MyCite, Google Scholar. December 2016 Vol. 25, No. 2 CONTENTS

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1 MyCite, Google Scholar December 2016 Vol. 25, No. 2 CONTENTS Editorial Venous Thromboembolism (VTE) in Patient on Clozapine Therapy The Challenge in Making the Diagnosis of Depression in Sashitharan D Palliative Patients 1-2 Abu Bakar AK Suhaila MS Ng CG Clozapine Induced Priapism: Original Paper Case Series Psychometric Properties of the Malay Thangam N Version of Alcohol, Smoking and Farah Radhiah H Substance Involvement Screening Sashitharan D Test (ASSIST-M) 3-13 Abdul Kadir AK Yee A Dissociative Identity Disorder with Salina M Depression in A Man with Traumatic Rusdi AR Childhood: A Case Report Zahari MM Sharmilla K Saifuddin TM Amilin N The Psychometric Properties of the Zafri A Positive Emotion Rating Scale Chinese Version (PERS-C) Suicidal Attempt in Huntington Disease: A Case Report Ng CG Chong SH Saifuddin TM Amilin N Comparison between Aripiprazole Zafri A with Quetiapine in Patients with Bipolar Disorder: A Retrospective Review Paper Outcomes Study A Review of The Use of Mirtazapine Ng CG in Cancer Patients Seed HF Thong KS Zaini S

2 Case Report Ng CG Sulaiman AH Huri NZ Shamsudin SH Clozapine and Polycythemia Rubra Vera: A Rare Side Effect or a Separate Medical Condition? A Case Report Brief Communication Tan HPJ Understanding Trypophobia: The Fear of Holes Venlafaxine Overdose in a Patient with Huntington s Disease Aminuddin I Lotfi HA Pak S Letter to Editor Parity of Esteem for Mental Health: Improving the Physical Health of People with Mental Illness Panirselvam RR

3 EDITORIAL The Challenge in Making the Diagnosis of Depression in Palliative Patients Ng CG Department of Psychological Medicine, University of Malaya, Malaysia Palliative care patients are often vulnerable to psychological distress and the development of depression [1]. However, it is challenging to distinguish between depression and grief or appropriate sadness in this group of patients. There are several approaches proposed in the making of diagnosis of major depressive disorder in palliative care patients. The standard approach is using Structured Clinical Interview for DSM IV (SCID) [2]. This etiological approach gives a more exact view on the presence of depression as these interviews will only include symptoms of depression if it is not attributed to medical conditions. The disadvantage of this approach is that the it is unlikely to have adequate knowledge to be able to determine whether the symptoms arise from a medical condition or are due to depression instead [3]. Other approaches have been recommended to overcome this diagnostic problem; inclusive approach, substitutive approach and exclusive approach [3, 4]. The inclusive approach includes all symptoms regardless whether or not the symptoms may be attributable to medical illness. This approach has the tendency to over diagnose depression in patients who are medically ill [3, 4]. The substitutive approach replaces the somatic or physical symptoms (disturbed sleep, poor appetite or lose of weight, poor concentration and fatigue) of DSM IV Criteria with psychological symptoms (eg: depressed appearance, social withdrawal or decreased talkativeness, self-pity or pessimism and cannot be cheered up). Endicott proposed such an approach to diagnose depression in cancer patients [3, 4]. The last approach is the exclusive approach (Cavanaugh Criteria), whereby the somatic symptoms of depression is removed and replaced with symptoms such as, not participating in medical care in spite of ability to do so, not progressing despite improving medical condition and/ or in functioning at a lower level than the medical condition warrants. To date, there is still lack of studies comparing the difference approaches and to determine the best diagnostic criteria to be used in palliative care patients. References [1] National Comprehensive Cancer Network (NCCN) (2013) Clinical Practice Guidelines in Oncology: Distress Management, Version 2. [2] Kelly B, McClement S, Chochinoc HM (2006) Measurement of psychological distress in palliative care. Palliative Medicine 20: [3] Trask PC (2004) Assessment of depression in cancer patients. 1

4 Journal of the National Cancer Institute Monographs 32: [4] Akechi T, Ietsugu T, Sukigara M, et al. (2009) Symptoms indicator of severity of depression in cancer patients: A comparison of the DSM IV Criteria with alternative diagnostic criteria. General Hospital Psychiatry 31: Corresponding Author Assoc Prof. Dr. Ng Chong Guan, Editor-in-Chief Malaysian Journal of Psychiatry chong_guan@um.edu.my 2

5 ORIGINAL PAPER Psychometric Properties of the Malay Version of Alcohol, Smoking and Substance Involvement Screening Test (ASSIST-M) Yee A 1, Salina M 2, Rusdi AR 1, Zahari MM 1, Sharmilla K 1 1 Department of Psychological Medicine, Faculty of Medicine, University Malaya, Kuala Lumpur, Malaysia 2 Department of Psychological Medicine, Faculty of Medicine, UiTM, Kuala Lumpur, Malaysia Abstract Background: The Alcohol, Smoking, and Substance Involvement Screening Test (ASSIST) developed by the World Health Organization is designed to identify individuals at risk for alcohol use problems and provide brief intervention. Objectives: To evaluate the validity and reliability of the ASSIST in Malaysia s official language, the Bahasa Malay, among a group of alcohol users. The study also aimed to assess the impact of alcohol on the quality of life of patients. Methods: The final version of ASSIST-M was administered to 51 patients who were identified as alcohol users and attended the outpatient psychiatric clinic during a three-month period from September to November of Patients completed ASSIST, ASSIST-M, Mini-International Neuropsychiatric Interview (M.I.N.I.), Malay version of The Alcohol Use Disorders Identification Test (AUDIT-M), CAGE Assessment for Alcohol Abuse (CAGE), and the World Health Organization Quality of Life Scale-Brief-Malay version (WHOQoL-Brief-M). Statistical procedures were performed to assess the reliability and validity of the ASSIST-M. Results: Factor analysis of ASSIST-M yielded one factor similar to the factor structure of the English version. The Cronbach s α coefficient of ASSIST-M was The parallel reliability of the ASSIST-M was high with the intra-class correlation (ICC) of 0.96 (P< 0.01). The test retest reliability of the ASSIST-M after the 1-week interval was high with the ICC of 0.94(P< 0.01). The ASSIST-M was positively correlated with the AUDIT-M (r =0.67, p <0.01) and the CAGE (r=0. 57, p < 0.01). ASSIST-M score showed a negative and statistically significant relationships with the physical (r= -0.28, p < 0.01) and social relationship (r= -0.37, p<0.01) subscales of the WHOQoL-Brief-M. The optimal cutoff point for ASSIST-M for alcohol use disorder was more than 14 with the with a sensitivity of %, specificity of %, positive predictive value (PPV) of 76.19% and negative predictive value (NPV) of 90%. Conclusions/Importance: The ASSIST-M displayed a fair psychometric performance in assessing alcohol use disorder in Malaysia. 3

6 Keywords: Alcohol Dependence, ASSIST, ASSIST-M, M.I.N.I., CAGE, WHOQoL Introduction According to the World Health Organization (WHO) estimation, the harmful use of alcohol results in 2.5 million deaths in alcohol or alcohol-related diseases each year. Of those deaths, 9% are young adults aged between 15 to 29 years. Although the status of alcohol consumption in Malaysia is rated as stable and moderate use by the WHO, there are groups of people who use unquantifiable amounts of alcohol and traditional alcohol beverages such as tapai and tuak in conjunction with harvest celebrations and social gatherings [1]. It is well known that harmful use of alcohol not only causes harm to the physical and psychological health of the drinker but also harms the well-being and health of those around the drinker. The Alcohol, Smoking and Substance Involvement Screening Test (ASSIST) is a screening instrument developed by the World Health Organization (WHO) and is used to identify problematic and risky behavior which may or may not occur with concomitant use of tobacco, alcohol, and other psychoactive drugs [2]. It was initially aimed for primary health care settings to identify patients with problems associated with substances, and to provide an intervention to at- risk patients. However, due to the simplicity of the scale, ASSIST can be also used by trained health care workers such as community nurses. Later, a brief intervention could be administered by the same interviewer. This would be an advantage in countries with limited resources such as Malaysia. Furthermore, the ASSIST can be used even when patients have low levels of literacy as it is a clinician-administered assessment 3. Therefore, primary health care professionals or health care workers can explain questions and ask probing questions to clarify inconsistent or incomplete responses. AUDIT (alcohol use disorders identification test) is a similar tool but designed only to measure alcohol use. Hence the necessity for ASSIST which measures tobacco, alcohol, and other psychoactive drugs. The ASSIST is brief screening tool which consists of eight items that investigates the lifetime use of substances, the frequency of using the substances, the urge of using the substances, the frequency of substance use that led to health, social, legal or financial problems, the frequency of failure to fulfill the usual role obligation due to substance use, whether anyone is concerned about their substance use and frequency of failed attempts to control, cut down or stop using the substance over the last 3 months. After that, a risk score is obtained and categorized into low, moderate or high which determines the type of intervention either none, brief intervention, brief intervention plus referral [4]. Analyses have shown that the ASSIST has excellent concurrent, construct, predictive and discriminative validity and is able to adequately screen for low, moderate and high risk substances [5, 6]. In this study, only alcohol use will be assessed. This study is part of a research which will be carried out in a remote area in The ASSIST has been validated and shown to be effective in different languages and different ethnicities across the world. Malaysia is a unique multi-ethnic country with the Malay language as the official 4

7 national language. Most Malaysians especially those who live in remote areas can only understand Malay. Therefore, the aim of this study was to to evaluate the validity and reliability of the Malay version of the ASSIST (ASSIST-M) based on a group of patients who consume alcohol. Hence, ASSIST-M would be a valuable tool for early detection and intervention for alcohol dependence or abuse among the natives of the remote area who spoke only the Malay language. Methodology The study was approved by the Medical Ethical Committee. Permission to use and translate the questionnaire was obtained from World Health Organization [7], ID: This study was conducted in three stages. Stage 1 Translation from English ( Source language ) of the Alcohol, Smoking, and Substance Involvement Screening Test (ASSIST) to Malay was done in parallel ( Target language ) by two doctors who were bi-lingual (Malay and English), whereas a bilingual language expert performed the back-translation. Discrepancies between the original version and the back-translation were discussed and adjustments were made until the consensus was reached by an expert panel. Discussion composed of three psychiatrists, all of whom were qualified professionals regarding psychometric instruments and had clinical experience in alcohol use disorder. At the end of this process, we produced a draft of the ASSIST-M (ASSIST-M- draft). Stage 2 The ASSIST-M- draft was then pilot tested among 10 medical staffs from the psychiatric ward at the University Malaya Medical Centre (UMMC), who are native speakers of the Malay language. Any flaws which were identified by these 10 respondents would be then corrected. The finalized version of ASSIST in the Malay language (ASSIST-M) was reviewed by a psychiatric consultant to ensure satisfactory face, semantic, criterion and conceptual equivalence. Stage 3 The final version of ASSIST-M was administered to 51 patients who were identified as alcohol consumers and who were followed up at the outpatient psychiatric clinic of UMMC during a three month period from September to November of As a rule of thumb in determining a priori sample size, Costello and Osborne (2005) [8], state that it is based on subject to item ratios of only 5:1. In this regard, it seems statistically appropriate to recruit a minimum sample size of 40 participants per group. Patients were approached by the research team to take part in the targeted sample size was 40 patients (5 patients to 1 item in the ASSIST M). Patients were approached by the research team to take part in the study and provided written informed consent for participation. All of the patients who consumed alcohol who also fulfilled the inclusion criteria were approached for the study. The inclusion criteria were as follows: (1) Above 18 years of age (2) Alcohol consumers in the psychiatric clinic and/ or ward (3) Willing to participate and keen to be interviewed (4) Able to fluently read and converse in both English and Malay. Those with the following were excluded: (1) Acute medical conditions (such as acute liver failure) (2) Using other psychotropic medications other than alcohol (3) Participants must not be in withdrawal or intoxicated state or in need of emergency care during the interview. 5

8 Fifty-one patients, who met the selection criteria and had given consent to participate in the study completed the demographic questionnaire, the English and the Malay versions of ASSIST, the Malay version of The Alcohol Use Disorders Identification Test (AUDIT-M) the alcohol use disorder subscale of the Mini-International Neuropsychiatric Interview (M.I.N.I.), CAGE Assessment for Alcohol Abuse (CAGE), and the Malay version of the World Health Organization Quality of Life- Brief scale (WHOQoL-Brief-M). One week later, the same patients who participated would again complete the ASSIST-M but by another researcher would determine the inter-rater reliability of the ASSIST-M. Instruments Socio-demographic questionnaire A brief questionnaire was used to record relevant background information including age, gender, ethnicity, citizenship, marital status, education level, religion, employment status, present occupation, and alcohol use. Mini International Neuropsychiatric Interview (M.I.N.I), K component, Version M.I.N.I is a short structured diagnostic interview designed to diagnose DSM-IV-TR lifetime and current. It is a relatively brief instrument that deals with 10 psychiatric disorders. The M.I.N.I has a good validity and reliability but can be administered in a much shorter period of time than SCID-P (Structured Clinical Interview for DSM-III- R Patient Edition) and the CIDI (Composite International Diagnostic Interview). In this study, only the subscale for alcohol use disorder (K component) was used to confirm the diagnosis among the participants. Malay version of The Alcohol Use Disorders Identification Test (AUDIT-M) The AUDIT is a screening instrument to detect excessive and harmful patterns of alcohol consumption. The AUDIT consists of a 10- tem scale which assesses recent alcohol use, alcohol dependence symptoms, and alcohol-related problems. The AUDIT typically takes 2-4 minutes to administer. The validation and reliability of Malay version of AUDIT was established with the good internal consistency, Cronbach α coefficients of and high test-retest reliability (Spearman s rho=0.955, p< 0.01) [9]. CAGE Assessment for Alcohol Abuse (CAGE) The CAGE is a screening instrument for the detection of alcoholism. It consists of 4 items only and takes less one minute to complete and is easy to understand. Two or more affirmative responses suggest that the patient has a drinking problem [10]. World Health Organization Quality of Life-Brief-Malay version (WHOQoL- Brief-M) The WHOQOL-Brief is used to assess the individual's subjective perception of quality of life for the past 2 weeks. It consists of 26 questions and covers mainly four domains (physical, psychological, social relationship and environment). The total scores of the WHOQoL-Brief range from 0 to 100, with higher scores reflecting a higher quality of life. The WHOQoL-Brief has been validated in the Malay language (WHOQoL-Brief-M) [11]. Statistical Analyses All analyses will be conducted by the Statistical Package for the Social Sciences version 21.0 (SPSS, Chicago, IL, USA). Descriptive statistics will be computed for the baseline characteristics of the participants. The Cronbach s alpha was used 6

9 to assess the internal consistency of ASSIST-M. Homogeneity of scale items was addressed through correlation coefficients between items and total scores if item was deleted. Construct validity was determined by principal component analysis with factor loading of >0.30 to determine the items for each factor. The intraclass coefficient (ICC) was used to examine the parallel reliability between the ASSIST-M with the ASSIST, and test-retest reliability of the ASSIST-M. The Spearman correlation was used to assess the correlation between ASSIST-M and the AUDIT-M, CAGE, WHOQoL-Bref-M. Receiver Operating Characteristic (ROC) analyses was applied to compare the screening performance of the ASSIST-M by using the Mini International Neuropsychiatric Interview- K component (M.I.N.I.- K component) as the standard diagnostic test of alcohol use disorder. The cut-off score of the ASSIST-M was determined by the co-ordinate points whereby the sensitivity and specificity are optimal in the ROC. The Area Under the Curve (AUC) of the ROC was determined. Result Characteristics of participants A total of 51 male patients participated in this study. The mean age was 40.1 years, ranging from 25 years to 66 years old. As shown in Table 1, majority of the patients were married (n=27, 52.9%), Indian (n=24, 47.1%), and of Hindu religion (n=18, 27.5%). 54.9% (n=28) of participants completed secondary school and more than 70% of them were employed. More than half of them had family history of alcohol consumption. Table 1. Socio-demographic characteristics of all participants Variables Total, n=51 (%) Age (mean ± SD) 40.1± 11.1 Marital Status Single 20 (39.2) Married 27 (52.9) Divorced 4 (7.8) Ethnicity Malay 6 (11.8) Chinese 16 (31.4) Indian 24 (47.1) Others 5 (9.8) Religion Islam 9 (17.6) Christian 11 (21.6) Buddha 9 (17.6) Hindu 18 (27.5) Others 3 (5.9) Education Level Primary 8 (15.7) Secondary 28 (54.9) Tertiary 15 (29.4) 7

10 Employment Status Employed 40 (78.4) Unemployed 11 (21.6) Family history of alcohol consumption 27 (52.9) Factor Structure and Internal Consistency of ASSIST-M The mean score of the respondents to the ASSIST-M was 11.19, standard deviation of The Bartlett s test of sphericity was significant (p <0.01) and the Kaiser-Mayer- Olkin measure of sampling adequacy for the ASSIST-M was 0.76 indicating middling [12] which indicated that factor analysis was appropriate. Only one factor was extracted with the Principle Component approach (eigenvalue >1.000) which accounted for 50.67% of total variance. (Table 2.) This result was consistent with the original ASSIST [13]. The ASSIST-M exhibited good internal consistency, with a Cronbach s alpha coefficient of was All items had corrected-item total correlations of more than 0.7. The deletion of any of the items would not increase the internal consistency of the total score. (Table 3.)The parallel reliability of the ASSIST-M was high as demonstrated by the intra-class correlation (ICC) of 0.96 (P< 0.01). The test retest reliability of the ASSIST-M after the 1-week interval was high with the ICC of 0.94 (P< 0.01). Table 2. Principal Component Analysis of ASSIST-M items Factor 2. In the past 3 months, how often have you used the alcohol? During the past three months, how often have you had a strong desire or urge to use alcohol? 4. During the past three months, how often has your use of alcohol led to health, social, legal or financial problems? 6. Has a friend or relative or anyone else ever expressed concern about your use of alcohol? Have you ever tried and failed to control, cut down or stop using alcohol? Cronbach alpha 0.80 Eigen value Explained variance (%) Loading below 0.30 is suppressed. 8

11 Table 3. Corrected Item Total correlations and Cronbach s ɑ if Item deleted for the ASSIST-Malay version Items Q2 In the past 3 months, how often have you ever used the alcohol? Q3. During the past 3 months, how often have you had a strong desire or urge to use alcohol? Q4. During the past 3 months, how often has your use of alcohol that led to health, social, legal or financial problems? Q5 During the past 3 months, how often have you failed to do what was normally expected of you because of your use of alcohol? Q6 Has a friend of relative or anyone else ever expressed concern about your use of alcohol? Q6 Have you ever tried to control, cut down or stop using alcohol? Scale Mean Scale Corrected Cronbach's if Item Variance if Item-Total Alpha if Deleted Item Deleted Correlation Item Deleted

