Study of Biases in the Prescription of SSRIs with Respect to Pharmacokinetic, Applicative, Demographic, and Commercial Aspects

Objective: To study the biases in the prescription of Selective Serotonin Reuptake Inhibitors and the variation between the literature and the perception of doctors prescribing SSRIs. Methodology: The five drugs under study were sertraline, fluoxetine, fluvoxamine, paroxetine, escitalopram. The factors influencing the psychiatrist’s perceptions/ practice considered in this study are: A) Pharmacokinetic factors of the drug (Contra indications, Drug efficacy, Onset of action, Duration of action and the Bioavailability) B) Uses of the drug (for Social Anxiety Disorder, Generalized Anxiety Disorder, Major Depressive Disorder, Obsessive Compulsive Disorder and Post-Traumatic Stress Disorder) C) Side effects (Somnolence, Anxiety, Tremors, Anorexia and sexual dysfunction) D) Patient’s Demographics (Gender, Age group, Special GroupsGeriatrics and Adolescents) E) Commercial aspects (Retail Price, Availability, Brand Value of the Parent Brand and Interpersonal Skills of the Medical Representative). Discussion: Contra-Indications: Theoretically, all SSRIs have the same number of contra-indications, since they have the same mechanism of action, though fluoxetine and paroxetine have a relatively higher potential of drug-drug interactions. Nonetheless, escitalopram was perceived to have the lowest, while fluvoxamine was perceived to have the highest number of contra-indications. Duration of action: There is no set difference between the duration of action of the 5 drugs under study, although, according to secondary research, 1/3 rd of the total therapeutic effect at six weeks was apparent by the 1 st week of treatment. Also, fluoxetine has the highest half-life at 2-4 days, while that of paroxetine is the least, at 16 hours. Yet, based on the study, Sertraline was perceived to have the highest duration of action. Demographics: Although there was no literature found to back this bias, Sertraline was the most preferred drug for us in geriatric patients, while Paroxetine was the least preferred. For adolescent populations, Paroxetine was the most preferred and Fluoxetine was the least preferred. Conclusion: There exists a gap between the theoretical evidence and the practical observations about the pharmacokinetics, uses and side effects of the 5 SSRIs under study. For example, sertraline, a drug proven to be useful in the treatment of depression, has an incorrect bias of causing anxiety as a side effect. This results in psychiatrists not prescribing an effective drug due to a bias with no theoretical basis, thus resulting in poorer treatment outcomes for the patient. For healthcare organizations, it means that they are losing out on almost half the potential patient population. Therefore, it would be useful for them to undertake communication campaigns that revolved around thwarting such biases, thus resulting in better treatment choices for patients and improved health outcomes.


Introduction
Depression is a common illness characterized by persistent sadness and a loss of interest in activities that one normally enjoys, accompanied by an inability to carry out daily activities, for at least two weeks. For the individual suffering from depression may experience loss of energy, indecisiveness, restlessness, variation in appetite, variation in sleep, reduction in ability to concentrate, feeling of being non worthy, feeling of hopelessness, judging oneself guilty and going to an extent of considering self-harm and even suicide. [1] Different categories of anxiety disorders such as major depressive disorder (MDD), social anxiety disorder (SAD), generalized anxiety disorder (GAD), obsessive compulsive disorder (OCD), post-traumatic stress disorder (PTSD) have characteristic symptoms and cognitions. There exists common co-existence of depression with all of the above categories of disorders. All above disorders respond to psychological treatments and drugs such as selective serotonin reuptake inhibitors (SSRIs), benzodiazepines and other sedative like compounds. [2] Selective serotonin reuptake inhibitors or serotonergic antidepressants are the class of drugs that are typically used as first line antidepressant treatment. Introduced more than a decade ago in the primary care setting, the exact mechanism of action for these drugs is still unknown, though the entire class is presumed to be functioning with a similar mechanism. The introduction of SSRIs into the antidepressive treatment area simplified the treatment options for depression manifold, since they have a broader therapeutic range. They also show lesser side effects, and do not have related complications such as urinary retention and slower cardiac conduction. Thus, patients undergoing SSRI treatment seldom need constant therapeutic dose management. [3]

Mechanism of Action
Though the exact mechanism of selective serotonin reuptake inhibitors is unknown, they are thought to increase the extracellular level of serotonin by reducing its reabsorption into a presynaptic cell. They thus increase the serotonin levels in the synaptic cleft that can now bind to the postsynaptic receptor. The selectivity for monoamine oxidase (MAO) transporters varies between SSRIs, with them having weak affinity for dopamine and norepinephrine transporters.

