Khat Chewing and Relapse in Peoples With Serious Mental Illness At Amanuel Mental Specialized Hospital: Comparative Study

Background people with serious mental illness using illicit drug exhibit poorer outcomes. But until now little is known about the impact of khat in thiss patient group. This study tried to assess the effect of khat chewing on relapse in people with serious mental illness. Method This is cross sectional comparative study involving 405 khat chewers and 400 non chewer people with serious mental illness. The study took three month involving interview (patient and care giver) and chart review. The study used Oslo Social Support Scale; Alcohol, Smoking, Substance Involvement Screening Test and questionnaire which include sociodemographic characteristics, illness related factors and relapse history. Result The study found that


Introduction
Serious mental illness (SMI) are among the top twenty conditions that result in the greatest burden of disability worldwide (1) and also in Ethiopia (2).Acute state of schizophrenia is the most disabling disease state of all Global Burden of Disease (GBD) causes (3).SMI are among the top ten burden of disease in Ethiopia (2).In Ethiopia, the life-time prevalence of schizophrenia, depression and bipolar disorder is reported to be 0.5%(4), 9.1%(5) and 0.5%(6) respectively.Schizophrenia was also the number one diagnosis for admission to mental hospital in the country (7).Also there is a high mortality rate (8) (9) and risk for suicide (9) (10) among people with SMI.Mental disorders are costly to individuals, families, communities and societies (11).
Khat (Catha edulis F) is an evergreen shrub that is believed to have originated from Ethiopia.It grows in many Eastern and Southern African countries and the Arabian Peninsula.Its fresh leaves are chewed and the juice is swallowed to exert its stimulating effect (12).Cathinone is the major active constituent in khat.Cathinone induces release of dopamine and serotonin thus increase the activity in their pathways (13).This are neurotrasmitters thought to be affected and causing SMI.
After khat chewing session ceases, unpleasant after-effects tend to dominate the experience like: insomnia, numbness, lack of concentration and low mood (14) (15).Some chewers also experience unpleasant effects during the chewing process, describing anxiety, tension, restlessness and hypnagogic hallucinations (15).Khat chewers display a range of experiences, from minor reactions to the development of a psychotic illness (15).
There is an ongoing international debate about a causal relationship between khat use and mental illness (16).Although there are many studies on khat in the general population, there are only few studies in mental illness patient.Moreover, there are very few studies on association of khat chewing with reemergence of the disease symptoms in serious mental illness.
Relapse is broadly recognized as the reemergence or the worsening of symptoms.More speci cally, certain criteria are used to de ne relapse; they include aggravation of symptoms, hospital admission in the past 6 months, and need for more intensive case management and/or a change in medication(17) (18).
Relapse in SMI causes worsening of symptoms, progressive cognitive deterioration, impaired functioning and reduced quality of life and families are affected by the emotional stress and nancial burden of living with and caring for the patient (19).Relapse may result in hospitalization, treatment resistance, personal distress, incarceration, and interference with rehabilitation efforts (18).Relapse increases the economic burden on health care systems because of its associated morbidity and re-admissions to hospital (18).Costs for relapse cases are much higher than those for non-relapse cases (17).Extended relapse duration and treatment intensity associated with relapse intensify the decrease in both general and regional brain measures (19).Repeated relapse episodes are also risk factors for development of treatment resistance (20).
Different studies indicate that SMI patients using illicit drug exhibit poorer outcomes in a variety of domains: symptom severity, psychiatric relapse, hospitalization, suicide (40) (41), incarceration, violence and victimization, physical health problems, homelessness (42), extended hospitalization (43), increased healthcare costs, reduced compliance with medications, increase treatment resistance (44), increased depression symptoms (45) and suicide ideation, as well as mania and bipolar disorder(46).The substances mostly studied are cannabis, alcohol and amphetamine but there is no large study on khat effect in people with SMI, but case reports (47) and qualitative study(48) noted that patients with serious mental illness who used khat had their illness exacerbated by the use of it.El-Sayed and Amin's small size comparative study of khat chewing patients with schizophrenia indicate that khat chewing attenuates all used treatment medications, aggravates the disease symptoms and also deteriorates all biochemical markers (49).Khat chewing is associated with disturbance of mood and behavior, aggravation of delusional symptoms, diminished response to antipsychotic therapy (50).Even though the above few studies indicate that khat could complicate the course of the illness, until now there are very few studies on association of khat chewing with relapse in serious mental illness.In Ethiopia, where mental health service is poor compared to other African countries (51), and only few number of patients attend mental health service(9) (52)(5) (53), khat chewing could have additional enormous negative impact on treatment and outcome in psychiatric patients.Relapse prevention is one of the key therapeutic goal in the treatment of serious mental illness.But until now the effect of khat chewing on this key outcome domain is not explored.
The main aim of this study is to assess relapse in khat chewer and non chewer people with SMI, speci cally; to compare the prevalence of relapse in khat chewers and non chewers and to assess the factors associated with relapse in both khat chewer and non chewer peoples with SMI