12 Concurrent and discriminative Validity of ASSIST-M Table 4 shows the Spearman s correlations between the ASSIST-M and the participants respective scores on the AUDIT-M, CAGE, and WHOQoL-Brief-M. The ASSIST-M was positively correlated with the AUDIT-M (r =0.67, p <0.01) and the CAGE (r=0. 57, p < 0.01). ASSIST-M score showed a negative and statistically significant relationships with the physical (r= -0.28, p < 0.01) and social relationship (r= -0.37, p<0.01) subscales of the WHOQoL-Bref-M. The discriminatory ability of ASSIST-M based on the Mini International Neuropsychiatric Interview (M.I.N.I.) for alcohol use disorder was high with the Area Under Curve (AUC) of (p<0.01). The optimal cutoff point for ASSIST-M for alcohol use disorder was more than 14 with the with a sensitivity of %, specificity of %, positive predictive value (PPV) of 76.19% and negative predictive value (NPV) of 90%. Table 4. Correlation (Spearman s rho) between the ASSIST-M with AUDIT-M, CAGE, WHOQoL-Brief-M ASSIST-M AUDIT-M CAGE D1 D2 D3 AUDIT-M ** CAGE **.438 ** D * D ** D ** ** ** D ** ** ** Note: D1=Domain1= Physical domain, D2=Domain2= Psychological, D3=Domain3= Social relationship, D4=Domain4= Environment ASSIST-M= Alcohol, Smoking, and Substance Involvement Screening Test- Malay version, AUDIT-M= Malay version of The Alcohol Use Disorders Identification Test (AUDIT-M), ** p < 0.01* p < 0.05 Discussion This study validated the Malay version of ASSIST (ASSIST-M) for alcohol use disorders where current study found that the factor analysis of the ASSIST-M was consistent with the original ASSIST where only one factor was extracted with the Principle Component Analysis [6]. Furthermore, ASSIST-M demonstrated good internal consistency with Cronbach s alpha of 0.80 which was consistent with the original ASSIST for alcohol use problem with high one week interval test-retest reliability of 0.94 which was similar to another study [14, 15]. The internal consistency of the Spanish and Parsi version of ASSIST was 0.93 [16] and 0.87 [17] respectively. The validity of ASSIST-M was assessed by correlating ASSIST-M with scores of other instruments which have demonstrated high validity for measuring alcohol abuse. The ASSIST-M showed significant positive correlations with the Malay version of AUDIT (AUDIT-M) and CAGE indicating significant concurrent validity for alcohol. The French version of ASSIST was compared with ASI (Addiction Severity Index) for alcohol and opioid scores, tobacco use with RTQ (Revised Fagerstrom 10

13 Tolerance Questionnaire) scores, and AUDIT for the alcohol scores [13]. The total substance involvement score was compared with MINI plus in the French scale however the rest of the substances were not assessed in our scale. Using Mini International Neuropsychiatric Interview (M.I.N.I) subscale for alcohol use disorder as the gold standard, the ASSIST- M showed a high sensitivity and specificity at the cut-off point of 14 which was higher that other studies in the West [14, 15]. This shows that the ASSIST M has high discriminative validity and so is a good screening tool. The cultural differences between the previous studies and in the local setting itself may have contributed to the differing cut-off point. Some alcoholic drinks in Malaysia are homemade such as tuak and this may not be construed as alcoholic beverages as it is made out of fermented rice. In addition to that, the inexpensive and widely available coconut based alcoholic beverage such as toddy may also not be construed as alcoholic beverage by many in the Malaysian population [1]. Therefore, these factors may have contributed to the higher cut off scores in the ASSIST-M as drinking these substances are common and also acceptable in Malaysia than the conventional alcoholic beverages. The findings from this current study showed that those with higher ASSIST-M scores had poorer quality of life in the WHOQoL-Brief- M especially in the physical and social domains indicating that for our sample, those who were at risk of alcohol use problems were more likely to be physically and socially impaired. Our study findings are consistent with studies reporting that individuals with alcohol use problems have poorer quality of life as compared to the general population or with other chronic health conditions 18 and the quality of life worsened with the presence of co-morbid psychiatric illnesses such as depression and anxiety [19]. This study has several limitations which included the small sample size, and the findings generalizability is limited as the patients were recruited from a University medical centre. Also predictive validity could not be assessed due to the cross sectional nature of the study. Concurrent validity for substances other than alcohol was not assessed and hence this tool cannot be used with substances. However, the findings from this study demonstrated that the Malay version of ASSIST is a valid and reliable screening tool for alcohol use disorder and this will aid in detecting the at risk individuals and allow for early interventions to be carried out. Declaration of Interests There are no conflicts of interest for either author. Acknowledgements We would like to thank the University of Malaya Research Management Centre for providing UMRG Grant (RP A) to fund this study. References [1] WHO, Global status report on alcohol and health : World Health Organization. [2] WHO, The alcohol, smoking and substance involvement screening test (ASSIST): development, 11

14 reliability and feasibility. Addiction, (9): p [3] Humeniuk, R., et al., The Alcohol, Smoking and Substance involvement Screening Test (ASSIST): manual for use in primary care/prepared by R. HumeniukƯ [et al] [4] WHO, The Alcohol, Smoking and Substance Involvement Screening Test (ASSIST). Manual for Use in Primary Care. Geneva, Switzerland: World Health Organization, [5] Hides, L., et al., The reliability and validity of the Alcohol, Smoking and Substance Involvement Screening Test (ASSIST) in firstepisode psychosis. Addictive Behaviors, (10): p [6] Humeniuk, R., et al., Validation of the alcohol, smoking and substance involvement screening test (ASSIST). Addiction, (6): p [7] Organisation, W.H. Global status report on alcohol and health [cited 2014 July 2014]; e/publications/global_alcohol_report /en/]. [8] Osborne, J.W. and A.B. Costello, Sample size and subject to item ratio in principal components analysis. Practical assessment, research & evaluation, (11): p. 8. [9] Yee, A., et al., Validation of the alcohol use disorders identification test (AUDIT) Bahasa Malaysia version among a group of alcohol users. Journal of Substance Use. 0(0): p [10] Ewing, J.A., Detecting alcoholism. JAMA: The Journal of the American Medical Association, (14): p [11] Hasanah, C., L. Naing, and A. Rahman, World Health Organization quality of life assessment: brief version in Bahasa Malaysia. Medical Journal of Malaysia, (1): p [12] Kaiser, H.F., An index of factorial simplicity. Psychometrika, (1): p [13] Humeniuk, R. and R. Ali, Validation of the Alcohol, Smoking and Substance Involvement Screening Test (ASSIST) and pilot brief intervention [electronic resource]: a technical report of phase II findings of the WHO ASSIST Project/prepared by Rachel Humeniuk & Robert Ali, on behalf of the WHO ASSIST Phase II Study Group [14] Khan, R., et al., Validation of the French version of the alcohol, smoking and substance involvement screening test (ASSIST). European addiction research, (4): p [15] Newcombe, D.A., R.E. Humeniuk, and R. Ali, Validation of the world health organization alcohol, smoking and substance involvement screening test (ASSIST): report of results from the Australian site. Drug and alcohol review, (3): p

15 [16] Valladolid, G.R., et al., Validation of the Spanish version of the alcohol, smoking and substance involvement screening test (ASSIST). Psicothema, (2): p [17] Tiburcio, S.M., et al., Validity and Reliability of the Alcohol, Smoking, and Substance Involvement Screening Test (ASSIST) in University Students. Adicciones, (1): p [18] Srivastava, S. and M.S. Bhatia, Quality of life as an outcome measure in the treatment of alcohol dependence. Industrial psychiatry journal, (1): p. 41. [19] Saatcioglu, O., et al., Quality of life, depression and anxiety in alcohol dependence. Drug and alcohol review, (1): p Corresponding Author Anne Yee Department of Psychological Medicine, University of Malya Center for Addiction Sciences (UMCAS), Faculty of Medicine Building, University of Malaya, Kuala Lumpur, Malaysia Tel: Fax:

16 ORIGINAL PAPER The Psychometric Properties of the Positive Emotion Rating Scale Chinese Version (PERS-C) Ng CG 1, Chong SH 2 1 Department of Psychological Medicine, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia 2 Department of Psychology, UCSI University, Kuala Lumpur, Malaysia Abstract Introduction: Positive emotions in depressed patients are always disregarded and overlooked due to the inadequacy of assessment tool. There is a newly developed self-report scale, yet has good psychometric properties named Positive Emotion Rating Scale (PERS). Objective: The aim of this study were to translate and examine the psychometric properties of the Chinese version PERS (PERS-C). Method: This is a cross-sectional study involved 52 depressed and 106 control subject. Both groups were assessed with PERS-C, original PERS, Malay version of Snaith-Hamilton Pleasure Scale (SHAPS-M) and Malay version of Center for Epidemiological Studies Depression (CESD- M). Results: PERS-C displayed good internal consistency (Cronbach s α = 0.91) and parallel reliability with PERS (r = 0.95, p<0.01). It was negatively correlated with CES-D (r= , p<0.01) and positively correlated with SHAPS-M (r = 0.73, p<0.01). The optimal cut-off value was 32, with sensitivity = 0.64 and specificity = 0.67, positive predictive value of 0.80 and negative predictive value of The area under the curve (AUC) for receiver operating characteristic (ROC) was 0.71 (95% CI = ). Conclusion: The PERS-C is a simple and easy-to-use tool to measure positive emotion for Chinese speaking subjects, with demonstrable satisfactory psychometric properties. Keywords: Depression, Instrument, Positive Emotion, Psychometric Properties Introduction Major depressive disorder (MDD), which is also referred as clinical depression is a common mental illness (World Health Organization, 2012). This disorder affects functioning of one s life by impacting the mood and behaviours as well as the physical functions such as sleep and appetite. People with MDD feel depressed nearly every day and have diminished interest or pleasure to the activities they once enjoyed, as defined in the diagnostic guideline of the DSM-5 (American Psychiatric Association, 2013). They also having the other symptoms of depression included fatigue, low 14

17 concentration, insomnia, felt worthlessness and have the recurrent thoughts of death (American Psychiatric Association, 2013). MDD has become the leading cause of disabilities worldwide (Kessler et al., 2003; World Health Organization, 2012). The negative emotions are being focused mostly in clinical practice. The consequence has shown that the positive emotion was under-reviewed or under-recognized among depressed subjects (Burgdorf & Panksepp, 2006; Carl, Soskin, Kerns, & Barlow, 2013). Positive emotions refers to optimum wellbeing or flourishing (Fredrickson, 2001) experience such as love, interest, joy and contentment. The contribution of positive emotion is important in expending ones thought and behavior tendencies when dealing with stress. (Fredrickson, 2001; Fredrickson, 2004). When people with positive emotion are undergoing stressful event, they are prone to have high resiliency as they have big capacity to recover quickly from difficulties or toughness. The increment of psychological resilience and emotional regulation are being promoted by the flexibility of cognition (Tugade & Fredrickson, 2007). Thus, positive emotion advocates ones well-being and able to enhance the quality of life (Cohn, Fredrickson, Brown, Mikels, & Conway, 2009). The risk of having depression and anxiety is because of the deficiency in positive emotions (Brown & Barlow, 2009; Gruber, Kogan, Quoidbach, & Mauss, 2013). Positive emotions broaden the thinking, attention and action. Hence, it is advantageous as a part of treatment of depression. Studies showed that symptoms of depression will decrease as well as prevent relapse when positive emotions increase (Santos et al., 2013). Hence, an assessment of positive emotion is needed in depressed patients, which frequent being neglected in the common practice. There are many assessment of emotion are developed to measure different type of emotional experiences as a result of people perceived different definitions of emotions (Lucas, Diener, & Larsen, 2009). Numerous studies on positive emotion have been done. However, there is still inadequacy of valid instrument to measure positive emotion among the depression patients (Ng, et al., 2016). This shows the importance of creating a valid instrumentation to evaluate positive emotion. The original PERS was developed to assess positive emotion. The instrument consists of eight items with six domains of positive emotions which are interest, love, contentment, pride, active and gratification. PERS has adopted the core domains into the questionnaire in order to provide extensive assessment of positive emotion. Previous study demonstrated that the tool has good reliability and validity (Ng et al., 2016). Up to date, this questionnaire is only available in English language and Malay language for the measurement of positive emotion. Therefore, the aim of this study is to translate the Positive Emotion Rating Scale (PERS) to the Chinese language and to study the psychometric properties of the Chinese version of Positive Emotion Rating Scale (PERS-C). Methods Study Design This was a cross sectional study conducted at the University Malaya Medical Centre (UMMC), from January 2017 until December Ethical approval was obtained from Medical ethical Committee, UMMC. Two groups of subjects were selected. The first group consisted of depressed subjects 15

18 based on DSM-5 diagnosis of major depressive disorder (MDD) (American Psychiatric Association, 2013) without other major psychiatric illnesses or psychosis. The second group is healthy subjects, recruited from family members, care takers, students and visitors, without MDD and other psychiatric illnesses. All participants from both group were able to read and understand Malay or English languages, age 18 years and above, and consented to this study. Both groups were explained about the study. Those who agreed and gave consents, would be recruited into the study. They were assessed using the sociodemographic information questionnaire, PERS-C and following tools. Positive Emotion Rating Scale (PERS) The PERS was developed to measure the positive emotion (Ng et al., 2016). It is a self-report questionnaire consisted of eight items. It is scored using a Likert scale ranges from one (never) to five (always). The cutoff score of 30 of the original scale demonstrated significant discriminant validity between depressed and nondepressed subjects, with sensitivity = 0.75 and specificity = It has a good validity and reliability to measure positive emotion in depressed patients, with high internal consistency (Cronbach s alpha 0.90) (Ng et al., 2016). Malay version Center for Epidemiologic Studies Depression Scale (CESD-M) The Malay version of CESD is a valid and reliable depression assessment scale (Sabki, Zainal, & Guan, 2014). It was developed by Radloff (1977). It is one of the most commonly used instrument in the study of psychiatry epidemiology to identify people at risk for clinical depression. The CESD consisted of 20-item self-report questionnaire, score ranging from 0 to 3. Total score ranges from 0 to 60, with higher score signifies greater depressive symptoms, with the cut-off score of 16 and more. It has good sensitivity and good specificity with high internal consistency in identifying people at risk of clinical depression (Lewinsohn, Seeley, Roberts, & Allen, 1997). Malay version Snaith Hamilton Pleasure Scale (SHAPS-M) The SHAPS is a self-rated instrument to assess hedonic capacity (Snaith et al., 1995). It consists 14 items with a set of four response categories: definitely agree, agree, disagree and definitely disagree. It will be scored as the sum of all 14 items. A higher total SHAPS score indicates higher level of anhedonia. In this study, SHAPS-M was used, which had been validated and showed to be reliable to assess anhedonia among depressed patients (Ng et al., 2014). Unlike the original English version, the SHAPS-M applied a reverse scoring. The SHAPS-M is scored as sum of all 14 items, with total score range from 14 to 56. The lower score of SHAPS-M indicates higher level of anhedonia. The cut-off value of total score SHAPS-M of 42 to distinguish depressed from non-depressed subjects, with good sensitivity (0.79) and specificity (0.74) (Ng et al., 2014). Procedure The English version of Positive Emotion Rating Scale (PERS) was translated to Chinese language by two bilingual (English and Chinese) researchers who were a psychiatrist and a psychologist. Subsequently, two different bilingual researchers back translated the Chinese version scale to English language. The translated version was pilot tested among 20 16

19 staffs for face validity. The finalized version of PERS-C was reviewed by two different bilingual researachers for the content validity and to ensure satisfactory face criterion and conceptual equivalent. All subjects consisted of depressed patients and healthy subjects who consented to the study were given the assessment questionnaires: sociodemographic and clinical background, PERS-C, PERS, CESD-M and SHAPS-M. Statistical Analysis The results were analysed with Statistical Package for Social Sciences (SPSS) version The descriptive statistics were used to examine the baseline characteristics of the subjects. The internal consistency of PERS- C was analysed with Cronbach s α coefficient. The parallel reliability between PERS-C and PERS was analysed with Spearman s correlation test. Spearman s correlation was also used to examine concurrent validity between the PERS-C with CESD-M and SHAPS-M. Mann- Whitney test was used to study the PERS-C total and item score between depressed subjects and healthy subjects. The optimal cut-off score of PERS-C for depressed cases was determined from the co-ordinate points which optimal sensitivity and specificity in the Receiver Operating Characteristic (ROC) was determined. The Area Under the Curve (AUC) of the ROC was determined. All of the analysis were 2-tailed with alpha value of Results A total of 52 depressed and 106 control subject consented for this study. The mean age was 36 years old, with the depressed group about eight years older than the control group. In both groups, there were more female and employed. Depressed group were mainly married (61.5%) while two third of the control group were single. Additionally, most of the depressed and healthy subjects achieved at least secondary level of education. Table 1. Sociodemographic background of participants Depressed Subjects Non-depressed Total (N: 158) (N:52) Subjects (N:106) Age (years), mean (sd) (13.94) (14.93) (15.02) Gender, n (%) Male 19 (36.5%) 52 (49.1%) 71 (44.9%) Female 33 (63.5%) 54 (50.9%) 87 (55.1%) Race, n (%) Chinese 51 (98.1%) 106 (100%) 157 (99.4%) Indian 1 (1.9%) 0 (0%) 1 (0.6%) Religion, n (%) Buddhist 37 (71.2%) 84 (79.2%) 121 (76.6%) Christian 7 (13.5%) 16 (15.1%) 23 (14.6%) Hindu 0 (0%) 1 (0.9%) 1 (0.6%) Others 8 (15.4%) 5 (4.7%) 13 (8.2%) Marital Status, n (%) Single 19 (36.5%) 70 (66.0%) 89 (56.3%) Married 32 (61.5%) 34 (32.1%) 66 (41.8%) Divorced 1 (1.9%) 1 (0.9%) 2 (1.3%) 17

20 Widow/Widower 0 (0%) 1 (0.9%) 1 (0.6%) Education level, n (%) Primary 6 (11.5%) 6 (5.7%) 12 (7.6%) Secondary 15(28.8%) 40 (37.7%) 55 (34.8%) Tertiary 31 (59.6%) 60 (56.6%) 91 (57.6%) Occupation, n (%) Not employed 11 (21.2%) 4 (3.8%) 15 (9.5%) Part-time 3 (5.8%) 6 (5.7%) 9 (5.7%) Full-time 28 (53.8%) 36 (34.0%) 64 (40.5%) Pensioner 1 (1.9%) 1 (0.9%) 2 (1.3%) Student 2 (3.8%) 48 (45.3%) 50 (31.6%) Housewife 7 (13.5%) 11 (10.4%) 18 (11.4%) Table 2. Antidepressants used by the depressed subjects (N=52) Frequency (N) Percent (%) Monotherapy SSRI SNRI NaSSA Agomelatine Vortioxetine TCA Combination therapy SSRI = selective serotonin reuptake inhibitor, SNRI = serotonin-norepinephrine reuptake inhibitor, NaSSA = noradrenergic and specific serotonergic antidepressant, TCA = tricyclic antidepressant Most of them treated with monotherapy of antidepressant (69.2%) with mostly on escitalopram followed by agomelatin. Less than one third of the depressed patients were on combination therapy of antidepressant (30.8%). Table 3. Comparison of PERS-C between depressed (N=52) and healthy subjects (N=106) PERS-C, mean (sd) Mean difference Mann-Whitney test p value Depressed Non Depressed Item (1.14) 4.30 (1.02) 0.59 < 0.01 Item (1.37) 3.89 (1.27) Item (1.30) 4.12 (1.14) 0.53 < 0.01 Item (1.34) 4.11 (1.15) 0.61 < 0.01 Item (1.16) 4.33 (0.93) 0.77 < 0.01 Item (1.08) 4.30 (0.98) Item (1.09) 3.99 (1.02) 1.26 < 0.01 Item (1.27) 3.96 (1.16) 0.90 < 0.01 Total (6.77) (6.92) 5.59 < 0.01 PERS-C = Chinese version of Positive Emotion Rating Scale 18

