|Ahead of print publication
Pharmacological profile of prescriptions containing antidepressants
Prafull Mohan1, Harpreet Singh2, Sharmila Sinha1, K Prabhakaran1
1 Department of Pharmacology, AFMC, Pune, Maharashtra, India
2 Department of Psychiatry, AFMC, Pune, Maharashtra, India
|Date of Submission||03-Jul-2020|
|Date of Decision||29-Jul-2020|
|Date of Acceptance||19-Nov-2020|
|Date of Web Publication||10-May-2021|
Department of Pharmacology, AFMC, Pune - 411 040, Maharashtra
Source of Support: None, Conflict of Interest: None
Background: The prescription of antidepressants is increasing due to the increasing incidence of depression and the use of antidepressants in other indications. There is a need to monitor their prescription practices not only to ensure evidence-based clinical use but also to align classroom teaching with the current clinical trends. Materials and Methods: This observational study was conducted in the department of psychiatry of a tertiary care hospital in western Maharashtra on anonymized prescriptions received within the study period. Results: A total of 214 prescriptions were analyzed with 268 instances of antidepressant prescription. 59.05% of prescriptions were of selective serotonin reuptake inhibitors (SSRIs), 18.11% of atypical antidepressants, 16.92% of tricyclic antidepressants (TCAs), and 5.90% of serotonin-noradrenaline reuptake inhibitors. 46% percent of prescriptions were as per defined daily doses (DDDs), 26% more than DDD and 28% less than DDD. Escitalopram and mirtazapine were the most commonly prescribed drugs. Both did not find mention in the National List of Essential Medicines and World Health Organization–Essential Medicines List (EML). Out of 214 prescriptions, 209 prescriptions were for psychiatric indications and the rest 5 were for nonpsychiatric indications. TCAs were prescribed more for psychiatric indications other than depression, while SSRIs were prescribed equally for depression and other psychiatric indications. Conclusion: Prescription trend in this study is in consonance with other contemporary studies. Extensive use of mirtazapine is a peculiar finding requiring further exploration. As in other studies, SSRIs have been used in doses more than their defined daily dose. Off-label use of antidepressants is widespread, but it should be backed by drug-specific robust evidence. EMLs and clinical usage derive from each other and need to be in mutual sync.
Keywords: Antidepressive agents, fluoxetine, formularies, prescriptions, serotonin uptake inhibitors
| Introduction|| |
Depression is an affective disorder that affects 2.7% of Indian & 4.4% of global population. Its prevalence is likely to increase., The prescription of antidepressants is also increasing because of the increasing incidence of depression as such increasing awareness and reducing stigma. In addition, antidepressants are being increasingly used for nondepression/nonpsychiatric indications such as obsessive–compulsive disorder, phobic states, anxiety disorders, neuropathic pain, attention-deficit hyperactivity disorder, premature ejaculation, enuresis, migraine, and pruritus. All the antidepressants have established clinical efficacy; there is growing concern about their acceptability due to side effects. 16%–25% of patients on antidepressants experience intolerable side effects. As a result, newer and safer antidepressants are always under development. While this has inflated the antidepressant inventory, a majority of prescriptions in India continue to be of selective serotonin reuptake inhibitors (SSRIs). In view of the increasing epidemiological importance of depression and increasing number of antidepressants, it is imperative that the Indian Medical Graduate is competent in providing early care to cases of depression. With integration being advocated and mandated by the Medical Council of India, there is a need to align the teaching and training of antidepressant drugs during para-clinical stint with the current clinical trends. This study aims to not only facilitate the said objective but also will work as an appropriation tool for the faculty of the department of psychiatry.
The results of the study can also be subsequently utilized for forecasting and provisioning purposes by administrators. This open-label observational study was carried out on anonymized prescriptions wherein the identity of the patient was concealed so as to make it ethically viable. Anonymization of prescription was done at the source itself so that there was no chance of patient identity being revealed to the study team.