Method
The Study Setting The study was conducted at Amanuel mental specialized hospital (AMSH) which is the only public mental specialized hospital in Ethiopia which provides services for people with mental illness, some neurological conditions and a rehabilitation service for people with substance addiction.AMSH is located at Addis Ketema Ki e Ketema, Addis Ababa, Ethiopia and has 280 beds.The hospital gives service for about 500 patients per day who are referred from around the country.The hospital also gives a masters level post-graduate program in psychiatry in collaboration with university of Gonder.

Study Design and Period
Institutional based Cross-Sectional study in patients with serious mental illness was conducted using interview and chart review.
The study was conducted for three consecutive months from May 1 to July 30/2017

Source and Study Population
All people with serious mental illness attending AMSH outpatient were the source population.Out of the source population those who came during the study period, selected randomly and who ful lled the inclusion criteria were taken as study population.

Inclusion and Exclusion Criteria
People who had follow up treatment for at least one year previously and age ≥ 18 years were the inclusion criteria.Exclusion criteria include people with SMI who have no capacity to understand purpose of the interview and respond properly; people with persistent severe symptoms of illness and those who were not volunteer to be interviewed.

Sample Size and Sampling Methods
The minimum sample size required for this study was determined by using Double Population Proportion Formula, 130 in each group were selected i.e 130 peoples with schizophrenia, bipolar disorder and depression khat user and non user in each group was used as a sample size for the study.Systematic random sampling technique was used to recruit the participants from the outpatient setting.
On average 4000 patients are served in the mood and psychotic case team in a month in the outpatient setting.The sampling fraction (k) was calculated to be 5. Conveniently, every 5th patient was selected after randomly picking one number as a starting point from 1 to 5 for both the khat user and non user group.

Data Collection Instruments
The Oslo 3-items Social Support Scale (OSS-3) and Alcohol, Smoking and Substance Involvement Screening Test (ASSIST) were structured questionnaires used to obtain information about social support and substance abuse.
The questionnaire for interview contained ve parts.Part I was aimed at collecting Socio-demographic characteristics and clinical related factors.Part II was questions important to assess medication adherence, questions to assess support and emotion of care giver towards the patient using Oslo social support scale.Part III included contains questions to assess substance use behavior using ASSIST.Part IV includes relapse history of patient within the past six month.Questionnaires were translated from English into Amharic and back translated into English for consistency check.
At the same time the patient's chart was reviewed retrospectively by data abstraction format.The data abstraction form contained diagnosis, duration of illness, relapse and hospital admission history, other co-morbid illness and medication pro les.

Data Collectors Recruitment and Training
Seven masters psychiatric professionals were recruited as data collectors after given the required training.The training was given to them regarding the data collection method, appropriate use of the data collection instruments focusing on uniform interpretation of questions, explanation of study objectives & getting oral consents from study patients, implementation of sampling technique and con dentiality of the collected data.