21 The PERS-C scores for the depressed subjects (mean=27.42, SD = 6.77) were significantly lower than healthy subjects (mean=33.01, SD = 6.92). For each individual item, the scores among the depressed group were significantly lower than the healthy subjects. Table 4. Spearman s Correlation (r) of the total score between PERS-C and original PERS, CES-D and SHAPS in the depressed subjects CES-D PERS-C SHAPS PERS CES-D ** -0.35* -0.40** PERS-C -0.43** ** 0.95** SHAPS -0.35* 0.73** ** PERS -0.40** 0.95** 0.71** 1.00 * p < 0.05, ** p < 0.01 PERS-C = Chinese version of Positive Emotion Rating Scale, PERS = English version of Positive Emotion Rating Scale, CES-D = Centre for Epidemiological Studies, SHAPS = Snaith-Hamilton Pleasure Scale The PERS-C exhibited good internal consistency, with Cronbach s alpha coefficient of Parallel reliability of PERS-C and PERS was good, as showed by Spearman s Correlation of 0.95, (p<0.01). The PERS-C was positively correlated SHAPS (r=0.73, p<0.01), and negatively correlated with CES-D (r=-0.43, p<0.01). Table 5. Sensitivity and specificity of each coordinates for the ROC curve of PERS-C to determine depressed cases in the study subjects PERS-C Score Sensitivity Specificity PERS-C = Chinese version of Positive Emotion Rating Scale, ROC = receiver operating characteristic The area under the receiver operating characteristic curve (AUC) was 0.71 (95% CI = ). The optimal cut-off score to differentiate depressed subjects from healthy subjects was 32, with sensitivity 0.64, specificity 0.67, positive predictive value = 0.80 and negative predictive value =

22 Discussion This study aimed to test the psychometric properties of the Chinese version of questionnaire. There are 52 depressed subjects are being compared with 106 healthy subjects. The result from this study has shown PERS-C with remarkable psychometric properties. Hence, it is applicable for measuring the positive emotion. The PERS-C shown had high reliability with internal consistency of Cronbach s α of There is significant correlation between PERS-C with CES-D and SHAPS. The score for depressed subjects of PERS-C (27.42) was significantly lower than the healthy subjects (33.01). From the results shown above, each of the items among the depressed subjects was significantly lower than the healthy subjects (p < 0.01). The optimum cut-off score to segregate depressed subjects was 32 with high sensitivity and high specificity. This result is differ from the original English version which has the cut-off score of 30 (Ng et al., 2016), but it showed the same cut-off score from the Malay version of PERS which has the cut-off score of 32. According to the list of the literature reviews, many studies were focusing on negative emotion. Furthermore, professions in clinical psychiatric practice were more concentrating on negative impacts on depressed subjects (Burgdorf & Panksepp, 2006; Carl, Soskin, Kerns, & Barlow, 2013). Thus, positive emotion is frequent being neglected in common practice. It is challenging in providing an effective tool to evaluate the level of positive emotion in depression. Hence, it is important to develop an effective instrument in this aspect. As Malaysia is a diverse country with different ethnic background, there is a need to establish an easy-to-use instrument that is applicable for the local setting. Different languages of questionnaire showed the importance and need for subjects. There are different races in Malaysia and not all of them are multilingual or bilingual. Hence, developing more languages can assess more depressed subjects of their positive emotion. Since there is an English version and also a Malay version, Chinese language should be included as Chinese is a common language used among the Chinese population in Malaysia. Although good psychometric properties of PERS-C is shown, limitations were found in this study. Firstly, samples may have the risk of bias as this tool is a self-evaluation tool. Respondents may rate the answers which are socially acceptable. Second, samples were homogenous due to they were taken from the same setting. The results cannot be generalised as it was not represented the general population. Conclusion The PERS-C is short and compressed selfrating tool which is easy to be administered. The current results of PERS-C demonstrated that the scale has good psychometric properties to evaluate positive emotion among adults who are proficient in in Chinese in Malaysia. References [1] American Psychiatric Association. (2013). Diagnostic and statistical manual of mental disorder (5th Edition). Washington, DC. [2] Brown, T. A., & Barlow, D. H. (2009). A proposal for a dimensional classification system based on the shared features of the DSM-IV anxiety and mood 20

23 disorders: implications for assessment and treatment. Psychological assessment, 21(3), doi: /a [3] Burgdorf, J., & Panksepp, J. (2006). The neurobiology of positive emotions. Neurosci Biobehav Rev, 30(2), doi: /j.neubiorev [4] Carl, J. R., Soskin, D. P., Kerns, C., & Barlow, D. H. (2013). Positive emotion regulation in emotional disorders: a theoretical review. Clin Psychol Rev, 33(3), doi: /j.cpr [5] Cohn, M. A., Fredrickson, B. L., Brown, S. L., Mikels, J. A., & Conway, A. M. (2009). Happiness unpacked: positive emotions increase life satisfaction by building resilience. Emotion, 9(3), doi: /a [6] Fredrickson, B. L. (2001). The role of positive emotions in positive psychology: the broaden-and-build theory of positive emotions. The American psychologist, 56(3), [7] Fredrickson, B. L. (2004). The broaden-and-build theory of positive emotions. Philos Trans R Soc Lond B Biol Sci, 359(1449), doi: /rstb [8] Gruber, J., Kogan, A., Quoidbach, J., & Mauss, I. B. (2013). Happiness is best kept stable: positive emotion variability is associated with poorer psychological health. Emotion, 13(1), 1-6. doi: /a [9] Kessler, R. C., Berglund, P., Demler, O., Jin, R., Koretz, D., Merikangas, K. R.,... National Comorbidity Survey, R. (2003). The epidemiology of major depressive disorder: results from the National Comorbidity Survey Replication (NCS-R). JAMA, 289(23), doi: /jama [10] Lucas, R. E., Diener, E., & Larsen, R. J. (2009). Measuring positive emotions, In Diener E. Assessing Well-Being. Netherlands: Springer. [11] Santos, V., Paes, F., Pereira, V., Arias-Carrión, O., Silva, A. C., Carta, M. G.,... Machado, S. (2013). The role of positive emotion and contributions of positive psychology in depression treatment: systematic review. Clinical Practice and Epidemiology in Mental Health: CP & EMH, 9, doi: / [12]Tugade, M. M., & Fredrickson, B. L. (2007). Regulation of positive emotions: Emotion regulation strategies that promote resilience. Journal of Happiness Studies, 8(3), [13] World Health Organization (2012). Depression A Global Public Health Concern. Geneva: World Health Organization. 21

24 Corresponding Author Dr Ng Chong Guan Department of Psychological Medicine, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia 22

25 ORIGINAL PAPER Comparison between Aripiprazole with Quetiapine in Patients with Bipolar Disorder: A Retrospective Outcomes Study Ng CG 1, Seed HF 2, Thong KS 3 1 Department of Psychological Medicine, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia 2 Hospital Sentosa, Kuching, Sarawak, Malaysia 3 Department of Psychiatry and Mental Health, Sarawak General Hospital, Kuching, Sarawak, Malaysia Introduction: Atypical antipsychotic drugs are effective in the treatment of bipolar disorder. Studies have shown that atypical antipsychotic drugs are more superior to typical antipsychotic in term of neurocognitive function, negative symptoms and extrapyramidal side effects. Both aripiprazole and quetiapine are atypical antipsychotic drugs that are effective and commonly used in all phases of bipolar disorder treatment. Objective: The aim of this study is to examine and compare the clinical outcomes of aripiprazole and quetiapine in bipolar disorder patients. Method: This was a retrospective cohort study among patients from psychiatric unit, University Malaya Medical Center. Prescription records dated between January 1, 2013 and December 31, 2014 for psychiatric unit were extracted. The data of the subjects with prescription of the two atypical antipsychotic, namely aripiprazole and quetiapine was extracted. The outcome measures were the co-prescription of antihypertensive drugs, antidiabetic drugs and lipid lowering drugs. Results: A total of 58 subjects were recruited, 11 were on aripiprazole and 47 were on quetiapine. Statistical analysis has shown that both aripiprazole and quetiapine do not have any association with compliance to the medication and also follow up. Study also revealed that there is no association between the aripiprazole and quetiapine group with the metabolic side effects that were measured such as systolic or diastolic blood pressure, waist circumference, weight, glucose level and body mass index. Conclusion: This study has shown that both aripiprazole and quetiapine were similar in terms of metabolic side effect, compliance to medications and follow up. Keywords: Aripiprazole, Quetiapine, Bipolar Disorder, Atypical Antipsychotic 23

26 Introduction Atypical antipsychotic drugs (APD) are emerging as treatments with valid efficacy in all phases of bipolar disorder [1]. Quetiapine and aripiprazole are both APD. Atypical antipsychotic drugs are generally described as drugs that produce minimal or no extrapyramidal side effects at clinically therapeutic dose [2]. Atypical APDs have cognitive benefits with superiority in some cognitive domain. Review of clinical studies on the effects of atypical antipsychotic among schizophrenia patients with cognitive impairment showed 30-50% significant improvement in specific cognitive domains or composite scores [3]. APDs such as olanzapine and risperidone demonstrated an overall superiority to haloperidol on a range of neurocognitive functions [4]. Besides, APDs such as clozapine, olanzapine and risperidone were better than typical antipsychotic such as haloperidol in improving negative symptoms [4]. However, all APDs will lead to significant weight gain in some patients [2]. The weight gain maybe mainly associated with H1 receptor blockage [3]. Other side effects of APDs include diabetes mellitus, hyperlipidaemia, sexual side effects and cataract [5]. Aripiprazole has been shown in clinical trials to have good efficacy, safety, and tolerability in treating Bipolar 1 Disorder patients with an acute manic or mixed episode and these improvements in manic symptoms were shown as early as day four 6. Findings from this trial also suggested that aripiprazole may offer significant benefit in rapid-cycling patients, a subpopulation of patients at risk for treatment non-responsiveness [6,7]. Patients with bipolar disorder are at high risk for metabolic syndrome with the risk greater in those taking prescribed antipsychotic medication [8]. Aripiprazole is an antipsychotic with a novel mechanism of action which differentiates it from the currently marketed typical and atypical antipsychotics. It is a dopamine D2 receptor partial agonist with partial agonist activity at serotonin 5HT1A receptors and antagonist activity at 5HT2A receptors [9]. This pharmacologically distinct antipsychotic leads to a low potential for weight gain, risk of developing diabetes or a deranged lipid profile [10]. Clinical trials have shown that aripiprazole was associated with minimal effects on cholesterol and glucose, comparable to effects with placebo [6]. Aripiprazole has a lower risk of EPS and hyperprolactinemia than other antipsychotics [11]. Quetiapine acts by blocking 5-HT2A receptors and D2 receptors. It also has affinity for different serotonergic and noradrenergic receptors. These actions explained the antipsychotic effects with lesser extrapyramidal symptoms, antidepressant and anxiolytic effects [12]. As quetiapine binds to H1 histamine receptors as well, it is associated with increased appetite and weight gain 12. Quetiapine has become a commonly used drug for bipolar patients with early response and sustained efficacy over 12 weeks [13]. Quetiapine is efficacious in treating acute mania, mixed and depressive episodes with good tolerability but has metabolic side effects such as obesity, dyslipidaemia and hyperglycaemia [1]. A head-to-head meta-analysis that looked into the metabolic side effects of second-generation antipsychotics showed that quetiapine had intermediate elevations in weight gain, cholesterol and glucose elevation amongst atypical antipsychotic [14]. On the other hand, CATIE study revealed that quetiapine has no more weight gain and metabolic changes associated with increased risk of 24

27 diabetes than those on other antipsychotics [15]. Studies have shown that both aripiprazole and quetiapine are effective in the treating patients with Bipolar Disorder. Our aim of this study is to examine the clinical outcomes of both drugs in bipolar disorder patients. Methods Setting and Design The study was conducted in University Malaya Medical Centre (UMMC), a referral and a teaching hospital located in Kuala Lumpur, Malaysia. This was a retrospective cohort study among patients from psychiatric unit, UMMC between January 1, 2013 and December 31, This study was approved by the Medical Ethics Committee, UMMC. Data Sources The pharmacy department in UMMC maintained all prescriptions records electronically in Medication Management and Use System Ascribe (Version 10.09) database. From this database, prescription records dated between January 1, 2013 and December 31, 2014 for psychiatric unit were Table 1. Socio-demographic characteristic Aripiprazole (n=11) extracted using IBM s Cognos Business Intelligence PowerPlay. The information extracted from the database includes patients gender, age, ethnicity and drug s generic name for every individual. The prescription of coverage was 100% for the above-mentioned study period. All drugs in the database were coded according to British National Formulary (BNF) classification. All subjects with at least one prescription of antipsychotic (ATC code = N05A) was selected. The data of the subjects with prescription of the two atypical antipsychotic, namely aripiprazole and quetiapine was extracted. The outcome measures were the co-prescription of antihypertensive drugs, antidiabetic drugs and lipid lowering drugs. Statistical Analyses Statistical analyses were performed using Statistical Package for the Social Sciences (SPSS version 22, IBM Corporation). The odds of co-prescription of antihypertensive drugs, antidiabetic drugs and lipid lowering drugs were calculated and analyzed with using Chi-Square analysis. All statistical analyses were tested with alpha less than 5% using two-tailed. Results Quetiapine (n=47) Age (years), Mean (sd) (14.12) (15.69) 25

28 Gender Male Female 3 (27.3) 8 (72.7) 5 (10.6) 42 (89.4) Ethnic Malay Chinese Indian Others 4 (36.4) 2 (18.2) 4 (36.4) 1 (9.1) 12 (25.5) 21 (44.7) 13 (27.7) 1 (2.1) A total of 58 subjects were recruited for this study. 11 subjects were on aripiprazole and 47 subjects were on quetiapine. The mean age for the aripiprazole group is years old and years old for quetiapine group. There were more female subjects in both groups represented by 72.7% in the aripiprazole group and 89.4% in the quetiapine group. Majority of the study subjects are Chinese, followed by Indian, Malay and others. Table 2. Comparison between patients on aripiprazole and quetiapine on compliance to medication and follow up Compliance to medicine Yes No Compliance to follow up Yes No Aripiprazole Quetiapine n (%) n (%) 10 (90.9) 6 (9.1) 11 (100.0) 0 (0) 41 (87.2) 6 (12.1) R OR 95% CI p Value (91.5) 4 (6.9) * 0.42 *Fisher s Exact Test. Compliance to medication based on repeat prescription in the pharmacy database. Compliance to follow up based on medical record documentation. Table 2 showed the percentage of subjects in both aripiprazole and quetiapine group who are compliant or not to medication and follow up. Statistical analysis has shown that the difference in medication, be it aripiprazole or quetiapine, do not have any association with compliance to the medication and also follow up. 26

29 Table 3. Metabolic parameters in patients on aripiprazole and quetiapine Baseline Sys BP Aripipraz ole Mean (sd) (13.12) Quetiapine Means Diff Mean (sd) (18.76) t 95% CI , p Value 0.47 Changes in Sys BP (11.87) (12.33) Baseline Dias BP (12.04) (11.44) , Changes in BP (5.83) (15.41) Waist circumference (cm) (13.45) (13.96) , Weight (kg) (15.01) (12.06) Glucose (mml/c) 7.97 (4.15) 7.51 (4.41) , BMI (4.23) (4.60) , Sys BP= systolic blood pressure, Dias BP = diastolic blood pressure, BMI = body mass index Table 3 looked into the differences of systolic or diastolic blood pressure, waist circumference, weight, glucose level and BMI between the aripiprazole and quetiapine group. Statistical analysis revealed that there is no association between 27

30 the aripiprazole and quetiapine group with these metabolic side effects that were measured. Discussion Overall, the results of our study show that aripiprazole has a higher percentage of compliance to medicine (90.0%) and compliance to follow up (100%) compared to quetiapine. However statistical analysis of this study has shown that the difference in medication, be it aripiprazole or quetiapine, do not have any association with compliance to the medication and also follow up (p=.602, p=.420). A study by Crespo-Facorro and colleagues found that patients treated with quetiapine was associated with a higher risk of treatment discontinuation due to insufficient efficacy in comparison to aripiprazole and ziprasidone, and also a higher rate of respondents with aripiprazole [16]. Quetiapine increases patients' risk for the development of metabolic syndrome whereas aripiprazole, unlike other atypical anti-psychotics, has not been associated with an increased risk for metabolic syndrome [17]. However, our study revealed that there are no differences between the aripiprazole and quetiapine group with these metabolic parameters (systolic or diastolic blood pressure, waist circumference, weight, glucose level and BMI) that were measured. Our findings showed that both Aripiprazole and Quetiapine have equal good tolerability and low metabolic side effects. This is similar with previous studies such as a study by Shoja Shafti et al. that mentioned Aripiprazole and Quetiapine has similar effectiveness and tolerability [18]. Another study also showed that both aripiprazole and quetiapine present with similar metabolic profiles in long term [19]. Small sample size, short duration of study and lack of placebo arm, which may have significance impact on the sensitivity of the study, were among the limitations of this study. A small sample size increases the margin of error and thus affecting the ability to detect an effect that may be present. As in this study, the prescription of coverage was already 100% for the study period, therefore extending the duration of study will increase the sample size and thus be beneficial. The use of placebo group is to look into the placebo effect, which means the effects from the treatment that are not depending on the treatment itself. Adding in a placebo group in this study increases the like hood of detecting treatment related beneficial or adverse effects. Besides, this study was carried out in one health centre therefor the results may not be able to generalize to other settings. A larger sample size and multicentre study are recommended in future study. In conclusion, our study has shown that both Aripiprazole and Quetiapine were similar in terms of metabolic side effect, compliance to medications and follow up. References [1] Muneer A. Pharmacotherapy of bipolar disorder with Quetiapine: A recent literature review and an update. Clinical Psychopharmacology and Neuroscience. 2015;13(1): [2] Haddad PM, Sharma SG. Adverse effects of atypical antipsychotics. Differential risk and clinical implications. CNS drugs. 2007;21(11):

