Antipsychotic drugs are the fundamental pharmacologic treatment for psychosis and schizophrenia. [1, 2] The key pharmacologic property of antipsychotics is their ability to block dopamine D2 receptors, which is also responsible for their extrapyramidal side effects. These are motor side effects that includeparkinsonism (tremor, akinesia, and rigidity), akathisia, dystonia, and tardive dyskinesia (TD), occurring acutely or during chronic treatment.² Antipsychotics also block D2 receptors in the mesocortical dopamine pathway, where dopamine may already be deficient in schizophrenia thus causing or worsening negative and cognitive symptoms. There are a recent class of antipsychotics referred to as “atypical antipsychotic”, so called due to the reported “atypical” clinical properties of equal positive symptom antipsychotic actions as the conventional antipsychotics, but low tendency for extrapyramidal symptoms and less hyperprolactinemia compared to conventional antipsychotics.[3,4]Atypical antipsychotics have pharmacological properties of serotonin–dopamine antagonism, with simultaneous serotonin 5HT2A receptor antagonism that accompanies D2 antagonism. Therefore, there should be less need for anticholinergic co-medication to be prescribed with the atypical.[4]Anticholinergic are used to treat EPS or prevent EPS induced by antipsychotics prescribed to patients.[2,5] Anticholinergics can cause peripheral side?effects such as dry mouth and constipation, and central adverse effects such as cognitive impairment, worsening of tardive dyskinesia, and delirium.[6,7]There is a great variance in the concurrent use of anticholinergics with antipsychotics in several countries.[8]The administration of anticholinergics with antipsychotic medication for prophylaxis against extrapyramidal side effects (EPS) is a practice seen in psychiatry clinical practice.[4]Though, the current treatment guidelines for schizophrenia generally do not recommend the prophylactic and chronic use of anticholinergic with antipsychotics.[9]The use of long?term anticholinergic with antipsychotics is still highly prevalent in some countries.[8-10] In Japan a study reported that adjunctive anticholinergic were prescribed in 56–75% of chronic inpatients with schizophrenia, showing a high misuse.[10] This is despite guidelines and studies done that have recommended mental health professionals not to prescribe anticholinergic(Artane) indiscriminately as prophylaxis to patients using antipsychotic drugs, unless they develop EPS.[9-11] Cholinergic neurotransmission is involved in various CNS functions, including sensory perception, motor control, cognitive processing, learning and memory, arousal, attention, and psychosis.[12] Anticholinergic drugs have been reported to cause cognitive dysfunction, as well as induce delirium and hallucinations in human beings.[12,13] Thus, they compound the cognitive disability that is already a cardinal feature of Schizophrenia and contributes greatly to the functional disability of the patient. The consistent or chronic administration of anticholinergic exacerbates the underlying cognitive impairment including memory, learning, attention and executive function.[6,14]Further, there is a great abuse of the drug Trihexyphenidyl by both the patient and the community for its euphoric and anxiolytic effects.[15]Thus, prevention measures to reduce its risk of abuse can be achieved by minimising exposure to anticholinergic. The implementation of treatment guidelines in clinical practice have proven difficult to achieve,[16] as reflected by major variations in the prescription patterns of antipsychotics between different regions and countries.[17] Lack of adherence to clinical guidelines has been identified as a significant impediment to the implementation of evidence-based practices and to the improvement of quality of care.[18] Clinicians’ inability to recommend antipsychotic treatments in line with clinical guidelines results in high incidences of side effects and treatment failure.[19]There is a lack of adherence to current treatment guidelines in the prescribing of antipsychotics with increased side effects,[20] which could be causing the tendency to prescribe anticholinergics. A significant portion (39.4%) of clinician prescribing could benefit from changes in their psychotropic prescription [21].