Data Quality Control
The data collection instrument which included the questionnaire and the data extraction format was assessed by a physician and expert in the eld of psychiatry and research for clarity and comprehensiveness of contents.Pre-test of the questionnaire was performed on 5% (40 patients) of the sample before conducting the study.The nal tool was then developed with some modi cations after reviewing the results of the pre-test.Patients who participated in the pretest were excluded in the nal analysis.The principal investigator reviewed and checked the data collected for completeness and the necessary feedbacks were provided daily to the data collectors throughout the study period.The quality of data was also checked at data entry, analysis, and interpretation and representation phases.

Data Analysis and Interpretation
Data was entered into Epidata exported and analyzed using SPSS v-21.Descriptive statistics including: frequency, percent, mean and standard deviation were used to summarize patients' baseline sociodemographic data and evaluate distribution of responses.
Univariate binary logistic regression analysis was performed to calculate crude odds ratio (COR) for each variable and those variables with p-value < 0.2 during that analysis were selected for multivariate binary logistic regression analysis and the result was expressed as adjusted odds ratio (AOR).A con dence level of 95% was used to determine factors associated with relapse.A p-value of ≤ 0.05 was considered as statistically signi cant.

Results
Socio-demographic characteristics A total of 405 ever khat user and 400 never khat user were included in the study.The mean age of the participants was 35.9 ± 10 (SD) and 36.2 ± 11 (SD) years for ever khat users and never khat users respectively.The majority of the respondents were in the age of 25-34 (40.5% and 33.3 %) forever and never khat users respectively.The prevalence of relapse was 22% (CI: 17.8-26.0)for khat users and 13% (CI: 10.1-16.1)among non khat users (x 2 , p = 0.001).Since there was no matching between the two groups ages, sex, ethinicity, religion, living arrangement, tobacco and alcohol use were not independent between the two group, khat chewer and non chewer, on chi square test (Table 1).2).
Those who were Singles had 26.2% and 10.1 % relapse among ever khat users and non user respectively.On the top of these, almost one third of unemployed participants got relapse among users and 11.6% got among non users.On the other hand, those who use high tobacco among ever khat users had 33% relapse rate and 66% among never khat user (Table 2).• * widowed and divorced Previous hospitalization history and having perceived stressor were associated with relapse in khat chewers' people with serious mental illness (Table 3).
The odds of getting relapse in khat chewers was six times (AOR = 6, CI: 3-12.5)more in those having previous hospitalization compared to those who don't have previous hospitalization.Patients having stress were two times (AOR = 2, CI: 1.1-3.7)more likely to relapse than those who don't have stress Treatment interruption, sleeping disorder, hospitalization history and diagnosis were the factors associated with relapse in non chewers with serious mental illness peoples (Table 3).
The odds of getting relapse among having treatment interruption for never khat users was nearly three times (CI: 2.7, 1.2-5.9)higher as compared to no treatment interruption (Table 3).

Sleeping disorder Yes
Based on ASSIS classi cation as risk of problems increase with the use of the khat, the relapse rate was also increasing when compared with non users of khat (Fig. 1).