31 [3] Meltzer HY. Update on typical and atypical antipsychotic drugs. Annual Review of Medicine. 2013;64: [4] Bilder RM, Goldman RS, Volavka J, Czobor P, Hoptman M, Sheitman B, et al. Neurocognitive effects of clozapine, olanzaoine, risperidone and haloperidol in patients with chronic schizophrenia or schizoaffective disorder. The American Journal of Psychiatry. 2002;159: [5] Üçok A, Gaebel W. Side effects of atypical antipsychotics: A brief overview. World Psychiatry Feb;7(1), [6] Sachs G, Sanchez R, Marcus R, Stock E, McQuade R, Carson W, et al. Aripiprazole in the treatment of acute manic or mixed episodes in patients with bipolar I disorder: a 3-week placebo-controlled study. Journal of Psychopharmacology Jul;20(4): [7] Calabrese J R, Shelton M D, Bowden C L, Rapport DJ, Suppes T, Shirley ER, et al. Bipolar rapid cycling: focus on depression and its hallmark. Journal of Clinical Psychiatry. 2001;62(14): [8] Vancampfort D, Vansteelandt K, Correll CU, Mitchell AJ, Herdt AD, Sienaert P, et al. Metabolic syndrome and metabolic abnormalities in bipolar disorder: A meta-analysis of prevalence rates and moderators. The American Journal of Psychiatry. 2013;170(3): [9] Potkin SG, Saha AR, Kujawa MJ, Carson WH, Ali M, Stock E, et al. Aripiprazole, an antipsychotic with a novel mechanism of action, and risperidone vs placebo in patients with schizophrenia and schizoaffective disorder. Archives of General Psychiatry. 2003;60(7): [10] Kemp DE, Calabrese JR, Tran Q-V, Pikalov A, Eudicone JM, Baker RA. Metabolic syndrome in patients enrolled in a clinical trial of aripiprazole in the maintenance treatment of bipolar I disorder. Journal of Clinical Psychiatry Sep;71(9): [11] Mailman RB, Murthy V. Third generation antipsychotic drugs: partial agonism or receptor functional selectivity? Current pharmaceutical design. 2010;16(5): [12] López-Muñoz F, Álamo C. Active metabolites as antidepressant drugs: The role of norquetiapine in the mechanism of action of quetiapine in the treatment of mood disorders. Frontiers in Psychiatry. 2013;4:102. [13] McIntyre RS, Brecher M, Paulsson B, Huizar K, Mullen J. Quetiapine or haloperidol as monotherapy for bipolar mania - a 12-week, double-blind, randomized, parallel-group, placebo-controlled trial. European Neuropsychopharmacology Oct;15(5): [14] Rummel-Kluge C, Komossa K, Schwarz S, Hunger H, Schmid F, Lobos CA, et al. Head to head 29

32 comparisons of metabolic side effects of second generation antipsychotics in the treatment of schizophrenia: A systematic review and meta-analysis. Schizophrenia Research Nov;123(2-3): [15] Swartz MS, Stroup TS, McEvoy JP, Davis SM, Rosenheck RA, Keefe Rs, et al. What CATIE found: Results from the schizophrenia trial. Psychiatric services May;59(5): [16] Crespo-Facorro B, Pérez-Iglesias R, Mata I., Ortiz-Garcia de la Foz V, Martínez Garcia O., Valdizan EM, et al. Aripiprazole, ziprasidone, and quetiapine in the treatment of first-episode nonaffective psychosis: results of a 6-week, randomized, flexible-dose, open-label comparison. Journal of Clinical Psychopharmacology Apr;33(2): [17] Nierenberg AA. A critical appraisal of treatments for bipolar disorder. Primary Care Companion to The Journal of Clinical Psychiatry. 2010;12(Suppl 1): [18] Shoja Shafti S, Kaviani H. Quetiapine versus aripiprazole in the management of schizophrenia. Therapeutic Advances in Psychopharmacology. 2015;5(3): [19] Bourgon JV, Pérez-Iglesias R, Ortiz-García de la Foz V, Crespo-Facorro1 B. Lack of differential long-term metabolic profile of aripiprazole, quetapine and ziprasidone in first episode of psychosis. European Psychiatry Apr;41: S388. Corresponding Author Dr Ng Chong Guan Department of Psychological Medicine, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia chong_guan@um.edu.my 30

33 CASE REPORT Clozapine and Polycythemia Rubra Vera: A Rare Side Effect or a Separate Medical Condition? A Case Report Tan HPJ Hospital Sentosa, Kuching, Sarawak, Malaysia Abstract This article highlights the case of a 44-year old Malay man who is diagnosed as having treatment resistant schizophrenia on Clozapine, which then developed Polycythemia Rubra Vera (PRV). It is known that a major side effect for Clozapine is of agranulocytosis, that is a potentially fatal side effect. However, there have been reported disturbances of other hematological parameters, which result in other abnormalities including leucopenia, leucocytosis, thrombocytopenia, thrombocytosis and eosinophilia. Could this case be a pure medical condition of PRV or is there a relation to the effects of Clozapine? In this paper, the aim is to report a case of blood dyscrasia in a 44-year old male who developed Polycythemia Rubra Vera a year after he was observed to have abnormal full blood count results. Keywords: Clozapine, Polycythemia Rubra Vera, Blood Dyscrasia Introduction Clozapine is a second-generation atypical antipsychotic that has been considered a gold standard for schizophrenic patients who have been diagnosed as treatment-resistant to two or more standard antipsychotics. The U.S. Food and Drug Administration (FDA) have approved Clozapine for the treatment of schizophrenia, recurrent suicidal behavior in patients with schizophrenia or schizoaffective disorder [1]. Although it has a good response to treating treatment resistant cases of schizophrenia and that it has relatively fewer extrapyramidal side effects compared to the other antipsychotics, the hematological side effects are one of concern when it happens. Agranulocytosis and Neutropenia are the most serious side effect that causes great concern for psychiatrist and physicians who encounter it. It is established from the premarketing experience and the data obtained from abroad, that the known intrinsic rate of agranulocytosis was estimated to occur between 1 2 %, while post-marketing data suggest an incidence of 0.38% [2]. The risk of death nowadays from agranulocytosis is estimated at 1:10000 [3]. Neutropenia risk with Clozapine is found to be approximately 3% with cumulative incidence reports of between the range of 0.9% and 19.8% (8-year cumulative incidence) [4,5]. However, there have not been many reports that mention about other changes in the hematologic parameters. The hematologic changes that have been 31

34 described with clozapine also include leukocytosis (0.6%), eosinophilia (1%), and thrombocytopenia/ thrombocytosis [6-8]. It is not known if a clear association can be related to polycythemia in the use of clozapine. A case report has seen a similar presentation of clozapine triggering a somatic disease of polycythemia vera [9]. This article aims to report a possible association and trigger between Clozapine and Polycythemia Rubra Vera, in the context of blood dyscrasia. Case Summary This case is a 44-year old male who has been diagnosed with Schizophrenia since 1987 when he was 15-years old. He presented in the first instance with being easily irritable with suspiciousness towards others. He also complained of being easily frightened for no apparent reason. There was a deterioration in school performance and with a difficulty in concentration and memory. He had a history of numerous hospitalizations since then and was tried on multiple typical and atypical antipsychotics with no remission in symptoms. In 1997, he had also undergone a course of Electroconvulsive Therapy (ECT). In 2001, he was deemed to fulfill the criteria of treatment-resistant schizophrenia and was commenced on Clozapine. At that point of time, his total white cell count was measured at x 10 9 /L. He was maintaining well on a dose of 350mg/ day Clozapine since Throughout the course of clozapine, his Total White Cell, Neutrophil, Granulocyte, Lymphocyte, Hemoglobin and Platelet count are shown as in the Figures 1-6 below (with average and a 2-period moving average). Total White Cell Count Mean, x 10 9 /L Mean 2 per. Mov. Avg. (Mean) TWC Max Mean Min Figure 1. Total White Cell count trend from 2001 to 2016 with a 2-period moving average 32

35 Neutrophil Count (%) % Mean 2 per. Mov. Avg. (Mean) Neu Max Mean Min Figure 2. Neutrophil Count trend from with a 2-period moving average 50 Lymphocyte Count ( ) % LEU Mean 2 per. Mov. Avg. (Mean) LEU Max Mean Min Figure 3. Lymphocyte Count trend from with a 2-period moving average 33

36 95.00 Granulocyte Count ( ) % Mean 2 per. Mov. Avg. (Mean) Gra Max Mean Min Figure 4. Granulocyte Count trend from with a 2-period moving average 22 Hb Count ( ) g/dl 16 Mean 14 2 per. Mov. Avg. (Mean) Hb Max Mean Min Figure 5. Hemoglobin Count trend from with a 2-period moving average 34

37 Platelet Count ( ) x10 9 /L Plt Max Mean Min Mean 2 per. Mov. Avg. (Mean) Figure 6. Platelet Count trend from with a 2-period moving average During a routine follow-up in September 2014, an increasing trend in his total white cell, platelet and hemoglobin count was noticed. He was referred for further investigation with the hematology department and was diagnosed with JAK2 polycythemia rubra vera in June 2015 and on monthly venesection. His dosage of clozapine 350mg/day was continued. In October 2015, he was admitted to the hospital after presenting with left sided body weakness and a loss of power in both the left upper and lower limbs (0/5). Computer tomography imaging of the brain showed Right Middle Cerebral Artery (MCA) and Anterior Cerebral Artery (ACA) infarct. His clozapine was subsequently stopped and was started on tablet olanzapine 15mg on nocte. Currently, he is bed bound and requires total dependence for his Activities of Daily Living (ADL), with poor rehabilitation potential and poor cognition. Since clozapine was stopped, there has been improvement in his blood counts. Consultations and medical examinations found no plausible explanation for the blood dyscrasia and myeloproliferative disorder, so it is assumed that it could have been linked to Clozapine, which has caused a somatic mutation. An informed consent was obtained from the patient s legal guardian prior to reporting this case. Discussion The mechanism of Clozapine induced blood dyscrasia is relatively unknown. Clozapine has been linked with a suppression of bone marrow and an acceleration of apoptosis of neutrophils [10]. Apart from that, there is also a suggestion of immune mediated response, which causes thrombocytosis or thrombocytopenia and may provide evidence towards the mechanism of agranulocytosis [11]. Most journal articles mention about the link between Clozapine and agranulocytosis/neutropenia. However, it is difficult to rule out the possible association 35

38 of Clozapine and its effect on other hematologic parameters such as leukocytes, granulocytes, hemoglobin and platelets. In the figures above, which show the mean levels of each parameter from year-to-year, a significant increase in parameters (TWC, Neutrophil, Granulocyte, Hemoglobin and Platelet) can be seen starting around the year 2011 (Figure 1,2,4,5,6). The only exception is lymphocyte, which shows a decrease in mean levels (Figure 3). The uncanny trend and elevation of the blood parameters suggests that there are effects of Clozapine on the hematopoietic system, which could lead to the derangements as seen in this patient. A study reported a case of a 41-year old female who also developed Polycythemia Rubra Vera while on Clozapine. In that case report, they found progressive elevation of blood cells, mainly of the red blood cells line and concluded that there are two different nosologic entities, treatment of the psychiatric condition revealing polycythemia rubra vera [9]. In another case that was reported, a middleaged male with ICD schizophrenia who failed to respond to neuroleptic medication (haloperidol 25mg/day, chlorpromazine 500mg/day), or olanzapine at 20mg/day for six weeks was started on Clozapine. He complained of nausea fifteen days after commencing clozapine and his platelet count was 454 x 10 9 /L, the erythrocyte sedimentation rate (ESR) 70mm/h and the C-reactive protein was 103. Eight days later, his platelet count has risen to 774 x 10 9 /L. He was apyrexial [8]. An article which was published by the British Medical Journal (BMJ) mentions that a trigger reaction which resembles acute myeloid leukemia or myeloproliferative disorder can be seen due to the direct action on the hematopoietic stem cells of the bone marrow by Clozapine [11]. Conclusion Frequent and active monitoring remains the mainstay of patients who are treated with clozapine, as the effects on hematological parameters can be various. The possibility of clozapine triggering a somatic mutation reaction causing polycythemia vera could not be ruled out. In this paper, a patient who developed blood dyscrasia during clozapine treatment has been reported and clinicians should exercise caution for the possible occurrence of this risk. it is therefore recommended that there should be active monitoring for patients who are on clozapine according to the Clozapine REMS guidelines [12]. Apart from that, close observation must be done to detect any derangement in the patient s full blood count which would require a reduction of dose or the withdrawal of clozapine. In the event that there are any unexplained persisting abnormalities in the patient s blood count, a prompt referral to a hematology specialist should be done to minimize the dangers associated with clozapine. Acknowledgements Dr. Ismail B. Drahman, Consultant Psychiatrist, Sentosa Hospital Kuching, Sarawak, Malaysia for proofreading the final manuscript. Dr. Rosliwati Bt. Md Yusoff, Consultant Psychiatrist, Sentosa Hospital Kuching, Sarawak, Malaysia for proofreading the final manuscript. Conflict of Interest No conflict of interest. 36

39 Financial Disclosure No financial support received. References [1] US Food and Drug Administration, "FDA Drug Safety Communication: FDA modifies monitoring for neutropenia associated with schizophrenia medicine clozapine; approves new shared REMS program for all clozapine medicines," 9 September [Online]. Available: gs/drugsafety/ucm pdf. [Accessed 3 June 2016]. [2] G. Honigfeld, "The Clozapine National Registry System: forty years of risk management," Journal of Clinical Psychiatry Monograph, vol. 14, no. 2, pp , [3] H. Y. Meltzer, M. Davidson, A. H. Glassman and W. V. Vieweg, "Assessing cardiovascular risks versus clinical benefits of atypical antipsychotic drug treatment," Journal of Clinical Psychiatry, no. 63, pp , [4] R. J. Flanagan and L. Dunk, "Hematological Toxicity of drugs used in psychiatry," Human Psychopharmacology Clinical and Experimental Journal, no. 23, pp , [5] C. Ratanajamit, C. Musakopas, S. Vasiknanonte and W. Reanmongkol, "Incidence and risk for neutropenia/agranulocytosis among clozapine users: A retrospective cohort study," International Journal of Psychiatry in Clinical Practice, no. 14, pp , [6] G. P. Panteleeva, M. Y. Tsutsulkovskaya, B. S. Belyaev and E. I. Minsker, "Clozapine in the treatment of schizophrenic patients: An international multicenter trial," Clinical Therapeutics, no. 10, pp , [7] J. A. Lieberman, C. Johns, J. M. Kane, K. Rai, A. V. Pisciotta, B. Saltz and A. Howard, "Clozapine induced agranulocytosis: Non-cross reactivity with other psychotropic drugs," Journal of Clinical Psychiatry, no. 49, pp , [8] M. E. Hampson, "Clozapine- Induced Thrombocytosis," The British Journal of Psychiatry, vol. 176, no. 4, p. 400, April [9] G. Marian, B. Ionescu, D. Ghinea and N. Alina, "P03-13 Clozapine treatment for resistant schizophrenia may reveal un unusual hematological disease: Polycythemia Vera. Case Report," European Psychiatry, vol. 24, p. S1012, [10] M. D. Mintzer, S. N. Billet and L. Chmielewski, ""Drug-Induced Hematologic Syndromes"," Advances in Hematology, p. 11, [11] K. Marlowe, "Thrombocytosis due to clozapine treatment: working towards an early marker for clozapine induced agranulocytosis," 37

40 The British Journal of Psychiatry, vol. 4, no. 177, pp , [12] Clozapine REMS, "Clozapine REMS," September [Online]. Available: mgclozapineui/rems/pdf/resources/ Clozapine_REMS_HCP_Guide.pdf. [Accessed 11 May 2017]. Corresponding Author Tan Hon Pin Jason, Hospital Sentosa, Kuching, Malaysia 38

41 CASE REPORT Venlafaxine Overdose in a Patient with Huntington s Disease Pak S Kettering Medical Center, 3535 Southern Blvd, Kettering, OH, USA Abstract Huntington s disease is incurable neurodegenerative disorder associated with high rate of suicide. About % of patients with HD commits suicides, compared to % in the general population. Venlafaxine is a serotoninnorepinephrine reuptake inhibitor used widely for depression and anxiety treatment. Venlafaxine poisoning can lead to adverse cardiovascular effects, including ventricular tachycardia, seizure, serotonin syndrome, and lactic acidosis. Herein, we report a case of a woman with HD who attempted suicide with venlafaxine. This case is exemplary for successful management of venlafaxine overdose management with lorazepam, yielding an excellent treatment outcome. Possible mechanism by which venlafaxine causes adverse effects is also discussed. Keywords: Venlafaxine, Huntington s Disease, Overdose, Intoxication, Suicide Introduction Huntington s disease (HD) is incurable and progressive neurodegenerative disorder, characterized by motor abnormality, cognitive decline, and psychiatric disturbance. HD is inherited in an autosomal dominant pattern and occur in about 7 10 people per 100,000 individuals [1]. Approximately % of patients with HD commits suicides, compared to % in the general population [2]. Multidisciplinary efforts are needed to proactively prevent suicide attempts in this high risk population. Also, provision of prompt and appropriate treatment in cases of intoxication from suicidal attempts is critical. Venlafaxine is a serotonin-norepinephrine reuptake inhibitor used mostly for major depression, generalized anxiety, social anxiety, and panic disorder. Venlafaxine poisoning can lead to ventricular tachycardia, seizure, and serotonin toxicity [3]. Central nervous system depression, lactic acidosis, and Tako-Tsubo cardiomyopathy also have been reported in cases of severe intoxication [4, 5]. Herein, we report a case of a woman with HD who attempted suicide with venlafaxine. This case is exemplary for successful management of venlafaxine overdose management with lorazepam, yielding an excellent treatment outcome. 39

