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An Observational Study on drug Utilization Pattern and Pharmacovigilance of Antidepressant Drugs

Introduction: Drug utilization is the marketing, distribution, prescription and the use of drugs in a society. The method of prescribing antidepressant drugs have changed worldwide in the last couple of years. 1 Numerous drugs are seen in this class with different mechanism of action and variable efficacy and safety profile. 2 Drug utilization studies are important for rational prescribing, as there is discovery of new drugs and the delayed recognition of their adverse effects. Depression requires chronic treatment thus making such studies important in minimizing the medication errors. 3 Methods: After getting approval from the instituitional human ethics committee and consent from the subjects, this study was conducted in which 80 prescriptions with one or more antidepressant drug was collected during a period of one year. The patients were followed up after one month and adverse events if any produced by medication were noted and analysed. Results: Out of 80 prescriptions analysed, 46.25% were males and 53.75% were females. Regarding the morbidity distribution, depressive disorder contributes to 68.75% and adjustment disorder contributes to 8.75% of diagnosis. Based on analysis by WHO/INRUD standard guidelines, the average number of drugs and antidepressant drugs per prescription were 2.7% and 1.01% respectively. The utilization of antidepressant drugs assessed by PDD/DDD ratio is equal to 1 for sertraline and escitalopram while it is less than one for other antidepressants. The adverse effects commonly encountered were weight gain, sedation, dry mouth, diarrhea, insomnia and constipation.


Introduction
Major depressive disorder (MDD) is one of the leading cause of disability in the developed world. In addition, major depression is associated with a variety of medical conditions from chronic pain to coronary artery disease. 1 Depressive episodes are characterized by sad mood, pessimistic worry, decreased interest in routine activities, poor concentration, insomnia or increased sleep, weight loss or weight gain because of changed eating patterns, feeling of guilt, decreased libido. 2 Antidepressants (AD are used in the management of depressive disorders and anxiety disorders. Additionally, antidepressants are used in the treatment of eating disorders, impulse control disorders, enuresis, sexual dysfunction, aggression. 4 Drug utilization study has been defined by the World Health Organization (WHO) as "marketing, distribution, prescription and use of drugs in a society with special emphasis on the resulting medical, social, economic consequences." The principal objective of drug utilization research is to enable rational use of drugs which is hard to find without the knowledge of prescription pattern. The analysis of prescribing patterns is to evaluate and suggest modifications if required in the prescribing pattern of medical practitioners to make medical practise rational and cost-effective. Prescribed daily dose (PDD) is the average daily dose prescribed which is prescribed according to a representative sample of population and is an indicator of the actual quantity of the drug or class of drug used per day over a given time period per user. 5 Changes in prescription pattern over a time are expected and what influences this change is a valuable tool in our understanding of drug use. Hence our research applies drug utilization studies to describe the prescription pattern of antidepressant drugs. This study was conducted to analyse the drug utilization pattern of antidepressants with the following objectives-1. To analyse the drug utilization pattern by using standard parameters.
2. To delineate the various drugs used in depressive disorder. 3. Documenting adverse drug reactions reported or experienced by the patient. Since drug utilization data of antidepressants are scarce, we conducted a study to describe the observed pattern of antidepressants use. The proposal for this drug utilization study has been submitted to The Institutional Human Ethics Committee, Rajah Muthiah Medical College, Annamalai university and the approval was obtained before the commencement of the study. The data of the patients visiting psychiatric OPD during the period July 2017 -June 2018 were collected. The individual participant was explained about the study and they were also assured that their identity would be kept confidential and they have the option to refuse participation in the study.

Materials and Methods
Informed consent was obtained from the s participant prior to the study both in English and Tamil format. Data collection: The following data were collected.
 Demographic details like name, age, gender, OPD no. and educational status  Prescription details like number of drugs, name of the individual drugs, dosages, dosing schedule and duration of drugs.  On the follow up, history of adverse events if any were noted. Data analysis: The data analysis were done as follows: a) Assessment of prescription pattern as per WHO/INRUD drug use indicators b) Classification of prescribed drugs according to the anatomical therapeutic chemical (ATC)-defined daily dose (DDD) c) The prescribed daily dose (PDD) and its ratio to DDD was calculated.

Morbidity distribution pattern
Out of the 80 prescriptions containing antidepressant drugs analysed, 55 prescriptions were of the diagnosis Depressive disorder, 7 were of Adjustment disorder, 6 were of Other anxiety disorders, 5 were of Schizoaffective disorder, 4 were of Obsessive compulsive disorder and 3 belongs to Alcohol dependence. The other drugs co-prescribed with antidepressants were antipsychotics, benzodiazepines, vitamin B complex, Multivitamin, H2 blocker etc. Among the antipsychotics-quetiapine, olanzapine and risperidone were the drugs found in 11.25% of prescriptions. Among the antianxiety drugs diazepam, lorazepam, clonazepam and alprazolam were the commonly prescribed drugs found in 1.25%, 15%, 68.75% and 7.5% of prescriptions respectively. Among the anti ulcer drugs, Ranitidine-H2 blocker was the commonly prescribed drug found in 11.25% of prescriptions. The tablet B-complex was found in 37.5% of prescriptions. Divalproate sodium is the mood stabilizer prescribed in 13.75% of prescriptions.