| Materials and Methods|| |
This single-center descriptive observational study is based on routinely generated hospital data (prescriptions) and was done in the department of pharmacology and psychiatry outpatient department (OPD) of a tertiary care hospital in western Maharashtra. Clearance of the institutional ethics committee was obtained before starting the study. Blinded and de-identified prescriptions of OPD patients for whom at least one antidepressant drug has been prescribed (for any indication) during the months of May and June 2019 were included in the study. Defined daily dose (DDD) of each drug was taken from the World Health Organization (WHO) Anatomical Therapeutic Chemical Index dated December 16, 2019, and prescribed daily dose (PDD) was calculated from the prescription(s). Prescribed drugs were also checked for their availability in formularies viz National Formulary of India (NFI), British National Formulary (BNF) AND essential medicine lists (EMLs) viz., WHO Essential Medicines List and National List of Essential Medicines (NLEM, 2019).
| Results|| |
A total of 214 prescriptions were analyzed, in which antidepressant drugs had been prescribed 268 times. 39 prescriptions had more than one antidepressant prescribed. 254 antidepressant drugs were distributed as SSRIs (59.05%), atypical antidepressants (18.11%), tricyclic antidepressants (TCAs) (16.92%), and serotonin-noradrenaline reuptake inhibitors (5.90%) [Figure 1]. Escitalopram (prescribed in 69 prescriptions, i.e., in 32% of prescriptions) was the most commonly prescribed drug, followed by mirtazapine (prescribed in 40 prescriptions, i.e., 19% of total prescriptions). Out of 268 instances of antidepressant prescription, PDD was equal to DDD in 46% of cases, less than DDD in 28% of cases, and more than DDD in 26% of cases [Figure 2].
|Figure 2: Comparative distribution of prescribed daily doses and defined daily doses|
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Antidepressants included in NLEM, WHO EML, and BNF are tabulated in [Table 1]. Both escitalopram and mirtazapine are listed in BNF but not in NLEM and WHO-EML. Fluoxetine (an SSRI) is the only drug which was listed in all the formularies. Out of NLEM, amitriptyline was prescribed in 12 (6%), imipramine in 3 (1.5%), and fluoxetine in 36 (17%) prescriptions.
Out of a total of 214 analyzed prescriptions, 209 prescriptions were for indications of depression/other psychiatric illness, while the rest 5 were for nonpsychiatric indications. TCAs were prescribed more for psychiatric indications other than depression, while SSRIs were prescribed equally for depression as well as other psychiatric indications. Other psychiatric indications included obsessive–compulsive disorder, anxiety, bipolar affective disorder, adjustment disorder, panic disorder, schizoaffective disorder, and alcohol dependence syndrome. Further, TCAs were also prescribed for nonpsychiatric indications, 8% of the times [Table 2].
| Discussion|| |
Prescription trend analysis is a common pharmaco-epidemiological tool to strengthen, optimize, and standardize prescription in any therapeutic domain. In this study, we chose depression as our area of investigation, keeping in mind the increased incidence of and complexity in prescribing antidepressants. In this study, the number of prescriptions in which more than one antidepressant were prescribed was 40 (18.86%). As only about 40% of individuals get clinical benefit on monotherapy, polytherapy has been found to be common in other studies also. In our study, almost 60% of antidepressants prescribed were SSRIs. Other studies have also arrived at similar observation with SSRIs contributing up to 80% of prescribed antidepressants.,,, Pharmacological profile of SSRIs which consists of equal efficacy and relatively better safety as compared to TCAs contributes to their widespread clinical use.
In our study, escitalopram (an SSRI) and mirtazapine (an atypical agent) were the top two antidepressants that were prescribed. Other studies have also observed escitalopram to be the most common antidepressant that is prescribed.,, Its established efficacy over other SSRIs coupled with ease of once-daily dosing and lack of food–drug interaction makes it a popular antidepressant., Prominence of mirtazapine in this study, however, is surprising. It is a newer atypical antidepressant which is considered to be a second (or even third line) antidepressant. Its property of causing sedation, dyslipidemia, and agranulocytosis restricts its widespread use. However, it may be specifically useful in patients who have associated anxiety, insomnia, or suffer from sexual side effects from other antidepressants. There is evidence to suggest that it has a faster onset of action as compared to SSRIs, making it a lucrative choice in acute-phase treatment of depression. Mirtazapine can also lead to a reduction in the use of benzodiazepines in major depressive disorders.