42 Case Presentation A middle aged woman with Huntington s disease complicated with Chorea presented with acute ingestion of 22 pills of 37.5 mg of extended release venlafaxine (total 825 mg) in an attempt of suicide. Reported time of ingestion was about an hour prior to her arrival to the Emergency Department. Her medical history was significant for recurrent major depressive disorder. She appeared very agitated and confused which were not part of her baseline. Her neurological status was at baseline with slurred speech and mumbling. Her blood pressure, heart rate, respiration rate, temperature, and oxygen saturation at room air were 105/67 mmhg, 120 /min, 31 /min, 98.3 F, and 97 %, respectively. The initial electrocardiogram (ECG) revealed sinus tachycardia with normal QTc interval of 476 ms and a normal QRS interval of 78 ms. Other laboratory parameters, including complete blood count, basic metabolic panel, cardiac enzymes, and thyroid hormone panel, were all within normal limit. CT of her brain did not show any abnormality, except atrophy of the caudate nucleus, which was consistent with her history of Huntington s disease. Patient was immediately given 1mg of intravenous lorazepam three times over the first four hours. In the following day, she was started on clonazepam 1 mg and thioridazine 100 mg twice daily for agitation and anxiety. The ECG taken on the second day showed sinus rhythm with QTc interval of 412 ms and a normal QRS interval of 78 ms. On third day, she was given intramuscular injection of 1 mg haloperidol due to persistent agitation. Afterward, the acute anxiety and agitation resolved. Subsequently, she was switched over to haloperidol 0.5 mg twice daily. On 5 th day of hospitalization, she was discharged on haloperidol 0.5 mg. At the time of discharge, she was stable with blood pressure, heart rate, respiration rate, temperature, and oxygen saturation at room air were 126/88 mmhg, 68 /min, 16 /min, 97.8 F, and 96 %, respectively. She had resolution of acute anxiety and agitation. Echocardiography done as an outpatient follow-up showed left ventricular ejection fraction of 55 % and did now visualize any abnormality. Discussion As venlafaxine overdose is rare, there is no evidence based guideline for treatment. Thus, only symptomatic and supportive treatment is provided for patients presenting with venlafaxine poisoning. Pathophysiology underlying the toxicity of venlafaxine and effective treatment strategy is a future area of research. Although the mechanism by which venlafaxine causes adverse effects remains largely unknown, there are two plausible hypotheses proposed. First hypothesis is that venlafaxine causes increased level of dopamine and norepinephrine, which, in turn, overstimulate beta receptors. In particular, this increased sympathetic outflow can cause tachycardia in heart. Alternative explanation is the blockage of sodium channels by venlafaxine, resulting in ventricular arrhythmia [3, 6]. In the present case, the patient who attempted suicide had HD. Suicide prevention and follow-up care are inherent challenges associated in caring for patients with HD. Thorough and frequent suicidal risk assessment, early diagnosis and intervention of comorbid mental illness, and support group therapy with other individuals with HD might reduce the risk of suicide. Also, use of medications with less adverse 40

43 effect profile, when possible, is strongly recommended for this patient population at risk for suicide. In conclusion, we presented a case of a patient with HD who attempted suicide by ingesting 825 mg of venlafaxine. Patient was tachypnenic, tachycardiac, and agitated. This case of venlafaxine poisoning was promptly managed with lorazepam. Symptoms of venlafaxine fully resolved and the patient was discharged in a good condition. This case highlights the danger of venlafaxine poisoning and high risk associated with HD. Clinicians caring for patients with HD should be aware of the risk of drug overdose and choose pharmacotherapy with low adverse profile, when possible. References [1] Wetzel HH, Gehl CR, Dellefave- Castillo L, Schiffman JF, Shannon KM, Paulsen JS. Suicidal ideation in Huntington disease: the role of comorbidity. Psychiatry Res. 2011;188: [2] Halpin M. Accounts of suicidality in the Huntington disease community. Omega. 2012;65: [3] Howell C, Wilson AD, Waring WS. Cardiovascular toxicity due to venlafaxine poisoning in adults: a review of 235 consecutive cases. Br J Clin Pharmacol. 2007;64: [4] Eldem I, Kendirli T, Azapagasi E, Ozdemir G, Yildiz C, Yildiz MM et al. Venlafaxine intoxication in an adolescent presenting with severe lactic acidosis. Turk J Pediatr. Vol 58. Turkey2016: [5] Neil CJ, Chong CR, Nguyen TH, Horowitz JD. Occurrence of Tako- Tsubo cardiomyopathy in association with ingestion of serotonin/noradrenaline reuptake inhibitors. Heart Lung Circ. 2012;21: [6] Bosse GM, Spiller HA, Collins AM. A fatal case of venlafaxine overdose. J Med Toxicol. 2008;4: Corresponding Author Stella Pak, M.D. Kettering Medical Center, 3535 Southern Blvd, Kettering, OH, USA Tel: (937) Stella.Pak@ketteringhealth.org 41

44 CASE REPORT Venous Thromboembolism (VTE) in Patient on Clozapine Therapy Sashitharan D, Abu Bakar AK, Suhaila MS Hospital Permai, Johor Bahru, Malaysia Abstract This article describes a case of Venous Thromboembolism (VTE), was developed in a patient with treatment-resistant schizophrenia. Patient was a 35 years-old female with treatment resistant schizophrenia who was tolerating her residual symptoms of perceptual disturbances. Despite good adherence towards treatment, she never had a complete symptom-free period. Patient also attempted suicide by trying to drown herself at a nearby beach. Considering the suicidal risk and persistency of her psychosis, patient was then initiated on Clozapine therapy. Over a period of 8 weeks, gradual dose increment resulted in an improvement of her symptoms where she was reported to have less frequency of perceptual disturbances. She was reviewed weekly for both her response and tolerability towards the Clozapine treatment. Entering the 11th week of her Clozapine therapy, Patient was admitted into the hospital for left leg tenderness in which she was later treated to be having deep vein thrombosis (DVT). Ultrasound finding revealed long segment thrombus seen from external iliac vein down to popliteal vein of her left lower limb. Patient s medication dose was maintained at the same dose up until the 16th week of her Clozapine therapy. There were no recurrences or reports of side effects and improvement of sleep patterns were reported by her but her psychotic symptoms still persists. There are always risks and benefits while treating a patient with Clozapine. Clinician should be aware of the risk of deep vein thrombosis (DVT) among treatment resistant schizophrenia patient. Keywords: Clozapine, Atypical Antipsychotics, Treatment Resistant Schizophrenia, Venous Thromboembolism, Deep Vein Thrombosis Introduction Clozapine had long been reserved as a special indication for treating schizophrenia. The complexity of its receptors selectivity and binding had been proposed to be the reason behind its efficacy. In the past few decades, despite the emergence of novel antipsychotics, they failed to prove superiority to clozapine in treating treatment-resistant schizophrenia. Tolerability-wise, clozapine therapy is proven to cause less risk of extrapyramidal side effects but they are associated with rare 42

45 side effects that are potentially fatal such as blood dyscrasias and myocarditis. Seizures have occurred in patient treated with clozapine are mainly dose related. It is managed with proper dose titration or reduction [2]. Clozapine treatment resulted in significant improvements in the patient s symptoms but it can cause alteration over the metabolism system which can lead to dyslipidemia-mediated-pancreatic-beta-cell damage, decreased insulin secretion, and insulin resistance in some individuals, later can lead to hyperglycemia and diabetic ketoacidosis [3]. Constipation is a wellknown collateral side effect of antipsychotic drugs such as Clozapine which will lead to fecal impaction, megacolon, perforation and also, in some cases, death [4]. The possible mechanism for the association between clozapine and venous thromboembolism (VTE) are multifactorial [5]. VTE usually occurs when one of three factors is present: damage to the vessel wall, static blood flow, or coagulation abnormalities. Clozapine, as well as other antipsychotics, has not been shown to cause direct damage to the vasculature in humans. However, static blood flow may be influenced by sedation and the sedentary lifestyle commonly associated with psychiatric disorders, their treatment, or both5. There is also increasing evidence that clozapine may cause a variety of different coagulation abnormalities such as an increased platelet adhesion as well as aggregation [5]. It has become a common clinical dilemma to risk potentially fatal side effects against a highly efficacious treatment option. Case Report Miss CJ, is a 35 years old who was treated for schizophrenia since many years ago. For the past few years, she had been tolerating her residual symptoms of perceptual disturbances. Despite good adherence towards treatment, she never had a completely symptom-free period. In late Nov 2016, Miss CJ attempted suicide by trying to drown herself at a nearby beach. It was later identified that she was reacting to the auditory and visual hallucinations that she had. Available evidence has shown that approximately 50% of patients with schizophrenia or schizoaffective disorder attempted suicide and approximately 10% of them will die of suicide. Considering the suicidal risk and persistency of her psychosis, Miss CJ was then initiated on clozapine therapy. Over a period of 8 weeks, gradual dose increment resulted in improvement of her symptoms where she was reported to have less frequency of her perceptual disturbances. She was reviewed weekly for both her response and tolerability towards the clozapine treatment. Hyper salivation was noted into her 9th week of treatment with a clozapine dose of 225mg/day. She was then initiated on benzhexol 4mg on a daily basis. Miss CJ continued to complain about hyper salivation and she described the condition was getting worse but she was unable to elaborate further. Further increment of benzhexol was decided by the doctor incharge at that time to a total dose of 6mg/day in divided dosing. By the 10th week of clozapine therapy, Miss CJ had her psychotic symptoms remitted, however, she was still complaining of similar side-effects. She persistently complained of hyper salivation. However other commonly associated side effects such as constipation, palpitation, fever and urinary incontinence were absent. Miss CJ was keen to be on the same dose of treatment as she was satisfied with her 43

46 improvement and was still able to tolerate the hyper salivation episodes. There was no evidence of any serious side effects such as agranulocytosis or any features suggesting cardiovascular complications. Entering the 11th week of her clozapine therapy, Miss CJ was admitted into the hospital for left leg tenderness in which she was later treated to be having deep vein thrombosis (DVT). Ultrasound finding revealed long segment thrombus seen from external iliac vein down to popliteal vein of her left lower limb. Miss CJ was then initiated on warfarin by the surgical team and a dose reduction of clozapine was then decided. At the point of discharge from the hospital, Miss CJ was on clozapine 125mg/day and benzhexol 4mg/day. Miss CJ began experiencing relapse symptoms of schizophrenia as she reported experiencing perceptual disturbances, thought disturbances and sleep difficulties. Her clozapine dose was maintained at the same dose up until the 16th week of her clozapine therapy. There was no recurrence or a new report of side effects and improvement of sleep patterns were reported by her, but her psychotic symptoms still persists. She continued to have regular psychiatry and surgical team review for her condition. Discussion Psychiatric patients have an increased risk for venous thromboembolism (VTE) due to multiple factors such as poor mobility, poor fluid intake, fever and rhabdomyolysis that occurs in neuromuscular syndrome6. In the case of Miss CJ, apart from the manifestation of hyper salivation, she was mobile and there were no other features of having side effects of neuroleptic intake. In this case of Miss CJ, who was on treatment of clozapine and had developed venous thromboembolism during the duration of this treatment. Clozapine, most often than not, is usually reserved for highly indicated scenarios such as treatment-resistant cases or highly suicidal cases. Benefits and risks of clozapine treatment had always been a debate among clinicians in achieving remission among schizophrenic patient. While it is easy to agree that risking potentially fatal side effects among patients with tolerable residual psychotic symptoms is inappropriate, it is not as simple when the psychosis leads to a similar fatality risk in the form of suicidality. Miss CJ definitely benefitted from the clozapine treatment as she remitted from the positive symptoms of schizophrenia and was free from self-harm act during that duration. It is believed that clozapine appears to reduce mortality in severe schizophrenics, mostly by decreasing suicide rates8. The venous thromboembolism (VTE) complication suffered by Miss CJ was a hindrance to her recovery process. As more and more case are reported to associate clozapine with venous thromboembolism (VTE), it is important to be thorough in the screening of deep vena thrombosis (DVT) risk among the target group of patients planned to be initiated on clozapine therapy. Some recent evidences supported the benefit of screening for DVT risk among patient treated with secondgeneration antipsychotics, including clozapine [7]. Psychiatric patients are identified to be having an increased risk of venous thromboembolism with the use of clozapine so the following of prophylactic measures should be considered. First, avoid strict bedrest or immobility; and an increased amount of exercise for most patients. Also, sufficient hydration is of 44

47 importance. Second, complaints such as swelling, pain or discoloring of the leg, chest pain or dyspnea merit special attention. Conducting physical examinations focusing on these complaints is essential. Lastly, the implementation of other deep venous thrombosis prophylactic measures (i.e. placement of elastic stockings, use of pneumatic compression or administration of subcutaneous heparin) should be considered in high risk patients [9]. Given the significance of the love-hate relationship of clozapine therapy, empowering patients with the decision making capacity, while allowing them to choose the best option of treatment for themselves is definitely the way to go forward. References [1] Meltzer, H.Y., Bastani, B., Ramirez, L. and Matsubara, S., Clozapine: new research on efficacy and mechanism of action. European Archives of Psychiatry and Clinical Neuroscience, 238(5), pp [2] Grover, S., Hazari, N., Chakrabarti, S. and Avasthi, A., Association of clozapine with seizures: a brief report involving 222 patients prescribed clozapine. East Asian Archives of Psychiatry, 25(2), p.73. [3] Nihalani, N.D., Lamberti, J.S., Olson, D., Olivares, T., Costea, G.O. and Tang, W., Diabetic ketoacidosis among patients receiving clozapine: a case series and review of socio-demographic risk factors. Annals of Clinical Psychiatry, 19(2), pp [4] De Hert, M., Dockx, L., Bernagie, C., Peuskens, B., Sweers, K., Leucht, S., Tack, J., Van de Straete, S., Wampers, M. and Peuskens, J., Prevalence and severity of antipsychotic related constipation in patients with schizophrenia: a retrospective descriptive study. BMC gastroenterology, 11(1), p.17. [5] Paciullo, C.A., Evaluating the association between clozapine and venous thromboembolism. American Journal of Health-System Pharmacy, 65(19), pp [6] Croxford, A., Clare, A. and McCurdy, K., Introduction of a Venous Thromboembolism Prophylaxis Protocol for Older Adult Psychiatric Patients. BMJ quality improvement reports, 4(1), pp.u w3226. [7] Yang, T.Y., Chung, K.J., Huang, T.L. and Kung, C.T., Massive pulmonary embolism in a young patient on clozapine therapy. The Journal of emergency medicine, 27(1), pp [8] Walker, A.M., Lanza, L.L., Arellano, F. and Rothman, K.J., Mortality in current and former users of clozapine. Epidemiology, 8(6), pp [9] Van Neste, Els G., Verbruggen, Ward, & Leysen, Mark. (2009). Deep venous thrombosis and pulmonary embolism in psychiatric settings. The European Journal of Psychiatry, 23(1),

48 Corresponding Author Sashitharan Damodaran Hospital Permai, Jalan Persiaran Kempas Baru, Johor Bahru, Malaysia 46

49 CASE REPORT Clozapine Induced Priapism: Case Series Thangam N, Farah Radhiah H, Sashitharan D, Abdul Kadir AK Hospital Permai, Jalan Persiaran Kempas Baru, Johor Bahru, Malaysia Abstract Clozapine is effective in treatment resistant schizophrenia. Priaprism is a rare side effect of Clozapine. It is a urological emergency and can lead to permanent damage to the penis. We present two cases two cases of clozapine induced priapism. Both patients were started on Clozapine in view of treatment resistant. For the first patient, priapism was noted after 2 years on Clozapine and treated conservatively. Clozapine was rechallenged in this patient but in a lower dosage and was augmented with amisulpride. He did not develop priaprism until date. In the second case, patient developed priaprism after 7 months on clozapine and required urological intervention. He redeveloped recurrent episode of priaprism as clozapine was restarted on the previous dose. In conclusion, priaprism is not related to dosage or duration of treatment of Clozapine. Thus, a careful risk-benefit assessment need to done as there is always a risk of priapism to recur when clozapine rechallenged. Keywords: Clozapine, Priapism, Urologist Introduction Clozapine is an atypical antipsychotic whose therapeutic effects were mediated by dopaminergic and serotonergic activity. It is effective for treatment resistant schizophrenia [1]. It has been shown to reduce the suicidality in schizophrenia [2-3] and is also useful in aggression. One of its rare side effects is priapism. An early case of priapism caused by clozapine was reported in 1992 [1]. Priapism is defined as sustained and persistent erection of the penis without any sexual desire or stimulation [5]. It is a urological emergency and can lead to permanent damage to the penis resulting in impotence, penile necrosis and urinary retention if left unattended. Priapism can be divided into a nonischemic type (high flow; arterial) which can be treated conservatively and an ischemic type (low flow; venoocclusive) which may become a urological emergency that requires immediate intervention [6]. Drug-induced priapism usually cause ischemic priapism accounting for 15% to 41% of all cases and antipsychotics-induced priapism is commonest. Clozapine has also been cited as to cause priapism apart from trazodone, chlorpromazine, and thioridazine [7]. This case series is on clozapine-induced priapism. 47

50 Case Scenario 1 This 34 years old male had Schizophrenia since He had been admitted in our setting from 2011 and developed priaprism after two years on clozapine. He had previously been treated with adequate doses of risperidone, olanzapine and amisulpride but without much improvement. He was then started on clozapine November Clozapine was started as per protocol and was slowly tapered up to 350mg per day. He wasn t on any other medication. Patient awoke from sleep one day with a painful penile erection that started at 6am that day. He alleged that the penile erection occurred spontaneously and denies sexual activity that day. There was neither fever nor urethral discharge. He was still able to pass urine in the morning. He said that this was the second episode. The first episode occurred a few months earlier, lasted for six hours and spontaneously resolved. He denied taking any other traditional medication. His vitals were stable and the total white count was normal. He was given pain killer to control his pain and ice pack compression was done. Clozapine therapy was withheld and he was seen by the urologist who suggested changing the antipsychotic and conservative management. A shared decision between the patient and the psychiatrist was to continue clozapine therapy in view of previous treatment resistance. He was restarted on clozapine 100mg twice daily and was slowly titrated up to a total dose of 300mg due to persistant psychotic symptoms. Further augmentation with Amisulpride was needed to stabilize his condition. However, no recurrent episode of priapism was reported by the patient upon restarting the clozapine. Case Scenario 2 This is a 27 years old male treated for Schizophrenia with Mild Intellectual Disability who was admitted in our setting from December 2016 for aggressive behaviour toward mother. He has been on follow up in another hospital from He had history of priaprism with Clozapine, IM Haloperidol and IM Paliperidone. Patient was started with Clozapine since January 2017 as patient did not show any improvement with sublingual Asenapine. Clozapine was optimized up to 325mg daily. In August 2017, patient developed spontaneous painful penile erection that lasted for hours. He was not on any other medication and denied sexual activity on that day. He was then referred to urologist and was diagnosed to have venous low flow priapism. Bedside aspiration was done and subcutaneous Lucrin was given. He was sent back to our setting and Clozapine was continued. Patient had recurrent episode of priaprism after 4 days. He was again referred to urology and treated conservative as it resolved spontaneously after few hours. Thereafter, Clozapine was withheld and no antipsychotic was started as patient is manageable in ward. Discussion Occurrence of priapism is thought to be related to alpha-adrenergic blockage mediated by the alpha receptors in the corpora cavernosa of the penis [8]. Clozapine is also an adrenergic antagonist. This adrenergic blocking action is seen in other drugs such as guanethidine, prazosin and trazodone which also noted to cause priapism. Corpora cavernosa is richly innervated by adrenergic fibers. These fibers maintain the penis in the detumescent state by means of vasoconstriction. Alpha Adrenergic blockade causes priapism by favoring erection, which is parasympathetically mediated, and by inhibiting the sympathetically mediated 48