Observed prescription pattern in depressive disorder
Clonazepam is a benzodiazepine commonly prescribed along with antidepressant medications in about 86.63% of prescriptions. The most commonly prescribed antidepressant in depressive disorder was escitalopram and the least commonly prescribed was mirtazapine. Mood stabilizer such as valproate was also prescribed for few cases.

Observed prescription pattern in Adjustment disorder
Escitalopram was the most common antidepressant prescribed for patients diagnosed with adjustment disorder followed by amitriptyline and sertraline. Among the benzodiazepines, lorazepam was prescribed.

Observed prescription pattern in other anxiety disorder
In case of anxiety disorders, benzodiazepines are used in which alprazolam aws more frequently prescribed drug followed by clonazepam. The other drugs which were prescribed were selective serotonin reuptake inhibitors in which fluoxetine is most prescribed and sertraline least. Observed prescription pattern in Schizoaffective disorder In case of schizoaffective disorder, the most common class of drug prescribed were selective serotonin reuptake inhibitors such as escitalopram.
Other drugs prescribed along with antidepressants were mood stabilizers such as valproic acid seen in 83.3% of prescriptions. Additionaly antipsychotics such as quetiapine and olanzapine were also prescribed.

Observed prescription pattern in obsessive compulsive disorder
The most common group of drug prescribed for this case was selective serotonin reuptake inhibitors such as fluoxetine. The other drugs prescribed along with antidepressants were benzodiazepines such as clonazepam seen in 75% of prescritions followed by lorazepam. Observed prescription pattern in alcohol dependence For this case, the most common class of drug used was benzodiazepines such as lorazepam. Among the antidepressant drugs that were prescribed, escitalopram was the most prescribed drug. All the patients with this diagnosis were prescribed multivitamin tablets also.  9 The prevalence of depressive disorders was more in females than in males, similar to a finding seen in a study. 10 In a study conducted by Kuehner et al, women were diagnosed with depression more than men. 11 Gender distribution has shown that the occurrence of depression is more in females similar to results of a study done in northern india. 12 Literature also mentions that females suffer from depression more than males. 13 The prevalence pattern of adjustment disorder showed 57.14% patients were females and 42.85% of them were males. A finding that correlates with a study conducted by Yaseen YA et al. 14

Prescription pattern analysis as per WHO/ INRUD
The average number of drugs per prescription was 2.7, a finding similar to many studies. 15,1 In the analysis of prescription of antidepressants, it is found that a large proportion around 69.51% of drugs are prescribed in their generic names. It is well understood that generic drugs reduce the cost of therapy and is thus recommended. Generic substitution can be beneficial, provided, adequate quality control is assured. 16 Among the prescribed drugs only 60% are from the state's essential list of medicines and are available free of cost. By including more drugs to the essential list of medicines, they can be made available free of cost to the patients which will decrease the economic burden of the disease and will improve the compliance of treatment removing the financial constraints.
The drugs which were prescribed with proprietary names are to be bought by patient at its own cost. Thus the socio economic status of a patient largely influences the selection of drugs for his diagnosis and here the role of pharmacoeconomics becomes significant which is explained clearly by Ajay Bera et al. 17 ATC/DDD classification When the PDD/DDD ratio is less than one it represents under utilisation and more than one represents over utilisation of drugs.