Benzodiazepines were used along with antidepressants in 21 instances out of 214 prescriptions. These primarily hypnotic/sedative classes of drugs have been in use for depression, mostly in combination with other antidepressant drugs. Combining benzodiazepines with other antidepressants has been shown to improve clinical response in early phase of illness, as compared to antidepressants alone. However, during later phases of illness, the benefit disappears. In view of additional benzodiazepine-associated safety issues and temporally limited clinical benefit, the use of benzodiazepines should be carefully considered. In our study, clonazepam was the most common benzodiazepine used and it was used in 19 out of those 21 instances. Long half-life and easy availability of clonazepam are the likely reasons behind this observation.
A comparison of a drug's DDD with its PDD provides an insight into the actual clinical use of the drug. In this study, 46% of prescriptions were as per DDDs, 26% more than DDD (mostly SSRIs) and 28% less than DDD (mostly TCAs). Other studies have also concluded that TCAs are frequently used below their dose levels and SSRIs near/above their dose levels. However, there is no scientific evidence to support the higher dose usage of SSRIs. On the contrary, it is the lower dose range that achieves the optimal balance between efficacy and safety. It is the inherent and perceived relative safety of SSRIs that lead to their being prescribed more than DDD, whereas a higher incidence of adverse drug reactions associated with TCAs appears to be the reason behind their being prescribed less than their DDD. The relative safety of SSRIs vis-a-vis TCAs is well known and has been outlined in other studies also.,
It has also been revealed in our study that a significant proportion of TCAs and SSRIs were for indications other than depression. This trend has been captured by other studies as well. However, the extent of such off-label use is more for TCA in other studies as compared to our study but less for SSRIs. We have not gone into the details of nonpsychiatric and other off-label indications as the small sample size is not going to throw up significant generalizable results. Common off-label indications of TCAs are neuropathic pain, migraine, diabetic neuropathy, tension-type headache, postherpetic neuralgia, restless leg syndrome, and nonspecific low back ache. Similar off-label indications for SSRIs are in obsessive–compulsive disorders, general anxiety disorders, eating disorders, and treatment of various addictions. Similarly, atypical agents (especially trazodone) are being used for the treatment of insomnia due to their inherent sedative properties. The main concern regarding off-label use of antidepressants is that the evidence regarding such use is heterogeneous within the same class of antidepressants. In other words, off-label use of antidepressants is not a class effect as such and it should be supported by drug-specific evidence and guidelines.
The fact that the most commonly used antidepressant does not find mention in NLEM and WHO-EML reflects that the drug formularies/lists need to be in sync with clinical usage data. There may also be a case for aligning clinical practice with EMLs and formularies. The effect of including a drug in NLEM is not exactly known. However, as per one study, drugs included in NLEM were found to be more economical than once not included. Moreover, inclusion in NLEM indicates the relative importance of a drug to an administrator which may lead to its better inventory management, especially in government health-care setup.
Analyzing prescription errors was not the aim of the study. However, we noticed that a sizeable proportion of prescriptions had problems such as illegibility and incomplete prescriptions. These prescriptions were not included in the analysis, and this could have added some selection bias in our study. In the prescriptions included in our study, all the prescriptions were in generic name which not only is as per organizational directives on the subject but also is a desirable attribute of any prescription.
| Conclusion|| |
This study describes the clinical use of antidepressant drugs in a tertiary care hospital in western Maharashtra. Broadly, the prescription trend is in consonance with other contemporary studies. However, the extensive use of mirtazapine is a peculiar finding which requires further exploration. SSRIs have been used in doses more than their described daily dose which is again in sync with other studies despite being of no additional benefit. The context of combined use of benzodiazepines requires further exploration as this combination has diminishing returns after some time. Off-label use of antidepressants is widespread. Such use should be backed by drug-specific robust evidence and not taken as a class effect. Drug formularies and lists of essential medicines and clinical usage derive from each other and need to be in mutual sync. The need of the same has been highlighted in this study as well.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Chattar KB, Karve AV, Subramanyam A, Tondare SB. Prescription pattern analysis of antidepressants in psychiatric outpatient department of tertiary care hospital in India. Asian J Pharm Clin Res 2016;9:77-9.
Rush AJ, Trivedi MH, Wisniewski SR, Nierenberg AA, Stewart JW, Warden D, et al
. Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: A STAR*D report. Am J Psychiatry 2006;163:1905-17.
Siddiqi RA, Shende RT. Prescription pattern of antidepressant drugs in a tertiary care centre of central India. J Cont Med A 2014;2:14-6.