51 detumescence. This theory is proven by intracorporeal injections of relatively nonspecific a-adrenergic blockers such as phenoxybenzamine and phentolamine [9]. It has also been suggested that priapism may be caused by the central nervous system effects of psychotropic drugs by prolonged stimulation of the psychic centers [10]. This theory explains the delay in onset of priaprism in this patient. Unfortunately, no correlation is found between dosage or duration of treatment and priapism in most cases of drug-induced priapism [11]. Priapism may be seen as an embarrassing condition by this patient as he admitted having a previous episode which he did not inform staff in the ward. Patients may find it hard to discuss about this openly in ward rounds and might require asking specifically about priapism. Decision making to rechallenge with clozapine was tough as there is a risk of priapism to recur. In such cases, a careful risk-benefit assessment involving the patient and significant others need to be done. Discontinuation of clozapine could lead to relapse and there will be limitation of antipsychotic choice in view of refractory schizophrenia. Patient should be informed regarding other options of antipsychotic medication and possibility of a relapse. Patient should be well informed on the possibility on recurrence of priapism and if it occurs to inform the staff or the clinician as soon as possible. Amisulpride and sulpride can be used for augmentation as it has no alpha-1 receptor affinity. In a nutshell, priaprism is a one of the rare but dangerous complications of antipsychotics which is a urological emergency and needing prompt intervention. References [1] Voruganti L, Cortese L, Oyewumi L, Cernovsky Z, Zirul S, et al. Comparative evaluation of conventional and novel antipsychotic drugs with reference to their subjective tolerability, sideeffect profile and impact on quality of life. Schizophrenia research Jun; 43(2): [2] Baruch Spivak, Evgeny Shabash, Brian Sheitman, Abraham Weizman, and Roberto Mester. The Effects of Clozapine Versus Haloperidol on Measures of Impulsive Aggression and Suicidality in Chronic Schizophrenia Patients: An Open, Nonrandomized, 6-Month Study. J Clin Psychiatry. 2003;64(7): [3] Meltzer HY, Alphs L, Green AI, Altamura AC, Anand R et al. Clozapine treatment for suicidality in schizophrenia: International Suicide Prevention Trial (InterSePT). Arch Gen Psychiatry Jan;60(1): [4] Seftelel AD, Saenz de Tejada I, Szetela B, Cole J, Goldstein I. Clozapine-associated priapism: a case report. J Urol Jan;147: [5] Keoghane SR, Sullivan ME, Miller MAW. The aetiology, pathogenesis and management of priapism. Br J Urol Int June 24;90: [6] Bivalacqua TJ and Burnett AL. Priapism: new concepts in the pathophysiology and new treatment strategies. Current Urology Reports Dec; 7(6): [7] Thompson JW Jr, Ware MR, Blashfield RK. Psychotropic 49

52 medication and priapism: a comprehensive review. J Clin Psychiatry 1990; 51: [8] Sood S, James W, Bailon M. Priapism associated with atypical antipsychotic medications: a review. Int Clin Psychopharmacol Jan; 23(1): [9] Segraves RT. Effects of psychotropic drugs on human erection and ejaculation. Arch. Gen. Psychiat. 1989; 46:275. [10] Hinman F Jr. Priapism:reasons for failure of therapy. J. Urol April, 83:420. [11] Thompson JW Jr, Ware MR, and Blashfield RK. Psychotropic medication and priapism: a comprehensive review. Journal of Clinical Psychiatry Oct; 51(10): Corresponding Author Thangam Nagarethinam Hospital Permai, Jalan Persiaran Kempas Baru, Johor Bahru, Malaysia than916@gmail.com 50

53 CASE REPORT Dissociative Identity Disorder with Depression in A Man with Traumatic Childhood: A Case Report Saifuddin TM, Amilin N, Zafri A Jabatan Psikiatrik dan Kesihatan Mental, Hospital Tengku Ampuan Afzan, Kuantan Pahang, Malaysia Abstract Dissociative identity disorder (DID) previously known as multiple personality disorder is associated with depression and traumatic childhood which can be either physically or sexually abuse. It is hard to establish diagnosis of DID because of the complexity and controversies that surrounding it. We report a case of a young man who has DID and Major Depressive Disorder in the background of traumatic childhood experience who was recently admitted to our inpatient psychiatric unit and demonstrated transitions to other distinct personality state. Keyword: Dissociative Identity Disorder, Major Depressive Disorder, Traumatic Childhood Introduction Dissociative identity disorder (DID) formerly known as multiple personality disorder presented with two or more distinct personality states [6]. It has been described as difficult to understand, difficult to diagnose, difficult to treat and difficult to discuss objectively because of controversies that surrounding it [2]. Patients with suggestive symptoms are often misdiagnosed as malingering or even having schizophrenia due to lack of experience and knowledge of clinicians resulting in small number of patient with this diagnosis [7]. DID is also connected with traumatic childhood, usually abuse [1]. The diagnostic process should include an effort to assess the patient s trauma history. Because of their dissociative amnesia, DID patients often provide incoherent history early in treatment; a more complete personal history typically emerges over time [8]. This case report present DID in a depressed young gentleman with history of traumatic childhood. Case Report Mr. C is an 18 years old Chinese gentleman who works as salesman. His parent was divorced at the age of 1 year old. He had history of being abused physically and emotionally by his step mother during his childhood. He had multiple episodes being beaten by his step mother to the extent of putting hot clothes iron onto his body. Every day he was locked in a store room and was only given small amount of food. His step 51

54 mother (who was baby-sitting other neighbor s baby) also abused other child. He also witnessing his step mother putting his neighbor s baby in the fridge to make them quiet. His father knew what had happen but just ignored it. He managed to run away from his house at the age of nine years old and found his biological mother. Afterward, he stayed with his mother. However, his mother was also verbally abusive toward him. He also had history of being bullied at school and was stopped schooling at the age of 14 years old. He had no close relationship to any of his family members and others except for one of his female friend. At the age of 16 years old he had history of being sodomized by a stranger. This occurred when he tried to protect his female friend from being raped. Subsequently his friend committed suicide because of the incident. Since then he always had sad mood, feeling guilt and had multiple episodes of deliberate self-harm. At the age of 18 years old, he was first admitted to psychiatric ward due to attempted suicide by cutting his wrist after quarrelling with his sister. He was treated as major depressive disorder with differential diagnosis of Borderline Personality Disorder. In ward, it was revealed that he also had gender dysphoria and wanted to be a female. Later, he was discharged with tablet Fluvoxamine 50 mg ON. After one week, he was admitted again due to attempted suicide by cutting his wrist after quarrelling with his mother because of his plan to change his gender to female. During interviewing session with patient on day two of admission, he dissociated into a personality known as Mrs. C. Mental state examination revealed marked shift in affect and mannerism in which he displayed famine gesture. His alter personality claimed that he was the one who work as salesman and admitted that he was the one who responsible to stopped him from pursuing her intention to commit suicide. He had multiple episodes of dissociated into Mrs. C during interview session usually after being asked regarding his childhood. His affect quickly turned from depressed mood to happy. He had no recollection of this episode. He was prescribed with Tablet Fluvoxamine up to 150 mg ON. Then his depressive symptom together with his dissociative states improving. He was also given supportive psychotherapy in ward. Upon discharge, he had no more suicidal idea and able to take care of himself and return to his family. Discussion DID is one of a collection of psychiatric conditions called dissociative disorders. Dissociative identity disorder (DID) patients function as two or more identities or dissociative identity states (DIS), categorized as neutral identity states (NIS) and traumatic identity states (TIS). NIS inhibit entrance to traumatic memories thus allowing daily life functioning. TIS have access and responses to these memories [4]. Clinical syndromes are characterized by a core of depressive and dissociative symptoms and a childhood history of significant trauma, primarily child abuse [3]. Study shows that dissociative disorders, including dissociative identity disorder, are common in inpatient settings [5]. Although it is common in psychiatric in-patient settings, it is rarely diagnosed due to the 52

55 lack of understanding of this phenomenon and the inclinations to adhere to the rigid common practice of using internationally diagnostic criteria [7]. In this case it is difficult for physician to established diagnosis of DID due to patient factors including patient guarded and not forthcoming during interview. Other includes doctors factor due to lack of experience in handling DID. Treatment for DID should follow basic principles of psychotherapy and psychiatric medical management, and therapists should use specialized techniques only as needed to address specific dissociative symptomatology [8]. In this patient, the medication use to treat depression shows improvement toward patient s dissociative state. There is three stages phase-oriented treatment approach: 1. Forming safety, stabilization, and symptom reduction 2. Confronting, working through, and integrating traumatic memories 3. Identity integration and rehabilitation [8]. In view of acute in-patient psychiatric hospitalization, we are focusing on phase one treatment for this patient in establish safety before discharge and the reduction of depressive symptoms. In summary, this case report illustrates a common co-morbid DID, depression and traumatic childhood. There is need to have suspicious when dealing with patient who had history of traumatic childhood as it might associated with other psychiatric illness including DID. References [1] Philip M Coons, 'Confirmation of Childhood Abuse in Child and Adolescent Cases of Multiple Personality Disorder and Dissociative Disorder Not Otherwise Specified', The Journal of nervous and mental disease, 182 (1994), [2] RP Kluft, 'Multiple Personality Disorder', Stress Consequences: Mental, Neuropsychological and Socioeconomic (2010), 60. [3] Frank W Putnam, Juliet J Guroff, Edward K Silberman, Lisa Barban, and Robert M Post, 'The Clinical Phenomenology of Multiple Personality Disorder: Review of 100 Recent Cases', The Journal of clinical psychiatry (1986). [4] AAT Simone Reinders, Ellert RS Nijenhuis, Jacqueline Quak, Jakob Korf, Jaap Haaksma, Anne MJ Paans, Antoon TM Willemsen, and Johan A den Boer, 'Psychobiological Characteristics of Dissociative Identity Disorder: A Symptom Provocation Study', Biological psychiatry, 60 (2006), [5] Colin A Ross, Colleen MM Duffy, and Joan W Ellason, 'Prevalence, Reliability and Validity of Dissociative Disorders in an Inpatient Setting', Journal of Trauma & Dissociation, 3 (2002), [6] B.J. Sadock, V.A. Sadock, and P. Ruiz, Kaplan & Sadock's Synopsis of Psychiatry: Behavioral Sciences/Clinical Psychiatry 53

56 (Lippincott Williams & Wilkins, 2014). [7] Manit Srisurapanont, Sawitri Assanangkornchai, Mohamad Hussain Habil, Orawan Silpakit, Nahathai Wongpakaran, Suwanna Arunpongpaisal, Siow-Ann Chong, MD Irmansyah, Philip George Joseph, and Thawatchai Leelahanaj, 'Asean Journal of Psychiatry _', ASEAN Journal of Psychiatry, 9 (2008). [8] International Society for the Study of Trauma, and Dissociation, 'Guidelines for Treating Dissociative Identity Disorder in Adults, Third Revision', Journal of Trauma & Dissociation, 12 (2011), Corresponding Author Dr. Tengku Mohd Saifuddin, Department of psychiatry, Hospital Tengku Ampuan Afzan, Kuantan, Pahang, Malaysia saifrao87@gmail.com 54

57 CASE REPORT Suicidal Attempt in Huntington Disease: A Case Report Saifuddin TM, Amilin N, Zafri A Department of Psychiatry, Hospital Tengku Ampuan Afzan, Pahang, Malaysia Abstract Huntington disease (HD) is a neurodegenerative disorder with psychiatric, cognitive, and motor symptoms. Psychiatric symptoms often manifest years before neurologic signs in HD patients. The present of psychiatric symptoms might increase risk of suicide in HD patient. We presented a case of HD who admitted to Psychiatry ward due to suicidal attempt and shows improvement with low dose of Olanzapine. Keyword: Huntington disease, Psychosis, Suicide, Olanzapine Introduction Huntington disease (HD) is a midlife onset autosomal dominant neurodegenerative disorder witch characterized by psychiatric, cognitive, and motor symptoms. Death occurs between 12 and 15 years from the time of symptomatic onset [6]. Psychiatric symptoms in HD patient can increase risk of suicide and premature death in this disorder. We presented a case of HD who admitted to Psychiatry ward due to suicidal attempt and showed improvement with low dose of Olanzapine. Case Report Mr. Y, 56 years old Chinese gentleman who was diagnosed as Huntington disease by Neuromedical department at the age of 52, was brought in by his roommate to casualty due to suicidal attempt by ingesting herbicide after quarreled with his friend tree days prior to the admission. His roommate had realized it after he had persistent vomiting. Upon further questioning, he admitted hearing voices which he described as second person and commanding in nature for 1 year duration. He also admitted feeling of depressed but not fulfilled the criteria for Major Depressive Disorder. When asked regarding reason he wanted to commit suicide, he keep on saying that he felt mad toward his friend. His judgment was also poor. There was difficulty in taking history from him in view of his speech difficulty. History from roommate revealed that he was socially withdrawn since one year ago. Most of the time he just stay in the house watching television. He was noted to have hallucinating behavior as was described by his roommate. Patient also noted to express that people wanted to do bad things to him. His roommate also noticed abnormal behavior such as burning newspaper (almost every day), throwing coins on the floor without no reason and squeezing plastic bottle to make disturbing noises repeatedly. 55

58 He also noted become more forgetful and become less amount of understandable speech. Mental state examination revealed thin build Chinese gentleman with chorea movement, with good eye contact. His mood was not depressed and his affect was restricted. He had disorganized speech. He admitted having auditory hallucination. Mini Mental State Examination showed deficit in his attention and memory. All blood investigation was normal. He was referred to medical team in casualty to look for possible progression of the disease and was discharged by medical team. Then he was admitted to psychiatric ward for observation in view of poor social support and he was medically stable. He was started with Tablet Olanzapine 2.5 mg per day. After started with Olanzapine, he was stable without any psychotic symptoms. From observation, he was cooperative with no abnormal behavior and no depressive symptoms noted. He also denied suicidal thought. His movement disorder was also improving. He was discharged to nursing home with tablet Olanzapine 2.5 mg ON after day six of admission. Discussion Huntington disease (HD) is a rare neurodegenerative disorder. Previously it has not been described in Malaysia until 1994 when the first case of HD was documented in a patient originating from the West Malaysian state of Perak [4]. HD has been considered a movement disorder. However, cognitive and psychiatric symptoms are among important clinical features of HD. This article illustrates the psychiatry manifestation and treatment of HD and provides advice to treating clinicians. Psychiatric symptoms often manifest years before neurologic signs in patients with inherited neurodegenerative disease. The most frequent example of this phenomenon is the early onset of personality changes in Huntington patients. In some cases the changes in mood and cognition are even more debilitating than their neurologic symptoms [8]. Moreover, non-motor, particularly behavioral and cognitive are found before individuals meet the diagnostic criteria for the disease. It became more frequent and severe over the course of the disease progression. Given the lack of empirical data, the management of non-motor problems is based on experts agreement [1]. This patient was started with low dose of Olanzapine for the psychotic symptom. Olanzapine is a good alternative treatment in HD, mainly for the psychiatric symptoms and moderately effective for the motor symptoms, possibly because of its effect on chorea. It was suggest to be used in HD patients with the adult onset form, severe chorea and/or severe psychiatric disturbances 5. During admission, this patient was observed for depressive symptoms. Depression is one of the most common psychiatric disturbances in HD, with highest prevalence manifested during stage 2 of the disease. Identification and treatment of depression in HD patients is an essential part of clinical management in this population due to the high risk of suicide [2]. Standard assessments for suicide risk may be reasonably applied to HD populations with prodromal, depression and a history of suicide attempts (two of the most established predictors in the suicide literature) as predictors of suicidal behavior in prodromal HD [3]. 56

59 The absence of psychiatric symptoms in HD patient does not indicate that there is a lack of suicidal ideation. If suicidal ideation is present, steps should be taken to refer individuals to the appropriate mental health professionals [7]. This patient represent the challenge that a clinician will face from the perspective of psychiatric diagnosis and treatment. Multidisciplinary team consist of neurology and psychiatric unit are needed for their care. Furthermore, further comprehensive research is needed to further clarify the psychiatric comorbidity to suicidality in HD patients. It will help to signifies appropriate therapies and may prevent premature death in this disorder. References [1] Francisco Cardoso, 'Nonmotor Symptoms in Huntington Disease', International Review of Neurobiology (2017). [2] Eric A Epping, and Jane S Paulsen, 'Depression in the Early Stages of Huntington Disease', (2011). [3] Jess G Fiedorowicz, James A Mills, Adam Ruggle, Douglas Langbehn, Jane S Paulsen, and PREDICT-HD Investigators of the Huntington Study Group, 'Suicidal Behavior in Prodromal Huntington Disease', Neurodegenerative Diseases, 8 (2011), [4] MK Lee, WK Ng, and D Jeyakumar, 'Huntington Disease: Report of First Case Documented in Malaysia', MEDICAL JOURNAL OF MALAYSIA, 49 (1994), [5] D Paleacu, M Anca, and N Giladi, 'Olanzapine in Huntington's Disease', Acta neurologica scandinavica, 105 (2002), [6] Jean Paul G Vonsattel, and Marian DiFiglia, 'Huntington Disease', Journal of neuropathology and experimental neurology, 57 (1998), 369. [7] Heather H Wetzel, Carissa R Gehl, Lisa Dellefave Castillo, Judith F Schiffman, Kathleen M Shannon, Jane S Paulsen, and Huntington Study Group, 'Suicidal Ideation in Huntington Disease: The Role of Comorbidity', Psychiatry research, 188 (2011), [8] Eric Wexler, 'Clinical Neurogenetics: Behavioral Management of Inherited Neurodegenerative Disease', Neurologic clinics, 31 (2013), Corresponding Author Dr. Tengku Mohd Saifuddin, Department of psychiatry, Hospital Tengku Ampuan Afzan, Kuantan, Pahang, Malaysia saifrao87@gmail.com 57

60 REVIEW PAPER A Review of The Use of Mirtazapine in Cancer Patients Zaini S 1,3, Ng CG 1, Sulaiman AH 1, Huri NZ 2, Shamsudin SH 3 1 Department of Psychological Medicine, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia 2 Department of Pharmacy, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia 3 Department of Pharmacy Practice, Kulliyyah of Pharmacy, International Islamic University Malaysia, Kuantan, Pahang, Malaysia Abstract Introduction: Cancer patients often have concurrent physical and psychological symptoms. These problems may become barriers towards the healing process. Antidepressants seem to be beneficial for the purpose of palliative care in this type of patients. One of the useful medications is mirtazapine, which is known as noradrenergic and specific serotonergic antidepressant (NaSSA). This paper examines the use of mirtazapine in physical and psychological symptoms of cancer patients. Methods: Literature search was done on PubMed (from inception to January 2017) by matching the key terms: noradrenergic and specific serotonergic antidepressants or NaSSA mirtazapine AND cancer or oncol* or malignancy or carcinoma. Eligible papers were screened at the title and abstract level. Various types of study included in this review, according to certain criteria. Additional papers were also identified by screening of reference lists. Results: A total of twelve papers were reviewed and summarized. Positive findings obtained for the use of mirtazapine in cancer patients associated with various symptoms, including depression, anxiety, cachexia, nausea, hot flashes, and pruritus. Some rare side effects are reported, including constipation, myalgia sedation, dry mouth, stimulation of appetite and weight gain. Conclusion: Mirtazapine has the potential to be beneficial for cancer patients suffering from these physical and psychological symptoms. However, more research studies with sufficient power are warranted to validate the findings. Keywords: Cancer, Antidepressant, Mirtazapine, Depression, Anxiety, Nausea Introduction Mirtazapine is considered as one of the recommended antidepressant for the treatment of Major Depressive Disorder (MDD), in addition to other classification of 58