Observed drug use pattern in depressive disorder
The most frequent class of drug dispensed was SSRI followed by TCA similar to other studies done in Italy and India. 21,20 Reason behind frequent use of SSRIs compare to TCAs is lesser side effects and better tolerability than the latter. 19 Escitalopram was the most common antidepressant prescribed overall and among SSRI also. Amitriptyline was the most common drug among TCAs. Sertraline was prescribed to a least number of patients. In a multicenter study done by Grover at al, 18 escitalopram was the most commonly prescribed anti depressant followed by sertraline. Escitalopram and clonazepam was the most common combination used as polytherapy. Benzodiazepines are co-prescribed in about 69.09% of the depressive disorder cases. Among the benzodiazepines, clonazepam was the most commonly prescribed drug followed by lorazepam, diazepam and alprazolam. Benzodiazepines are quite safe medications. Though their use reduces the requirement of anticholinergics, there is no significant improvement in the general mental state. 22 They can lead to falls, particularly in the elderly. With long term use the adverse effects encountered were addiction, memory loss, depression, tolerance, and dependence outweighs the benefits and increased moratlity. 23 These drugs are prescribed for acute therpay, maximum of four weeks or their minimum effective doses given in intermittent doses. 24 Observed drug use pattern in adjustment disorder Antidepressants were prescribed in patients with adjustment disorder with brief depressive reaction or acute stress reaction. An analysis of pattern prescription of antidepressants showed significant increase in the prescription more among patients with less severe psychiatric disorders (among them, AD). This suggested that in general, AD based on symptoms is viewed as a depression, with no attention given to the concept of timelimited and stress related event that truly defines it. 25 Among the antidepressant, there was a threefold increase in the use of SSRIs. The second line treatment was benzodiazepines to tackle the depression component of adjustment disorder as antidepressants usually take two weeks to show clinical response. 26 Observed drug use pattern in other anxiety disorder Anxiolytics i.e. benzodiazepines remain the mainstay treatment followed by antidepressants. Among the anxiolytics, the most common drug used was alprazolam followed by clonazepam and lorazepam. In a study done at Manipal teaching hospital, Nepal similar finding was noted. 27 indicating the use of shorter acting ones, as it is observed that continuous and prolonged use of longer acting Benzodiazepines results in dependence and withdrawal symptoms when the dosage is decreased or therapy is stopped. 28 Antidepressants and Benzodiazepines are the most commonly prescribed psychotropic drugs. Published evidence just tells us that antidepressants are effective in moderate and severe depressive illness. 29 Benzodiazepines are extremely effective in promoting sleep and relieving anxiety in short term. 30 Observed drug use pattern in schizoaffective disorder In a study conducted by Kingshuk lahon et al, the most common antidepressant which was prescribed for schizoaffective disorder was escitalopram, a finding similar to our study. 1 Mood stabilisers are the most commonly prescribed group of drugs along with antipsychotics in which Divalproate sodium was frequently prescribed. Observed drug use pattern in Obsessive compulsive disorder Antidepressants were preferred in cases of obsessive compulsive disorder, particularly a SSRI-fluoxetine was started as first line treatment. SSRIs are the first-line of treatment as seen in many randomized controlled trials (RCTs), according to several metaanalyses, 31 .

Observed drug use pattern In alcohol dependence
For decreasing the withdrawaI symptoms, BZDs like Lorazepam was prescribed in our study which was in line with the studies done by Hoey LL et al, where Lorazepam was the common BZD being prescribed. 33,32 Hence, BZDs are effective in treatment of withdrawal symptoms in alcohol dependent patients. In our study multivitamins were prescribed to all patients with alcohol dependence.as seen in many studies. This indicates that multivitamins are necessary to treat nutritional deficiencies commonly suffered by alcoholic patients. Alcohol dependence is associated with various psychiatric comorbidities. An integrated approach is essential to address this issue as seen in the study be Ismene, et al. 34. In our study too other coexistent affective disorders were treated with antidepressants.

Adverse events
Weight gain during antidepressant treatment is either a symptom of depression or a residual symptom in patients who overeat when depressed. Weight gain is seen during both acute and chronic treatment with antidepressants and this mainly contributes to noncompliance.
Antidepressants interfere with serotonin, the neurotransmitter that regulates anxiety, mood and controls appetite. These changes may increase cravings for carbohydrate-rich foods. When people are depressed, their appetite is affected. So when antidepressants take effect, appetite usually increases. Depression can also lead to fatigue and inactivity, and a lack of physical activity causes weight gain. If a person gains weight while taking antidepressants, it may indicate that the medication is not combating their depression effectively. Escitalopram and fluoxetine showed an increase in in weight gain among patients which correlates exactly with study conducted by Fava et al. 35 The other adverse effect which are commonly noted were sedation, dryness of mouth and constipation by amitriptyline which was also noted in many studies. The most frequently co prescribed antidepressant was sertraline which produced diarrhoea and insomnia in few patients.

Conclusion
Among the patients receiving antidepressant medications, depressive disorder was the most common diagnosis followed by adjustment disorder, other anxiety disorder, schizoaffective disorder, obsessive compulsive disorder and alcohol dependence.  A significant percentage of patients of cases falls in the age group of 20-40 years followed by 41-60 years.  A larger proportion of drugs has been prescribed in their generic names.  The average number of antidepressants per prescription was 1.01.  In depressive disorder, the most common drg prescribed single drug was escitalopram amd two drug therapy was escitalopram and clonazepam while the least commonly prwscribed drugs were nitrazepam and lithium.
 In adjustment disorder, the most commonly prescribed antidepressant drug was escitalopram and sertraline.  The most commonly co prescribed antidepressant and anti anxiety drug were fluoxetine and alprazolam respectively.  A minor part of the total cost per prescription was borne by the patients and this indicates majority of the drugs available at free of cost.  The principles of rationality in prescribing the drugs were followed according to the various drug use indicators given by WHO/INRUD.