Lahon K, Shetty HM, Paramel A, Sharma G. A retrospective drug utilization study of antidepressants in the psychiatric unit of a tertiary care hospital. J Clin Diagnostic Res 2011;5:1069-75.
Tripathi A, Avasthi A, Desousa A, Bhagabati D, Shah N, Kallivayalil RA, et al
. Prescription pattern of antidepressants in five tertiary care psychiatric centres of India. Indian J Med Res 2016;143:507-13.
] [Full text]
Motevallyzadeh HR, Baneshi MR, Rameshk M, Nakhaee N. Prescribing pattern of antidepressant drugs among general practitioners and psychiatrists: A study from Iran. Russian Open Med J 2013;2:205.
Nahas AR, Sulaiman SA. Prescribing patterns of antidepressants among depressive men in Malaysia: A survey. J Young Pharm 2018;10:98-101.
Grover S, Avasth A, Kalita K, Dalal PK, Rao GP, Chadda RK, et al
. IPS multicentric study: Antidepressant prescription patterns. Indian J Psychiatry 2013;55:41-5.
] [Full text]
Sanchez C, Reines EH, Montgomery SA. A comparative review of escitalopram, paroxetine, and sertraline: Are they all alike? Int Clin Psychopharmacol 2014;29:185-96.
Cipriani A, Santilli C, Furukawa TA, Signoretti A, Nakagawa A, McGuire H, et al
. Escitalopram versus other antidepressive agents for depression. Cochrane Database Syst Rev 2009;15:CD006532.
Watanabe N, Omori IM, Nakagawa A, Cipriani A, Barbui C, Churchill R, et al
. Mirtazapine versus other antidepressive agents for depression. Cochrane Database Syst Rev 2011;7:CD006528.
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, active-controlled, 24-week trial. Ann Gen Psychiatry. 2016 Oct 19;15:27. doi: 10.1186/s12991-016-0115-1.
Johnson DA. The use of benzodiazepines in depression. Br J Clin Pharmacol 1985;19 Suppl 1:31S-5S.
Ogawa Y, Takeshima N, Hayasaka Y, Tajika A, Watanabe N, Streiner D, et al
. Antidepressants plus benzodiazepines for adults with major depression. Cochrane Database Syst Rev 2019;6:CD001026.
Bushnell GA, Stürmer T, Gaynes BN, Pate V, Miller M. Simultaneous antidepressant and benzodiazepine new use and subsequent long-term benzodiazepine use in adults with depression, united states, 2001-2014. JAMA Psychiatry 2017;74:747-55.
Johnson CF, Williams B, MacGillivray SA, Dougall NJ, Maxwell M. 'Doing the right thing': Factors influencing GP prescribing of antidepressants and prescribed doses. BMC Fam Pract 2017;18:72.
Furukawa TA, Cipriani A, Cowen PJ, Leucht S, Egger M, Salanti G. Optimal dose of selective serotonin reuptake inhibitors, venlafaxine, and mirtazapine in major depression: A systematic review and dose-response meta-analysis. Lancet Psychiatry 2019;6:601-9.
Katzung BG, editor. Basic and Clinical Pharmacology. 14th
ed. New York: McGraw-Hill Education; 2018. p. 532-50.
Wong J, Motulsky A, Abrahamowicz M, Eguale T, Buckeridge DL, Tamblyn R. Off-label indications for antidepressants in primary care: Descriptive study of prescriptions from an indication based electronic prescribing system. BMJ 2017;356:j603.
Everitt H, Baldwin DS, Stuart B, Lipinska G, Mayers A, Malizia AL, et al
. Antidepressants for insomnia in adults. Cochrane Database Syst Rev 2018;5:CD010753.
Mercier A, Aubin AI, Lebeau JP, Schuers M, Boulet P, Hermil JL, et al
. Evidence of prescription of antidepressants for non-psychiatric conditions in primary care: An analysis of guidelines and systematic reviews. BMC Fam Pract 2013;4:14-55.
Sarangi SC, Kaur N, Tripathi M, Gupta YK. Cost analysis study of neuropsychiatric drugs: Role of National List of Essential Medicines, India. Neurol India 2018;66:1427-33.
] [Full text]
Benet LZ. Principles of prescription order writing and compliance instructions. In: Gilman G, editor. The Pharmacological Basis of Therapeutics. 8th
ed. USA: Maxwell Macmillan International; 1991. p. 1640-49.
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[Table 1], [Table 2]