Onset of Action
Conventional wisdom suggested that treatment with SSRIs needs to be continued for at least 2 to 4 weeks for visible therapeutic effects. Recent studies concluded that treatment is associated with symptomatic improvement in depression by the end of the 1 st week of use. [5] Figure 1 shows the oral bioavailability of SSRIs. The absorption of SSRIs is usually good, with peak plasma concentrations observed after about four to six hours of oral administration. The absolute bioavailability of escitalopram is about 100%, whereas that of the other molecules is comparatively lesser due to the fact that they undergo substantial first pass metabolism. The apparent oral clearance values after single dose vary from 26 L/h for escitalopram to 167 L/h for paroxetine. Despite of repeated studies, no reliable evidence exists for establishing a relationship between the clinical efficacy and the plasma concentrations of any of the SSRIs. [6]

Duration of Action
Recently, an analysis of placebo-controlled trials of SSRIs showed that the therapeutic response of the drugs is highest in the first week. The benefits of the treatment gradually decline over the successive weeks of administration. 1/3 rd of the total therapeutic effect at six weeks was apparent by the 1 st week of treatment. Being a placebo controlled trial, it was apparent that the improvement was unlikely to be occurring due to any placebo effect. [7] Figure 1 shows the various uses of the SSRIs. Depending on the SSRI molecule, they can be used to treat a number of disorders such as major depressive disorder (MDD), social anxiety disorder (SAD), generalized anxiety disorder (GAD), obsessive compulsive disorder (OCD), post-traumatic stress disorder (PTSD) and for the treatment of certain phobias. [8] Figure 1 shows the various side effects, specific to each of the SSRIs. Gastrointestinal (GIT) disturbances are the most frequent side effect of SSRI use. During phase IV clinical trials it was established that fluvoxamine has the highest reports of GIT disturbances as a side effect, while fluoxetine and sertraline are associated with anxiety, insomnia and agitation. Based on the tolerability, we have:

Side Effects and Tolerability
Escitalopram > fluoxetine > sertraline > paroxetine > fluvoxamine Paroxetine and fluvoxamine were also reported to have the highest amount of side effects, and thus had the highest discontinuation rates as well. The most troubling adverse effects during the course of long-term SSRI therapy were reported to be weight gain, sexual dysfunction, and sleep disturbance. [9]

Gender
There exists a genuine gender difference in depressive disorders having its roots in adverse childhood or adolescence experiences along with the coping strength of the individual. But whether this has any role in the prescription of SSRIs is a matter of investigation. [10]

Special Groups
Patients in the geriatric age group are usually administered many medications on a daily basis. Due to aging, their body is less efficient at elimination of these drugs. It also has increased sensitivity towards the pharmacotherapeutic side effects and the adverse effects that may occur due to drugdrug interactions. Since they co-administer many drugs at a time, the chances of drug-drug interactions to occur increases manifold. [11] Children and adolescents have a delicate system, which is yet developing. Thus, chronic administration of drugs or coadministration of drugs may have extreme or unforeseen adverse reactions to the body. Thus, for both these age groups, it is essential to carefully monitor the drug combinations being administered. If required, therapeutic drug monitoring should be employed. Furthermore, in both these cases, only specialists who are well trained in geriatric, pediatric and adolescent psychiatry should be prescribing SSRIs. [12]

Current Market Scenario
According to the Drugs and Cosmetics Act, 1940, antidepressants are classified as Schedule X drugs. For this reason, they cannot be advertised or marketed to the end consumers in any way, since they can be procured only through a prescription of a registered medical practitioner. Detailing about antidepressants to doctors and psychiatrists is a tough business. The detailing process cannot simply rely on characteristics such as brand value. Unless a new and improved molecule is introduced into the market by any organization, psychiatrists are less likely to switch brands having the same SSRI molecule. But sadly, the amount of resources being invested into R&D of SSRIs is constantly declining, and thus there have not been any new SSRI molecules introduced into the market since 2002 (escitalopram). [13]