Discussion
In this study the prevalence of relapse was signi cantly higher in khat chewers than in non chewers.The study found that like other illicite substance; amphetamine, alcohol and cannabis; khat chewing causes relapse of the disease in SMI.Cathinone; similar substance with amphetamine and the main active constituent of khat through its activity on enhancing dopaminergic and serotonine activity and the decreased e cacy of antipsychotics in khat chewers, it could result in increase of relapse rate in serious mental illness This is in line with the case studies (47) (54); qualitative studies(48) (55) and few quantitative studies (50)(56) (57).
In addition to khat chewing stressors and having previous hospitalization were the factors for increased relapse rate in serious mental illness patients.In different studies stressful life event is among the factor for relapse (33)(34)(28).Studies of khat chewing in the general population described some chewers' experience unpleasant effects during the chewing process, describing anxiety, tension, restlessness and hypnagogic hallucinations; the cumulative effect of khat chewing and subsequent stress could over folds relapse rate in this already debilitating disease.
Hospitalization history is the other main factor for relapse in khat chewers of serious mental illness people.This is also the case with other studies (25)(58).Aggravation of symptoms of the disease is among the main reason for readmission to psychiatric hospital, substance use like khat are among the main reason for readmission in this hospital, where this study was conducted (55) this indicates khat could be among the main reason for increased previous and subsequent hospitalization and or relapse.
Treatment interruption, sleeping disorder, hospitalization history were the factors associated with relapse in non chewers with serious mental illness peoples.In line with this study nding treatment interruption or discontinuation is among the reasons for relapse in different studies (35)(33) (23).This indicates the need for longer maintenance treatment rather than interrupting treatment.Comparative study of guided antipsychotic discontinuation verses maintenance treatment showed that relapse rate was 52% and 16% in the treatment discontinuing and maintenance treatment, respectively (30).
Sleep disorder is the other factor associated with relapse.It is common to hear that many of the admitted patients in this hospital, where this study was undertaken, complain that they have disturbed sleep and they feel it one reason for their readmission to the hospital.
Even though it is not revealed in this study, khat causes sleep disturbance (59) and treatment interruption (60) this could potentially increase relapse in patients with serious mental illness.
From the ASSIST classi cation of risk of different health and social problems from the use of khat, as the risk of problems was increasing from the use of khat the risk of developing relapse of the disease was also increasing.The amount of khat use is among the main reason for increasing risk in the ASSIST classi cation.So, relapse of disease is the other additional risk incurred from the use of khat excessively.Other studies also found that it is the amount of khat which matters most in relation with increase of psychiatric morbidity in the general population (56) (61).
Limitation of the study include: The interview for khat chewing behavior was dependant on response from the patients and care-givers which may compromise the reliability of the data collected due to social desirability issue and other factors.They may perceive that they might not be well treated if they reveal their khat chewing habit.This could affect to assess the real khat chewing behavior of the respondents.
The lack of common measuring tools for relapse could also affect the result.Relapse measure in this study was dependant on respondents and review of their medical record rather than using instruments for measuring the psychopatology of the respondents; cross sectional nature of the study could also hinders from assessing reliable data.

Conclusion
The study indicates that the prevalence of relapse was higher in khat chewers when it is compared with non chewers' in peoples with serious mental illness.And also as the amount of the khat chewed increased the relapse rate was also increased.Khat chewing imposes additional burden for the already debilitating disease.Additionally previous hospitalization history and presence of stressors were the factors for increase of relapse in khat chewers.Previous hospitalization, treatment interruption and sleep disorders were the factor associated with relapse in non khat chewers of serious mental illness patients.
Amanuel Mental Specialized Hospital and other stake holders need to make educating the patients and care givers about the impact of khat chewing treatment and prevention as integral part of intervention for relapse prevention in patients with SMI.Complete treatment interruption without discussion with patient and physician is commonly seen in the hospital.
Independent variablesSociodemographic variables: age, sex, ethinicity, religion, place of residence, address, marital status, educational level, occupation, family income, living arrangement.Clinical and medication related variables: diagnosis, duration of illness, duration untreated, treatment interruption, perceived stressor, medical illness, psychiatric hospital admission, co-morbid psychiatric illness.Substance use: tobacco, alcohol, cannabis and khat

Figure 1 percentage
Figure 1

Table 1
Socio demographic and patient behavioral characteristics of Khat ever user and non user participants and the chi square test of the participants at Amanuel mental specialized hospital, Addis Ababa, 2017 Relapse among participants with perceived stressor was 36.1% and 21.2% among Khat users and non users respectively (Table

Table 2
Distribution of relapse related to some variables among ever khat users and non user participants in Amanuel mental specialized hospital, 2017

Table 3
Through close follow up using different intervention strategies, interruption of treatment should be minimized.Sleep disturbance also need to be adequately