Tipare de prescriere a benzodiazepinelor într-un departament ambulatoriu al unui spital de neuropsihiatrie

1. Introduction

1.1. Background of the study

Schizophrenia is a severe type of mental disorder compared to other mental disorders that include anxiety disorders, depression, bipolar disorder, post-traumatic stress disorder, eating disorders, disruptive behavior and dissocial disorder, and neurodevelopmental disorders⁽¹⁾. Its treatment employs the use of psychotropic medicines that work by adjusting the number of major chemicals (called neurotransmitters) in the brain. The psychotropics are classified into five classes, according to the Anatomical Therapeutic Code (ATC), and they include: antipsychotics, antidepressants, anti-anxiety medications, stimulants, and mood stabilizers⁽¹⁾. Antipsychotics are primary drugs for treatment, but other classes are relevant, being commonly used in the management of skeletal muscle spasticity, insomnia and seizure disorders associated with the illness. The combination of benzodiazepines, a group of anti-anxiety medications, and antipsychotics often results in more favorable treatment outcomes regarding the positive and negative symptoms. However, the long term use of benzodiazepines is associated with risks such as depression, post-traumatic stress disorder, sexual dysfunction, delirium, neurocognitive disorder, psychosis and mania^(2,3). The increase of benzodiazepine dose usually produces first anxiety, followed by anticonvulsant effects, a reduction in muscle tonus and, eventually, sedation and hypnosis. Symptoms of benzodiazepine overdose include impaired coordination, diminished reflexes, confusion, seizures, respiratory depression, hypotonia and coma⁽⁴⁾. Moreover, their use in the elderly leads to side effects that include cognitive impairment, increased sedation and unsteadiness⁽⁵⁾.

Despite the wide published literature on the deleterious side effects of the increased dose of benzodiapines^(4,6) and prescriptions for patients in advanced ages, the psychiatrists often prescribe high doses of benzodiazepines for patients with schizophrenia and also prescribe them in elderly patients⁽⁵⁾.

Evaluating the prescription pattern of benzodiazepines facilitates the understanding of these risks in patients with schizophrenia⁽⁷⁾.

Keeping this in mind, our study aimed to evaluate the prescription pattern of benzodiazepines for the treatment of schizophrenia in an outpatient department of a neuropsychiatric hospital in Nigeria. It specifically evaluated the benzodiazepine prescriptions considering the patients age, it assessed the commonly prescribed benzodiazepines, and also assessed the doses of the prescriptions.

2. Methodology

2.1. Study design

The study employed a retrospective, descriptive, cross-sectional study of one year (from 1 April 2022 to 31 March 2023) based on prescriptions that included benzodiazepines for adult schizophrenia patients, aged at least 18 years old.

2.2. Study site

The study was conducted in Anambra State Neuropsychiatric Hospital, Nawfia, Anambra state, in the southeastern part of Nigeria. Nawfia is a town in Njikoka local government area of Anambra State in Nigeria. It is bordered by Umuokpu town, Enugwu-ukwu town, Enugwu-agidi town, Amawbia town, and Nise town.

Anambra State Neuropsychiatric Hospital is known in Nigeria for providing mental health services since 1991. The services include diagnosis and treatment of mental related disorders, being also considered as a referral center for neuropsychiatric cases⁽⁸⁾. According to the hospital’s medical record as at 2023, the majority of the daily clientele were outpatients who came to fill prescriptions or visit the physicians for treatment or counseling.

2.3. Population of the study

Outpatients with diagnosis of schizophrenia, with 18 years of age or older, who visited the hospital for treatment or to fill prescriptions.

2.4. Sampling technique

Sample size calculation for a finite population⁽⁹⁾:

S = X²NP (1-P)⁄d²(N‑1)+X²P(1-P)

where:

X = 1.96 (Z value for 95% confidence interval)

N = 113 (Population size)

P = 0.5 (50% Population proportion)

d = 0.05 (degree of accuracy/margin of error)

Sample size =
1.96²×113×0.5 (1‑0.5)⁄0.05²(113-1)+1.96² ×0.5(1‑0.5)

= 3.8416×113×0.5(0.5)⁄0.0025(112)+3.8416×0.5(0.5)

= 108.52⁄1.24

= 88.

Allowing for 10% drop out rate accounted to a minimum sample size of 97 prescriptions.

2.5. Method of data collection

The prescription papers containing prescriptions for schizophrenia patients were collected from the pharmacy department during the analyzed study period. Purposive sampling technique was used. Information gathered from the prescription was used to complete data collection questionnaire. Data regarding the name of the benzodiazepine drug, formulation, frequency and strength of drug prescribed were collected.