Generic Competition
Since 2001, most of the major SSRI molecules have been going off patent. Prozac (fluoxetine) was the first to lose its patent in the year 2001, followed by Paxil (paroxetine) in 2003, Celexa (citalopram) in 2004 and finally Zoloft (sertraline) in 2006. The parent companies of Paxil and Prozac came out with modified versions of the molecule in order to extend the term of their patents under the Patent Term Restoration Act, but by the year 2012, generic version of all the SSRI molecules had reached the market. The flood of generics in the market made it tougher for the branded generics to survive. Thus, it became essential for these companies to employ better detailing skills than the generic versions, to ensure that psychiatrists stayed loyal to their brands. [14]

Cost of Drugs
The cost of the drug is an important factor during prescription of antidepressant drugs. Other than fluoxetine and escitalopram, none of the other SSRI molecules have any price cap attached to them. Even in the case of fluoxetine and escitalopram, fixed dose combinations do not come under the purview of the National List Of Essential Medicines, only those formulations containing only the aforementioned APIs do. Since manufacturers are free to market their brands at any price, the cost of the drug for the consumer becomes one of the major factors in increasing the saliency of a particular brand in the market.

Objectives
The objective of the study was to capture the biases of practicing psychiatrist in the city of Mumbai, India with respect to the prescription of SSRIs considering pharmacokinetic, applicative, demographic, and commercial aspects.

Methodology
To meet the objectives a primary data collection was planned to cover maximum possible practicing psychiatrist in Mumbai, India. A structured questionnaire employing 5 point Likert agreement scale was used and responses were collected by visiting the doctors in their practicing places. A list of 186 psychiatrists practising in Mumbai was obtained from the database of online app 'Practo' (https://www.practo.com) which gives the contact details of the required speciality of the doctors and is freely accessible to all for booking appointments for doctor consultation. Out of these 60 were selected randomly as target respondents to be contacted using the free random number generator available from Google. Out of these finally 49 psychiatrists agreed to meet and gave their responses in span of 3 months from 14 th July 2016 to 14 th October 2016.
The collected data is analyzed using IBM SPSS version 19 using T test, One way ANOVA and Ranking tools.
Generalized Significance level used for the study: 5%

Pharmacokinetic Properties
Refer to figure 1. The experience / perceptions / opinions of psychiatrists on different characteristics of drugs under study were significant. Figure 2 shows the % score given by psychiatrists to drugs under study, the clustered bar charts and one way ANOVA for the particular pharmacokinetic properties. In One way ANOVA within the group, significant mean differences were observed in only two pharmacokinetic characteristics of the drugs: 'Low contra indications' and 'Long duration of action'.

Uses of SSRIs
Refer to figure 2. For each type of disorder under study, the preferences for all drugs were significant. Figure shows the % preference score for the use of the particular drug by psychiatrists, the clustered bar charts and the one way ANOVA for the drugs preferred for the particular disorder type. Significant mean differences were observed in preferences for the 5 drugs when variances within the group were tested using One way ANOVA.

Side Effects
Refer to figure 3. The experience/opinion of psychiatrists on each type of side effect under study arising from use of the 5 drugs was significant. Figure shows the % score given by psychiatrists to drugs under study, the clustered bar charts and one way ANOVA for the various side effects under consideration. Except for sexual dysfunction, significant differences were observed in experience/opinion about occurrence of side effects.

Patient's Age
Refer to figure 4. Significant preferences for all drug molecules for the classes were observed. Figure shows the % preference score, the clustered bar charts and one way ANOVA for the two age classes under consideration. Significant mean differences were observed in preferences for the 5 drugs in both the age classes when variances within the group were tested using one-way ANOVA.

Gender of Patients
Refer to figure 5. Preferences for all drug molecules were significant for both male and female patients. Figure 6 shows the psychiatrist's preference scores (%), the clustered bar charts and one way ANOVA of the drugs under study for male and female patients respectively. One way ANOVA for female patients turned out to be non-significant whereas for male patients it was found to be significant.

