drug use may improve some measures of cognitive function and subjective QOL in patients with chronic schizophrenia.
4. The clinical high-risk state for psychosis is associated with robust and widespread impairments in neurocognitive functioning and social cognition.
5. Transition to psychosis is particularly associated with deficits in verbal fluency and memory functioning.
6. Efforts to improve cognitive deficits in early psychosis may enhance adherence and subsequently improve long-term outcomes.
7. No study has examined the effects of concomitant anticholinergic drugs with LAI antipsychotics on cognitive function and safety in patients with schizophrenia. Anticholinergic drugs should be restricted to those patients with EPS that cannot be controlled by lowering the dose of LAI antipsychotics.

Conclusion

Anticholinergic antiparkinsonian drugs can cause distressing peripheral and central side-effects. They can worsen global cognitive function in schizophrenia and may offset the benefits of SGA or LAI antipsychotics in the treatment of the illness. Anticholinergics should be used prudently and only as long as necessary to control EPS.[7] If possible, clinicians should try to taper them gradually while monitoring for EPS.[59] Patients with early psychosis are at higher risk for developing acute EPS, thus anticholinergics should not be administered irresponsibly without enough provisions against the side-effects. The disadvantages of long-term anticholinergic use on cognitive function may outweigh the benefits, and clinicians should re-evaluate the need for anticholinergic agents before recommending any cognitive enhancements in schizophrenia

Acknowledgments

Dr Ogino has no conflicts of interest with any commercial or other associations in connection with the submitted manuscript. Dr Miyake has received speaker's honoraria from Dainippon Sumitomo, Eli Lilly, Mitsubishi Tanabe, Otsuka, and Yoshitomi. Dr Miyamoto is a consultant for Dainippon Sumitomo and has received advisory board honoraria from Chugai Pharmaceutical, and speaker's honoraria from Dainippon Sumitomo and Eli Lilly. Dr Yamaguchi has received advisory board and/or speaker's honoraria from Daiichi Sankyo, Eizai, Eli Lilly, Janssen, Otsuka, and Takeda.

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