Inclusion criteria:

• prescriptions with a benzodiazepine drug for confirmed diagnosis of schizophrenia patients from 18 to 65 years old.

Exclusion criteria:

• prescriptions for affective disorders;
• prescriptions of clear experience of more than one discrete psychotic episode;
• prescriptions for those on clozapine who require close monitoring.

2.6. Ethical considerations

A formal letter was written to the hospital management stating the purpose of the research, and approval was obtained from the hospital ethics committee (Ref: NPHN/010).

3. Results

3.1. Age and gender distribution of the patients who received benzodiazepine drugs

A total of 338 prescription papers for schizophrenia patients were assessed. Out of the total of assessed prescription papers, 102 (30.18%) prescription papers contained benzodiazepines.

The prescriptions were ordered to 55 (53.92%) males and 47 (46.08%) females, while the largest age group was from 26 years to 35 years old, which constituted 47 (46.08%) patients, and the smallest age group was from 56 to 65 years old, which constituted 7 (6.86%) patients (Table 1).

Diazepam was the only prescribed parenteral benzodiazepine drug, and contributed only to 6.86% of the prescriptions.

However, the oral prescribed benzodiazepines were: diazepam (37.26%), nitrazepam (12.74%), and clonazepam (43.14%) – Table 2.

The prescribed doses for injection diazepam were all 10 mg intramuscularly, then repeated in 3-4 hours as needed.

The prescribed daily doses (PDD) of oral diazepam with anatomical therapeutic code (N05BA02) were 5 mg and 10 mg (the desired daily dose [DDD] is 10 mg), and the prescribing frequency was 5 mg (3) and 10 mg (35). The median of the PDD/DDD ratio was 1 (Table 3).

The prescribed daily doses of oral nitrazepam with anatomical therapeutic (N05CD02) were 10 mg and 20 mg (the desired daily dose [DDD] is 5 mg), and the prescribing frequency was 10 mg (7) and 20 mg (6). The median PDD/DDD ratio was 2 (Table 3).

Oral clonazepam with anatomical therapeutic code (N03AE01) had prescribing frequences of 15 (1 mg) and 34 (2 mg). The desired daily dose is 8 mg. The median PDD/DD ratio was 0.25 (Table 3).

4. Discussion

Our results demonstrated that the use of benzodiazepines reduced with advancing age groups. The age group 56-65 years old had the lowest frequency of use of benzodiazepine. The reason may be in accordance with the studies that suggested the avoidance of benzodiazepines in the elderly because it causes cognitive dysfunction, especially in verbal memory, visuospatial abilities, attention and learning^(10,11).

Diazepam injection was the only parenteral benzodiazepine used. This is consistent with the study that revealed diazepam to be as effective as fluphenazine in aborting prodromal symptoms of relapse in patients with schizophrenia that were otherwise medication free⁽⁷⁾. Studies show that high-dose use of benzodiazepines is associated with risk of premature death⁽¹²⁾. However, there were high-dose prescriptions of diazepam, this being in line with studies on diazepam use in schizophrenia which concluded that high doses of diazepam are useful and improve neuroleptic-resistant chronic schizophrenia patients^(13,14).

Clonazepam was the most frequently used oral benzodiazepine in our study. Clonazepam may be preferred because the risk of withdrawal syndrome and rebound anxiety is lower in the short-term administration^(15,16). It also has lower lipid solubility, and it is less likely to cause anterograde amnesia than other high-potency benzodiazepines⁽¹⁷⁾.

5. Conclusions

Few prescriptions of benzodiazepines were made for patients in the age group of 56-65 years old. Clonazepam was the most prescribed benzodiazepine, while the parenteral diazepam and oral nitrazepam were prescribed in high doses.

Limitations of the study

Firstly, we used a single institution, and our results may not represent what is obtainable in other institutions. Secondly, we could not assess the prescribers to obtain information on their rationale for the prescriptions.

Recommendations

• We recommend further research with in-depth interview of psychiatrists on the use of benzodiazepines for the treatment of schizophrenia.
• We recommend multicenter approach to study the use of diazepam for the treatment of schizophrenia.
• We recommend continuous mandatory training for psychiatrists on the utilization of benzodiazepines in the treatment of schizophrenia.

Autor corespondent: Amala Chukwunwike Ofor E-mail: ofachcurepharm@gmail.com

CONFLICT OF INTEREST: none declared.

FINANCIAL SUPPORT: none declared.

This work is permanently accessible online free of charge and published under the CC-BY.