The study was a Cross sectional study done at a Psychiatric tertiary hospital in Zambia. The study aimed to determine the prescribing patterns of anticholinergics in relation to antipsychotics and the level of adherence to recommended standard guidelines.Ethical clearance for the proceedings of the study was obtained from ERES CONVERGE REB. Clearance to access patient files was obtained from the Ministry of Health - CHCH.All information obtained from the participants was regarded as confidential and was used only for the purpose of the study. Information of the prescribing patterns during the period of December 2018 to March 2019 was collected using patient files. All patients on antipsychotics were included in study except those whose documentation of medication regimen was not complete.  The study had a study sample of 316 patient files that were recruited using simple random sampling.The Maudsley Prescribing Guidelines in Psychiatry-12th edition and the NICE 2014 guidelines, were used as the standard tool for comparison of adherence, as these are globally recognised guidelines.Information including age, sex, diagnosis, antipsychotics patient is on, if patient is on anticholinergic and any reported extrapyramidal adverse effects, were collected from patient files and entered into an information form. Codes were used for files and no names of patients recorded for their privacy. The data was collected over a period of six (6) weeks, in February and March 2019. The information filled in forms were then used for analysis. Data was analysed using the Statistical Software Package (SPSS version 21). Statistical tests were at 5% significance interval. The Pearson’s Chi-Squared test was used for comparison between the different prescribers responses and between different variables of patient data. Percentage was used to measure the demographics and anticholinergic prescribing. The relationships of antipsychotics and anticholinergics prescribing were analysed using the Chi-square, P<0.005.

Anticholinergics dosage was prescribed correctly in 42.0% of the patients, thus 58% were incorrectly prescribed anticholinergic. The minority (6.0%) of patients on anticholinergics were first prescribed anticholinergicsonly when they experienced EPS. The majority of patients (83.1%) had been prescribed an anticholinergic when they first started antipsychotics with no reason documented for the concurrent prescribing with an antipsychotic.

Table 1: Anticholinergic prescribing pattern in relation to adherence factors.

Tailed 0.00. There was a significant correlation between the initiation anticholinergic and EPS or risk of EPS documented with Sig, 2 tailed of 0.00.

Table 2: Chi-Square Values Of Anticholinergic And Antipsychotic Prescribing Patterns.

*Below 20 years documented EPS or risk of EPS is 98.2%

There was no significant correlation between the lack of adherence in the administration of antipsychotics and the age of patients with a Sig. 2 tailed of 0.26. There was no correlation between the type of antipsychotic used and the type of lack of adherence, with a Sig. 2 tailed of 0.06. There was no significant correlation between the types of lack of adherence against anticholinergic administration, with a Sig. 2 tailed of 0.19. There is no significant correlation (Sig. 2 tailed 0.19) between the type of lack of adherence in prescribing patterns of antipsychotics and the administration of anticholinergics.

Table 3: Cross tabulation - Age against adherence of regimen.

*Below 20 years 29.8% were non adherent

Table 4: Chi-square values of adherence factors.

*Below 20 years documented EPS or risk of EPS is 98.2%

There was no significant correlation between patient regimen adherences to guidelines with when/reason patient started anticholinergics, Sig. 2 tailed of 0.605. There was no significant correlation between the type of lack of adherence of regimen with administration of anticholinergic or reason started anticholinergic, with Sig. 2 tailed of 0.09 and 0.15 respectively.

Table 5: Pearson correlation values of adherence.

The lack of adherence in the prescribing of anticholinergics has an impact on the compliance, cognition, and overall outcome of