61 antidepressants, which known as selective serotonin reuptake inhibitors (SSRIs) [1, 2]. In comparison to SSRIs and other antidepressants, mirtazapine has special pharmacological profiles, which include antagonistic effects on α 2 -adrenaline, histamine H 1 and serotonin 5-HT 2A receptors [3]. Additionally, it is said to be effective for anxiety, due to antagonistic activity in the 5-HT 2c receptor [4]. Onset of action for mirtazapine is reported to be faster than SSRIs [5, 6]. A recent study reported that mirtazapine may reduce benzodiazepine use in patients with MDD [7]. Cancer patients are commonly associated with depressive spectrum disorder, with the prevalence is higher compared to normal population. According to a paper [8], the highest range can be up to 58%. Depression in cancer patients may be associated with nausea and sleep disturbance [9]. Nausea could be from treatment side-effects of chemotherapy, which is worsen by occurrence of vomiting and frequent urination [10]. Then, sleep may be disturbed by these side effects, in addition to the psychiatric problem itself; making sleep disturbance has become the most frequent symptoms experienced by cancer patients [11, 12]. In treating cancer patients with antidepressant, several factors should be taken into consideration. Even though SSRIs had become the first line treatment for depression in general population, cancer patients may have different situation. Together with SSRIs, serotonin norepinephrine re-uptake inhibitors (SNRIs) show similar issue of limited use in cancer patients due to precipitation of sleep disturbance and nausea, as a result of agonist effects on 5-HT 2 and 5-HT 3 receptors [9, 13]. Therefore, mirtazapine has been the treatment of choice for cancer patients, due to its antagonistic effects on 5-HT 2 and 5-HT 3 receptors [14]. Among the benefits of mirtazapine for cancer patients with depressive symptoms include the ability to control nausea and vomiting [15], help sleep continuity [16], as well as increase appetite that may help anorexic patients to gain weight [14]. In view of these benefits, mirtazapine should be prioritized for this type of patients. The depressive symptoms may be controlled, while other concomitant conditions are taken into consideration. However, insufficient evidences were found in the literature to support the practice of this medicine. Therefore, this paper aims to review the use of mirtazapine in cancer patients, focusing on palliative aspect of the patient care. Methods To identify the studies on the use of mirtazapine in cancer, we conducted a search on PubMed (from inception to January 2017) by matching the key terms: noradrenergic and specific serotonergic antidepressants or NaSSA mirtazapine AND cancer or oncol* or malignancy or carcinoma. We included controlled trials, review article, meta-analysis, editorial, commentary, correspondence and letter to editor published fully in peer-reviewed journal and written in English. Reference lists from the selected relevant articles were searched for additional trial or studies. For the purposes of discussion, the main outcomes of the included studies were extracted and tabulated. Results A randomized controlled trial, a cohort study and a case series were identified in studying 59

62 the use of mirtazapine for depression in cancer patients. There were also three cohort studies and a case series reported the use of mirtazapine for symptoms associated with cancer such as cachexia, anorexia, nausea, insomnia, hot flush and pruritus. A randomized controlled trial from Turkey [17] was conducted to compare the effectiveness of mirtazapine and imipramine for the psychiatric problems of depression and anxiety as well as distressing symptoms of cancer patients, such as nausea, vomiting, pain, sleep disturbances and appetite loss. The interventions groups consist of mirtazapine (n = 20) and imipramine (n = 13), while control group is placebo (n = 20) in 6 weeks treatment duration for patients with mixed types of cancer. The findings show significant changes on the mean total scores of anxiety and depression in mirtazapine group, instead of imipramine group and placebo group. Similar to these psychiatric problems, sleep disturbance also can be controlled by using mirtazapine. In terms of appetite loss, nausea, vomiting and pain, there were no significant differences among the three groups. However, this study [17] has limitation of not using effective dosages of medications for the study subjects, as well as using mixed type of cancer patients. Different inclusion criteria in terms of cancer type and stages may influence the results. Therefore, more systematic researches by using improved criteria are warranted. Next, we included a cohort study related to the treatment of depression in cancer patients. The study [18], which had 6 months treatment duration, used prospective, naturalistic open label design. Similar to previous study, it included all stages of cancer patients. Even though significant reduction in depression scores as measured by 17-item Hamilton Rating Scale for Depression (HAM-D-17) had been observed, the small sample size (n = 21) had limited the generalization of this study conclusion with other settings. Besides, another paper [19] had reported case series on mirtazapine for the depression and nausea treatment in breast and gynecological oncology. According to this author, during the year of 2000, 19 out of 20 oncology patients had successfully been treated with mirtazapine. The age ranges for those women are from 36 to 74 years old. All of them were diagnosed with gynecological or breast cancer and also have mood, anxiety or adjustment disorders. They also experienced a reduction in nausea symptoms, improvement in sleep continuity, decrement in depressive symptoms, and increment in appetite. A letter to editor [20] had reported regarding the use of mirtazapine for depression and comorbidities among older patients with cancer. There are several studies that have provided evidences to improve comorbid symptoms associated, such as cancer cachexia, as well as nausea and vomiting among elderly cancer patients. Despite of rare adverse effects which include reversible neutropenia, drowsiness at low doses and constipation, mirtazapine had fewer gastrointestinal side effects (nausea, vomiting and diarrhea), if compared to SSRIs. Another benefit of mirtazapine is that the lower price than ondansetron, the most widely used antiemetics for cancer. Furthermore, we found a review article [21] related to the claim of mirtazapine, to be an alternative to ondansetron in producing antinausea effects. Mirtazapine had been suggested as the first-line options in treating 60

63 nausea induced by chemotherapy and cancer itself. Besides having superior or equal efficacy in the control of nausea and vomiting in comparison to ondansetron, mirtazapine has longer half-life. Besides, two letters to editors have been found, related to mirtazapine usefulness in the treatment of nausea in cancer patients. The first letter [22], mentioned that instead of binding to re-uptake protein as seen in fluoxetine, mirtazapine binds to the 5HT 3 receptor as similar as binding site for ondansetron. Therefore, mirtazapine can produce antinausea effect, improve appetite, and weight gain as a result of its side effects. This is important since weight loss is a common problem for cancer patients who are under chemotherapy regimen. The second letter [23], mentioned that, apart from the reduction of nausea in cancer patients, mirtazapine can also ameliorate cancer cachexia. As a result of increase food intake after administration of mirtazapine, weight will be gained. At the same time, significant improvement in quality of life can be obtained. 61

64 Table 1. Summary of included papers of mirtazapine for cancer patients First author & Year (Ref. No.) Title Type of Paper Description of findings Cankurtaran ES, et al (17) Mirtazapine improves sleep and lowers anxiety and depression in cancer patients: superiority over imipramine. Randomized Controlled Trial (RCT) Significant changes on the mean total scores of anxiety and depression in mirtazapine group, instead of imipramine group and placebo group. Ersoy MA, et al (18) An open-label long-term naturalistic study of mirtazapine treatment for depression in cancer patients. Cohort Study Significant reduction in depression scores as measured by 17-item Hamilton Rating Scale for Depression (HAM-D-17) had been observed. Thompson DS, 2000 (19) Mirtazapine for the treatment of depression and nausea in breast and gynecological oncology. Case Series 19 out of 20 oncology patients had successfully been treated with mirtazapine, during the year of Raji MA, et al (20) Mirtazapine for depression and comorbidities in older patients with cancer. Letter to Editor Several studies have provided evidences to improve comorbid symptoms associated, such as cancer cachexia, as well as nausea and vomiting among elderly cancer patients. Kast RE, et al (21) Cancer chemotherapy and cachexia: mirtazapine and olanzapine are 5-HT3 antagonists with good antinausea effects. Review Paper Mirtazapine had been suggested as the first-line options in treating nausea induced by chemotherapy and cancer itself, due to its superior or equal efficacy in the control of nausea and vomiting in comparison to ondansetron. 62

65 Kast R, 2001 (22) Mirtazapine may be useful in treating nausea and insomnia of cancer chemotherapy. Letter to Editor Mirtazapine can produce antinausea effect, improve appetite, and weight gain, due to the binding with 5HT 3 receptor as similar as binding site for ondansetron. Kapoor S, 2013 (23) Additional advantages of mirtazapine therapy in cancer patients: beyond its role as an antidepressant. Letter to Editor Apart from the reduction of nausea in cancer patients, mirtazapine can also ameliorate cancer cachexia as well as improve weight gain. Jiang SM, et al (24) Intervention of mirtazapine on gemcitabine-induced mild cachexia in nude mice with pancreatic carcinoma xenografts. Animal Study The results showed intervention mice were eating more food than control. Riechelmann RP, et al (25) Phase II trial of mirtazapine for cancer-related cachexia and anorexia. Cohort Study Mirtazapine is a promising agent for cancer-related cachexia and anorexia (CRCA). Kim SW, et al (9) Effectiveness of mirtazapine for nausea and insomnia in cancer patients with depression. Cohort Study Mirtazapine could be used as an effective treatment option in managing cancer patients with nausea and sleep disturbance. Biglia N, et al (26) Mirtazapine for the treatment of hot flushes in breast cancer survivors: a prospective pilot trial Cohort Study Hot flushes reduction had been observed after 12 weeks treatment of mirtazapine 30 mg per day among those women with the history of cancer. Lee JJ, et al (27) Effective use of mirtazapine for refractory pruritus associated with carcinoma en cuirasse. Case Report Cancer patient who had pruritus with cutaneous infiltration may get benefit from the use of mirtazapine for the palliative relief. 63

66 We found an animal study [24] related to this issue. Gemcitabine had been used on nude mice for seven days to produce mild cachexia model. Therefore, mirtazapine can be used to test the hypothesis. The results showed intervention mice were eating more food than control. However, this animal study result should be supported by clinical test in human study. Therefore, we include two cohort studies related to the effectiveness of mirtazapine in treating cachexia and nausea. First cohort study [25] mentioned that mirtazapine is a promising agent for cancer-related cachexia and anorexia (CRCA). This was a phase II trial among nondepressed patients with CRCA, treated with mirtazapine until 8 weeks study duration. Even though the results are encouraging, interpretation should consider the small sample size (n = 17) and single site study only. Then, second cohort study [9] mentioned that mirtazapine could be used as an effective treatment option in managing cancer patients with nausea and sleep disturbance. This cohort study was done for 4 weeks with the outcomes were measured at baseline, days 1, 3, 5, 7, 14, and 28. However, the positive findings should also be treated with cautions since this study lacks of control group. Hot flashes (HF) may become a comorbid symptoms associated with cancer patients. A prospective pilot trial [26] using mirtazapine for HF treatment had been done on breast cancer survivors. HF reduction had been observed after 12 weeks treatment of mirtazapine 30 mg per day among those women. However, data from this preliminary study need to be justified in a larger randomized controlled-trial (RCT). A case report had been published in 2016 [27], stating that cancer patient who had pruritus with cutaneous infiltration may get benefit from the use of mirtazapine for the palliative relief. Despite of other systemic and topical therapies for pruritus management, oral mirtazapine had successfully managed the patient s condition that had a severe treatment refractory pruritus associated with carcinoma en cuirasse. The dosage of mirtazapine used in these patients was 7.5 mg orally nightly and finally, increased to 15 mg orally daily. Discussion In the current review, we found that mirtazapine had several contributions in treating psychological and physical symptoms associated with cancer patients. Mirtazapine acts by blocking the serotonin (5-HT) receptors, specifically at 5-HT 2 and 5-HT 3 subtypes, in addition to its potent antagonist of central 2α-adrenergic autoreceptors. Furthermore, it will also enhance the activity of 5-HT 1 postsynaptic receptors, and eventually increase both noradrenergic and serotonergic transmission, contributing to the widely used term of noradrenergic and specific serotonergic antidepressant (NaSSA) [20, 28]. The most beneficial characteristic of mirtazapine is the absence of exacerbation of nausea or suppression of appetite, which are the most commonly side effects reported for other antidepressant medications19. Furthermore, mirtazapine can potentially be a cost-effective antiemesis therapy, since it is cheaper than ondansetron, the widely used antiemesis, currently. On the other hand, hot flashes (HF) in cancer patients, especially women, can also be reduced by using mirtazapine. This may be due to its mechanism that will increase central serotoninergic and noradrenergic 64

67 activity as a result of antagonistic effects at alpha 2 receptors along the central presynaptic membrane. Additionally, mirtazapine inhibits other receptors such as histamine, that is commonly located at the postsynaptic [26]. Once daily dosing of mirtazapine is a convenience choice for women, due to long half-life (20 to 40 hours) with delayed clearance in women (37 hours), if compared to men (26 hours) [29]. Pruritus in cancer patients may be reduced by mirtazapine, due to its unique mechanisms of action as current hypotheses supported the view of antagonism effects in various receptors, including serotonin (5- HT 2 & 5-HT 3 ), histamine (H1) and α2- adrenergic. However, precise mechanism of pruritus alleviation by mirtazapine has yet to be defined [27]. Nevertheless, mirtazapine has some side effects. One of them is myalgia, as mentioned in a study [19]. However, it seems to be not significant due to rare occurrence, with 2% incidence rate from short-term controlled studies. Another paper14 reported several side effects of mirtazapine, including sedation, dry mouth, stimulation of appetite and weight gain. Similarly, these side effects are quite rare and some of them are desirable. Mirtazapine shows a favourable safety profile, with a wide therapeutic index, and has less inhibitory effect on cytochrome P450 enzymes, contributing to unlikely of drug interactions to occur [14, 30]. However, alcohol and benzodiazepine should be avoided when administering mirtazapine, since the sedation effect may get worsened [30]. Conclusion has potential to be a useful medication for cancer patients suffering from depression and anxiety symptoms with concurrent problems of nausea, cachexia, sleep disturbances, low appetite, hot flashes, or pruritus. However, more research studies with sufficient power are warranted to validate the use of mirtazapine in cancer patients for treating these physical and psychological symptoms. Acknowledgements There is no conflict of interest. References [1] Bauer M, Pfennig A, Severus E, Whybrow PC, Angst J, Möller HJ, et al. World Federation of Societies of Biological Psychiatry (WFSBP) Guidelines for Biological Treatment of Unipolar Depressive Disorders, Part 1: Update 2013 on the acute and continuation treatment of unipolar depressive disorders. World Journal of Biological Psychiatry. 2013;14(5): [2] Lam RW, Kennedy SH, Grigoriadis S, McIntyre RS, Milev R, Ramasubbu R, et al. Canadian Network for Mood and Anxiety Treatments (CANMAT) Clinical guidelines for the management of major depressive disorder in adults. III. Pharmacotherapy. Journal of Affective Disorders. 2009;117(SUPPL. 1):S26-S43. [3] De Boer T. The pharmacologic profile of mirtazapine. Journal of Clinical Psychiatry. 1996;57(SUPPL. 4): In a nutshell, it is reported that mirtazapine 65

68 [4] Berg KA, Harvey JA, Spampinato U, Clarke WP. Physiological and therapeutic relevance of constitutive activity of 5-HT2A and 5-HT2C receptors for the treatment of depression. Progress in Brain Research2008. p [5] Thompson C. Onset of action of antidepressants: Results of different analyses. Human Psychopharmacology. 2002;17(SUPPL. 1):S27-S32. [6] Watanabe N, Omori IM, Nakagawa A, Cipriani A, Barbui C, McGuire H, et al. Mirtazapine versus other antidepressants in the acute-phase treatment of adults with major depression: Systematic review and meta-analysis. Journal of Clinical Psychiatry. 2008;69(9): [7] Hashimoto T, Shiina A, Hasegawa T, Kimura H, Oda Y, Niitsu T, et al. Effect of mirtazapine versus selective serotonin reuptake inhibitors on benzodiazepine use in patients with major depressive disorder: a pragmatic, multicenter, open-label, randomized, activecontrolled, 24-week trial. Annals of general psychiatry. 2016;15(1):27. [8] Massie MJ. Prevalence of depression in patients with cancer. JNCI Monographs. 2004;2004(32): [9] Kim SW, Shin IS, Kim JM, Kim YC, Kim KS, Kim KM, et al. Effectiveness of mirtazapine for nausea and insomnia in cancer patients with depression. Psychiatry and clinical neurosciences. 2008;62(1): [10] Lee K, Cho M, Miaskowski C, Dodd M. Impaired sleep and rhythms in persons with cancer. Sleep medicine reviews. 2004;8(3): [11] Grond S, Zech D, Diefenbach C, Bischoff A. Prevalence and pattern of symptoms in patients with cancer pain: a prospective evaluation of 1635 cancer patients referred to a pain clinic. Journal of pain and symptom management. 1994;9(6): [12] Theobald DE. Cancer pain, fatigue, distress, and insomnia in cancer patients. Clinical Cornerstone. 2004;6(1):S15-S21. [13] Andrews JM, Nemeroff CB. Contemporary management of depression. The American journal of medicine. 1994;97(6):S24-S32. [14] Anttila SA, Leinonen EV. A review of the pharmacological and clinical profile of mirtazapine. CNS drug reviews. 2001;7(3): [15] Pae C-U. Low-dose mirtazapine may be successful treatment option for severe nausea and vomiting. Progress in Neuro- Psychopharmacology and Biological Psychiatry. 2006;30(6): [16] Alam A, Voronovich Z, Carley JA. A review of therapeutic uses of mirtazapine in psychiatric and medical conditions. The primary care companion for CNS disorders. 2013;15(5). [17] Cankurtaran ES, Ozalp E, Soygur H, Akbiyik DI, Turhan L, Alkis N. 66

69 Mirtazapine improves sleep and lowers anxiety and depression in cancer patients: superiority over imipramine. Supportive care in cancer. 2008;16(11): [18] Ersoy MA, Noyan AM, Elbi H. An open-label long-term naturalistic study of mirtazapine treatment for depression in cancer patients. Clinical drug investigation. 2008;28(2): [19] Thompson DS. Mirtazapine for the treatment of depression and nausea in breast and gynecological oncology. Psychosomatics. 2000;41(4): [20] Raji MA, Barnum PD, Freeman J, Markowitz AB. Mirtazapine for depression and comorbidities in older patients with cancer. Annals of Pharmacotherapy. 2007;41(9): [21] Kast RE, Foley KF. Cancer chemotherapy and cachexia: mirtazapine and olanzapine are 5- HT3 antagonists with good antinausea effects. Eur J Cancer Care (Engl). 2007;16(4): [22] Kast R. Mirtazapine may be useful in treating nausea and insomnia of cancer chemotherapy. Supportive Care in Cancer. 2001;9(6): [23] Kapoor S. Additional advantages of mirtazapine therapy in cancer patients: beyond its role as an antidepressant. Journal of pain and symptom management. 2013;45(3):e3-4. [24] Jiang SM, Wu JH, Jia L. Intervention of mirtazapine on gemcitabine-induced mild cachexia in nude mice with pancreatic carcinoma xenografts. World J Gastroenterol. 2012;18(22): [25] Riechelmann RP, Burman D, Tannock IF, Rodin G, Zimmermann C. Phase II trial of mirtazapine for cancer-related cachexia and anorexia. American Journal of Hospice and Palliative Medicine [26] Biglia N, Kubatzki F, Sgandurra P, Ponzone R, Marenco D, Peano E, et al. Mirtazapine for the treatment of hot flushes in breast cancer survivors: a prospective pilot trial. The breast journal. 2007;13(5): [27] Lee JJ, Girouard SD, Carlberg VM, Mostaghimi A. Effective use of mirtazapine for refractory pruritus associated with carcinoma en cuirasse. BMJ supportive & palliative care. 2016;6(1): [28] Kent JM. SNaRIs, NaSSAs, and NaRIs: new agents for the treatment of depression. Lancet. 2000;355(9207): [29] Davis MP, Khawam E, Pozuelo L, Lagman R. Management of symptons associated with advanced cancer: olanzapine and mirtazapine. Expert review of anticancer therapy. 2002;2(4):