Treatment, thus a need to pay attention to its prescribing. The minority (6.0%) of patients on anticholinergics in our current study were first prescribed anticholinergics only when they experienced EPS, followed by 10.9% that had no reason documented though were started on anticholinergics sometime after being administered antipsychotics. We cannot assume that those that were commenced anticholinergics at a later date had developed EPS or it was just the preference of the clinician who attended to them at a later date. This brought out the lack of documenting tendency by the clinicians for EPS or its risk or any reason that they could have considered when prescribing the anticholinergic. Documentation in medical care allows for communication among health care practitioners. It further ensures that accurate, appropriate, and concise documentation is done, an essential component of ensuring that the patient care provided is evident, not only for patient safety but for continuity.²²The clinicians will have to be encouraged to be documenting the reason for their prescribing anticholinergics and the length of time for which a patient will have to take the anticholinergic. The majority of patients (83.1%) had been prescribed anticholinergic when they first started antipsychotics with no reason documented for the concurrent prescribing. The concurrent prescribing of anticholinergics with antipsychotics was a practice observeddespite discouragement of such practice by several guidelines.[9,11] Adjunctive anticholinergic prescribing has been reported to be high in Asia with percentages of 56-75% reported.[10,23]A similar picture was seen in the African continent, with a report of 62.2% of patients being on antipsychotic/anticholinergic combinations in Nigeria and the common (82.6%) anticholinergic agent prescribed being Trihexyphenidyl (Benzhexol/Artane) despite its increased risk for abuse.²⁴Thus further investigating the factors that could be contributing to these trends would be beneficial. There was no significant correlation between documented EPS or risk of EPS in file against age with a Sig. 2 tailed of 0.34.Thus indicating that a risk of age, the younger and elderly who would justify a temporal administration of antipsychotics was unlikely to be the reason for the concurrent prescribing.[25,26]There was a significant correlation between patients on anticholinergics and type of antipsychotic administered Sig.2 tailed 0.00, this should be expected as a reduced tendency to concurrently prescribed anticholinergics with antipsychotics should be observed with the administering of atypical antipsychotics as they have a reported lower tendency to cause EPS.[4-28] Lack of adherence in the prescribing of antipsychotics has been reported to be high, indicated by a 96.8% lack of adherence in prescribing for a first- episode schizophrenia.[29] The lack of adherence in the prescribing of antipsychotics is likely to cause EPS and thus increase tendency to administer anticholinergics. Another factor to consider is the pattern of polypharmacy or high dosages of antipsychotic as that has been associated with an increase in anticholinergic prescribing. [30]If a clinician gives a high dose of antipsychotic they would want to cover the patient on anticholinergic to prevent EPS as that practice increases the risk of EPS. Limitation in the study was that patient files were used to collect information and no follow up was made to clinicians who prescribed the anticholinergics to enquire why they had prescribed; as a large number had prescribed without any reason documented. There is a possibility that a proportion of those prescriptions were justifiable. There is need for further studies, prospective cohort studies, to be conducted to ascertain the magnitude of the problem and to determine the associated factors for the concurrent anticholinergic prescribing by clinicians.

There is a lack of adherence in the prescribing of anticholinergics with antipsychotics. There is a need to investigate further the associated factors that could be contributing to this trend, other than those related to antipsychotic prescribing pattern. Further, there is a need for continuous medical education to guide clinicians on the recommended standard practice of anticholinergic prescribing with antipsychotics.

Would like to acknowledge the input of Mr Christopher Njovu in the analysing of data. We also thank Dr Tony A Tsarkov, Dr Peter Petlovani and Dr Waqas Sheikh for their helpful comments. Further wish to thank Chainama Hills College Hospital Management and the staff for their warm reception and assistance.

Authors’ Contribution

All authors had made substantial contributions to conception and design, and providing revisions. All authors have given final approval of this final version to be published.

FB was the principle investigator and lead the acquisition of data and analysis, and interpretation of data.

JM was the assistant supervisor of the study as an academic supervisor.

RP was the principle supervisor of the study, in the academic supervisory role.

FB and JM are accountable for all aspects of the article in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Ethical Approval

Ethical clearance to conduct the study before commencing the study was gotten from ERES CONVERGE IRB (I.R.B No.00005948; E.W.A No.00011697). The ethical approval reference number was Ref. No.2019-Jan-016.

Conflicts Of Interest

There was no conflict of interest identified. No support was received from any organisation for the submitted work.

Funding

This was a self-funded study by an individual, the principle investigator, as part of the partial fulfillment of the requirements for the degree of Master of Medicine in Psychiatry.

Informed Consent

For this objective of the study clearance was gotten from the Ministry of Health to access the patient files.

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