70 [30] Davis MP, Frandsen JL, Walsh D, Andresen S, Taylor S. Mirtazapine for pruritus. Journal of pain and symptom 2003;25(3): management. Corresponding Author Syahrir bin Zaini, Department of Psychological Medicine, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia Tel: (+6013)

71 BRIEF COMMUNICATION Understanding Trypophobia: The Fear of Holes Aminuddin I & Lotfi HA Department of Psychological Medicine, University of Malaya, Malaysia Abstract The sight of clustered holes can bring about uneasiness in people, and the disgust response towards it is called trypophobia. Reactions in humans vary from nausea to severe depression. We explore the possible causes of this unique phenomenon, such as evolutionary adaptation and spectral features. We also uncover the clinical features and its relationship to other psychological conditions for example, obsessive-compulsive disorder. Keywords: Trypophobia, Fear of Holes, Phobia Introduction Trypophobia is a repulsion of clusters of small holes or objects that are reminiscent of clusters of holes [2]. It is different from other types of phobia in the sense that its discovery was birthed from the rapid advancement of technology. The term was first coined in 2005 in an online forum, stemming from the Greek words trýpa and phóbos, meaning hole and "fear" respectively [3]. Ever since then, its documentation on the Internet has been widely reported compared to other types of phobia [2] with various Internet-based support groups, where people provide testimonials regarding their struggles with trypophobia. Proposed etiology i. Evolutionary adaptation towards danger Organisms that fail to adapt to their environment and pass on their gene will fall as a fatality of the war of nature [7], said Charles Darwin. Human beings are built with an innate and perceptive neurobiological system that promotes adaptation to change and provides efficient aversion mechanisms towards danger [6]. Physical signs like scars, sores and spots, as well as spots found on dangerous animals like the blue-ringed octopus, the king cobra and also holes found on a hornets nest [2] may induce trypophobia. ii. Unique spectral features Images that act as a stimulus towards trypophobia, such as a cluster of holes, show a feature of high contrast energy at midrange spatial frequencies [2]. This feature does not reach humans conscious awareness, thus can lead to fear in adults [8]. Any images with the same spectral feature will act as a trigger and induce this feeling of disgust as a survival adaptation [2], even though the stimuli are harmless such as the 69

72 head of a lotus seed, a pink coral reef and soap bubbles. A study done showed that preschoolers showed discomfort towards trypophobic image due to the unique spectral feature rather than its danger. In this study, the children showed discomfort towards the image of a starfish with spots covering its body. However, after showing another picture of a starfish, only this time the spots were removed, the children do not exhibit any signs of discomfort [8]. iii. Learned behavior Another theory is that this phobia is learned rather than an innate response mechanism towards danger. The primitive discomfort towards holes is heightened through various experiences such as bitten by a snake or a hornet and this lead to adults reporting of being a trypophobe [8]. Interestingly, most of the respondents did not have an upsetting experience involving holes itself that predisposed them to trypophobia [13]. iv. Overgeneralized emotional response It is found that increased emotional functioning that facilitates avoidant behavior with respect to potential threats, results in trypophobia [4]. In this study, The Trypophobia Questionnaire (TQ) was used. TQ consists of predictors of trypophobic proneness, such as core disgust sensitivity, Personal Distress (PD) and proneness to visual discomfort. PD is the proneness to have self-oriented feelings of anxiety and unease [11,12]. Trypophobia is thought to not only be an extension of the feeling of disgust towards holes, trypophobic images may also act as a self-oriented negative stimuli towards individuals who are already has a high proneness to trypophobia [4]. There are no gender differences in trypophobia proneness [9]. However the core disgust sensitivity is higher in female [4]. This explains the reason individuals with trypophobia are predominantly, female [13]. Why is it unique? Despite being a topic that has had quite a following online, it is under-reported in scientific literature. In fact, trypophobia is not recognized as a disorder, neither does it have its own formal definition in DSM-5 [9,16]. In addition to that, those with trypophobia are self-reported or selfdiagnosed [17]. With trypophobia, the stimuli might be harmless, such as soap bubbles, honeycomb or the seed head of lotus flowers - making the phenomenon difficult to explain in terms of learning theory [2]. Clinical features Symptoms can be divided into 3 categories: cognitive-related (eg; feelings of uneasiness and aversion), skin-related (eg; skin crawling and itching) and physiological symptoms (eg; nausea, difficulty breathing) [17]. The symptoms are chronic, persistent, and affect mostly women. One can also experience symptoms when not in direct contact with the clusters of holes. Severity varies between individuals; from no anxiety at all to having 25 panic attacks per month. Comorbid psychiatric diagnoses include major depressive disorder and generalized anxiety disorder [13]. Despite the distress and impairment in daily function, a majority of them have never sought treatment [13]. 70

73 Resemblance to obsessive-compulsive disorder. A 2017 study suggested that rather than fear, trypophobia is more accurately described as a disgust-based aversion [15]. The association to disgust links trypophobia to obsessive-compulsive disorder (OCD), however it is worth noting that has also been described in specific phobia [14]. The clinical features of trypophobia versus OCD have been assessed, and it was concluded that individuals were more likely to meet the diagnostic criteria for specific phobia than OCD. There are also cases whereby an individual experiences both OCD and trypophobia [13]. What is the recommended approach in the management of trypophobia? There is no specific treatment for trypophobia except by removing the stimuli by progressive spatial filtering of the offensive images [2]. However, trypophobia is associated mostly with common psychiatric diagnoses such as major depressive disorder and generalized anxiety disorder. Hence, treatment should be designed accordingly. Individuals reported significant psychological distress and impairment and among these individuals who seek treatment specifically for trypophobia, only 50% of the patients found it to be helpful, mostly through online support groups [13]. Conclusion/Suggestion Steps need to be taken to first come up with a diagnostic classification. In view of the psychological distress that an individual with trypophobia faces, as well as the low numbers of them seeking professional help, awareness on the topic and effective treatment is called for. References [1] George Grall, N. (2017). If These Photos Disgust You, You May Have Trypophobia. [online] News.nationalgeographic.com. Available at: /07/trypophobia-fear-of-holesstudy-spd/. [2] Cole, G. and Wilkins, A. (2013). Fear of Holes. Psychological Science, 24(10), pp [3] Abbasi, J. (2011, July 25). Is trypophobia a real phobia? Popular Science. Retrieved from [4] Imaizumi, S., Furuno, M., Hibino, H. and Koyama, S. (2016). Trypophobia is predicted by disgust sensitivity, empathic traits, and visual discomfort. SpringerPlus, 5(1). [5] Skaggs W (2014) Fear of holes. Scientific American. Mind 25:12. doi: / scientificamericanmind b. [6] Mobbs, D., Hagan, C., Dalgeish, T., Silston, B., and Prévost, C. (2015). The ecology of human fear: survival optimization and the nervous system. Front Neurosci. 9: 55. doi: /fnins [7] Darwin, C. (1871). The Descent of Man and Selection in Relation to Sex. London: John Murrey. [8] Can, W., Zhuoran, Z. and Zheng, J. (2017). Is Trypophobia a Phobia?. Psychological Reports, [online] 71

74 120(2), pp Available at: / [Accessed 31 Jul. 2017]. [9] Imaizumi S, Furuno M, Hibino H, Koyama S (2016) Development of the Japanese version of Trypophobia Questionnaire. Jpn J Pers 25. [10] Olatunji BO, Haidt J, Mckay D, David B (2008) Core, animal reminder, and contamination disgust: three kinds of disgust with distinct personality, behavioral, physiological, and clinical correlates. J Res Pers 42: doi: /j.jrp [11] Davis MH (1980) A multidimensional approach to individual differences in empathy. JSAS Cat Sel Doc Psychol 10:85. [12] Davis MH (1983) Measuring individual-differences in empathy: evidence for a multidimensional approach. J Pers Soc Psychol 44: doi: // [13] Vlok-Barnard, M. and Stein, D. (2017). Trypophobia: an investigation of clinical features. Revista Brasileira de Psiquiatria, [online] (0). Available at: =S &script=sci_art text [Accessed 31 Jul. 2017]. [14] Sawchuk, C., Meunier, S., Lohr, J. and Westendorf, D. (2002). Fear, disgust, and information processing in specific phobia:. Journal of Anxiety Disorders, 16(5), pp [15] Kupfer, T. and Le, A. (2017). Disgusting clusters: trypophobia as an overgeneralised disease avoidance response. Cognition and Emotion, pp [16] American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5). Arlington: American Psychiatric Publishing; [17] Le, A., Cole, G. and Wilkins, A. (2015). Assessment of trypophobia and an analysis of its visual precipitation. The Quarterly Journal of Experimental Psychology, 68(11), pp Corresponding Author Irdina Amin Faculty of Medicine, University of Malaya Lembah Pantai, Kuala Lumpur Malaysia dinamyusoff@gmail.com 72

75 LETTER TO EDITOR Parity of Esteem for Mental Health: Improving the Physical Health of People with Mental Illness Lessons from Bintulu and Around the World Panirselvam RR Department of Psychiatry and Mental Health, Hospital Bintulu, Sarawak, Malaysia Abstract The parity of esteem remains as a global mental health challenge. The divide is greater in the developing world where physical health of individuals with mental health conditions often takes a backseat. This article explores the extent of the problem and feasible solutions both in global and regional perspectives of Bintulu; a low resource centre in Sarawak, Malaysia. Starting from the self which focuses on empowering mental health providers in becoming cognizant of monitoring physical health in service users. The discussion then delves on the overarching role of mental health teams in supporting allied services including primary health care teams and caregivers. Finally the need to improve healthcare systems in becoming more comprehensive and inclusive to service users is analysed. In conclusion practical evidence based solutions necessitate in achieving parity of esteem. Keywords: Low And Middle Income Countries, Primary Care, Global Mental Health, Physical Health Introduction All human beings are born free and equal in dignity and rights (Article 1, Universal Declaration of Human Rights, 1948). This document among many of its kind were written in the years post the Second World War in hope that the countless lives lost would not be forgotten and the lessons learned at that unprecedented cost would be remembered. Article 25 of the aforementioned document enshrines the right to health. The preamble of the Constitution of the World Health Organisation two years prior provides an aspirational and holistic definition of health. Yet nearly seventy years down the road, paradoxically the quality of physical health of people with mental illness has not improved with the rest of the world. People with severe mental illness die at least a decade earlier, live a life ridden with the wealth of ill-health and have been left behind in the wave of progress in physical health. The parity of esteem or lack of it as highlighted in the advocacy volume of the 73

76 Annual Report of the Chief Medical Officer 2013 and the Royal College of Psychiatrists report Whole-person care: from rhetoric to reality. Achieving parity between mental and physical health from the UK summarise the evidence for the grim situation. At this point one does wonder about the developing world. A world where the sun goes down in gunshots, economies are trying to lift themselves up and statistics are merely smokescreens. Where do people with mental illness figure in this numberless abyss? Furthermore regardless of location how are the priorities in physical health for individuals with mental illness upheld? The burden of physical health in mental illness is a revolving door conundrum. Mental illness on its own predisposes to physical conditions either in cause or effect. A person with mental illness often comes from an impoverished background with socioeconomic challenges which prevent access to healthcare. Poor housing, sanitation, nutrition, employment opportunities and high risk behaviours summon a gamut of diseases mainly infectious in origin. The effect of having a mental illness itself increases the likelihood of having physical illnesses and vice versa. For example, persistent depression despite treatment increases cardiovascular risk (Nicholson, 2006) and nearly a third of individuals with coronary heart disease have depression (Ramamurthy et al., 2013). An individual s mental state could further deter them from seeking the help they need. An illustration of these groups would be individuals who could not care for themselves, leave their dwellings or refuse life-saving interventions. This spirals into possibly poorer service provider attitudes towards individuals with mental illness. Hert 2011 aggregates these findings and one noteworthy finding from many: mental health service users have low rates of surgical interventions, such as stenting and coronary artery bypass grafting. Conversely treating mental illnesses is not without physical consequences. Obesity and subsequently metabolic syndrome due to second generation dopamine antagonists are common feature in most mental health clinics. The length of treatment in most cases that span across entire lifespans compounds this further. Incarceration and prolonged institutionalisation which occur in some parts of the world prevent access to proper screening and healthcare. Mental health service providers are at crossroads in this challenge. At one end we face the trials of any health service especially resource limitations with increasing demands and at the other end we fight almost daily battles delivering mental healthcare in face of stigma. We can easily become discouraged when confronted with service users who are also physically unwell or at risk to the point that we become therapeutically nihilistic and stomach this as a necessary evil. Article 12 of the International Covenant on Economic, Social and Cultural Rights (1966) recognises the right of everyone to the enjoyment of the highest attainable standard of physical and mental health. We can choose to heed this clarion call by being catalysts for change rather than opting helplessness. I work in a middle income country at a low resource centre covering a population across km 2. Being neither here or there, it is vital that our modus operandi is efficient, costconscious and situationally appropriate. In this essay, three viewpoints of improving physical health in mental illness are discussed: self, support and system. Self Mental health professionals are the cornerstone for care of individuals with 74

77 mental illness. By virtue or in due process, the service user comes in contact with mental health-workers regularly leading to greater therapeutic rapport. A typical followup in a general adult medical clinic at our set-up is 10 minutes while a mental health follow-up could last from twenty minutes to an hour. This scenario may not translate in minutes across the world but generally we have longer consultations due to the nature of work than our colleagues elsewhere and should use that window of opportunity. Most mental health professionals started training in general health before pursuing mental health. The basics should not be allowed to rust. The stethoscope and tendon hammer should never be hung up! Medical education in physical health needs to be continued and constantly updated. Vital signs or systems like the Early Warning Score should be a norm of day-to-day practice to detect a deteriorating patient. Follow-up appointments need to consider weight trends and progress in other comorbidities. Learning to listen to beyond our usual field of work may do justice as mental health service users may not articulate physical health symptoms in the same manner as others. The common aspects of health that require an extra antenna on our part with mental health service users would include oral health, metabolic syndrome, smoking, high risk behaviour and infectious diseases. Investigations and physical examinations are frequently forgotten after the first few months. Prompt sheets serve as good reminders as demonstrated by Pasha et al, 2015 and Ramanuj, This idea can be applied electronically in centres with information technology support or by a simple highly visual card on the service user s follow-up book. A nifty small book with temporal records of vital signs, investigations and medications costs very little to initiate and maintain. It will not only offer service providers a tap to perform examinations or order investigations, a prod to review them but also an overview to the service user and increase their awareness of their own health. Advocacy thereby becomes paramount on this front to ensure that service users are able to communicate their needs to other healthcare professionals. This should not be misconstrued as paternalism or overreaching ones limits but viewed as ongoing support. The power of a good therapeutic relationship is often underestimated. It will not be enough at times to just give a referral letter! A telephone ring to see if the service user has the means to get there or even accompanying a service user with his caregiver to assist in the referral should not seem outlandish. These may take time but make strides in outcomes. When we work together we are able to advice each other on our specialities and prevent unnecessary mishaps; for example drug interactions. Communications happen and liaison relationships foster. Service heads should lead by being role models in putting physical health in the forefront of training and practice. Audit cycles can be mooted and pitfalls to best practice can be identified. Personal development needs to be inventive because situations change but service has to go on. Support Health is a state of complete physical, mental and social well-being and not merely the absence of disease or infirmity (WHO 1946). Health requires cohesive effort of various specialities for best outcomes. Mental health service users have different and often challenging needs. Behaviours 75

78 which are socially unacceptable or even silence are common place. Most physical health providers have little training or expertise in understanding or even managing such clinical features. Left perplexed and unsupported, this can become a deterrent to provide optimum care. The need to be supported is therefore overwhelming. Goldberg and Huxley s filter model recognises the pathways to care in mental illness. Most service users come into contact with services through primary care. In countries like Malaysia, sparsely populated rural areas are managed by health clinics which are only manned by community health attendants and nurses. Such areas are remote, have minimal amenities and often lack proper access. Basic training to integrate mental and physical health is important to prevent diagnostic overshadowing. Periodic specialist visits to these clinics can ensure regular expert input (Figure 1). This can be supplemented with the aid of telecommunications by means of secure wireless satellite internet services to update progress of service users. While sending an ECG as an image record no longer seems alien in most places, prudence must be exercised with new technology. It must be discussed with service users and caregivers regarding access and protection of information that is shared electronically. Similarly general practitioners can be supported through a local mental health network. Dual directional care streams can be established rendering better physical and mental health outcomes (Figure 1). Care can be delivered closer to the service user s home and regular monitoring of physical health becomes easier to prioritise. This is also significant in terms of understanding local cultural beliefs and acceptable practice standards where the primary healthcare team would be able to lead and deliver better care. 76

79 Malaysian Journal Of Psychiatry, December 2016, Vol. 25, No. 2 Figure 1. Schematic representation of support and dual-directional relationships of a mental health department in a major healthcare facility within its catchment area of primary care clinics in Sarawak, Malaysia (Example used is Hospital Bintulu and clinics in Kapit division, Sarawak. This map is correct until March 2017 where-in services to KD Punan Bah were transferred to Hospital Kapit. A new visiting clinic to KK Tatau has been established in a two monthly basis since middle of 2016 which is not represented in the map. Legend: KK is Klinik Kesihatan i.e. health clinic and KD is Klinik Desa i.e. village clinic). Community mental health teams can form smart partnerships with primary health teams to overcome barriers of accessibility for service users who are not able to attend health facilities. Mental health teams could utilise their rapport as previously discussed to provide access to primary healthcare providers. Therefore home based monitoring and investigations are made possible through mobile units. This provides an excellent middle ground in situations of socioeconomic constraints, distance conflict to ensure continuity of care. or Mentorship and support within the mental health team and allied health teams should not be forgotten in this process. Junior staff should be trained alongside seniors to ask difficult questions, to touch and examine patients. Staff should be familiarised and comfortable with the service framework. Regular meetings with liaison services like physiotherapy, occupational therapy and 77