Commercial Factors
The overall ranking of the 4 marketing related factors with respect to the importance given by psychiatrists while prescribing Applicative, Demographic, and Commercial Aspects SSRI was derived from the individual psychiatrists' ranking responses. The factors considered were availability of the drug, cost of the drug, and brand value of the drug and the interpersonal skills of the medical representative. Refer Figure 6 for the bar chart.

Pharmacokinetics
Psychiatrists experience/opinion wrt the contra indications, efficacy, onset of action, duration of action and bioavailability of the 5 drug molecule brands under study are significant.
Refer to figure 1, for performance of the drugs w.r.t. contra indications. Use of Escitalopram witnesses least contra indications whereas use of Fluvoxamine risks maximum contra indications.
Considering duration of action of the drugs, Sertraline has the highest duration of action whereas Fluoxetine, Paroxetine and Fluvoxamine display least duration of action.
With respect to efficacy, bioavailability and onset of action, there are no significant differences within the 5 drugs under study.

Uses
Refer to figure 2. For the treatment of seasonal affective disorder (SAD) Fluoxetine along with Paroxetine are the most preferred whereas Fluvoxamine is the least preferred drug.
For the treatment of generalized anxiety disorder (GAD) Sertraline is the most preferred whereas Fluvoxamine is the least preferred drug molecule brand.
For the treatment of major depressive disorder (MDD) Paroxetine is the most preferred whereas Fluvoxamine is the least preferred drug molecule brand.
For the treatment of obsessive compulsive disorder (OCD) Escitalopram is the most preferred whereas Paroxetine is the least preferred drug molecule brand.
For the treatment of Post-Traumatic Stress disorder (PTSD) Fluoxetine along with Sertraline is the most preferred whereas Fluvoxamine is the least preferred drug molecule brand.

Side Effects
Refer to figure 3. Paroxetine has the highest risk of patient experiencing the side effect of somnolence where as it is least for Fluoxetine.
Escitalopram has the highest risk of patient experiencing the side effect of anxiety where as it is least for Fluoxetine.
Sertraline and Escitalopram have the highest risk of patient experiencing the side effect of tremors where as it is least for Paroxetine and Fluvoxamine.
Fluoxetine has the highest risk of patient experiencing the side effect of anorexia where as it is least for drugs Sertraline and Escitalopram.
With reference to the side effect of sexual dysfunction, there are no significant differences amongst the drugs.

Patient's Age
For treatment of geriatric patients all the 5 antidepressant drug molecules under study were used by psychiatrists. Refer to figure 5 for % preference scores. Sertraline was the most preferred, whereas paroxetine was the least preferred drug. Also, psychiatrists indicated moderate but considerable preference for the drug fluvoxamine. Psychiatrists displayed high preference with negligible difference between drugs sertraline and escitalopram, although they displayed low preference with negligible difference between drugs fluoxetine and paroxetine.
For treatment of adolescent patients all the 5 antidepressant drug molecule drugs under study were used by psychiatrists. Refer to figure 4 for the % preference scores. Paroxetine was the most preferred drug whereas fluoxetine was the least preferred drug. Drug pairs with insignificant difference in preference of psychiatrists were: sertraline and escitalopram, sertraline and fluvoxamine and escitalopram and paroxetine.

Patient's Gender
Psychiatrists used all 5 drug molecules under study for treatment of male patients. Refer to figure 5. Sertraline, Escitalopram and Fluoxetine were equally preferred. Paroxetine was the least preferred but was not far behind on the preference scores. Drug pairs with significant differences were: Paroxetine with each one of Sertraline, Escitalopram and Fluoxetine.
Psychiatrists used all 5 drug molecules under study for the treatment of female patients. Refer to figure 5. All the 5 drug molecules were almost frequently preferred with no significant differences amongst them.

Ranking of Commercial Factors
Referring to figure 6, amongst the four commercial factors, ease of availability of drug in the market was considered as the most important factor, followed closely by the cost of drug. Brand value and interpersonal skills of the MR were rated to be relatively of low importance.

Difference Between Literature and
Psychiatrist Perceptions/ Practice geriatric). 2. Gender of the patient. 3. Uses of SSRI for a particular indication. It also helps ranking the commercial aspects of SSRIs. For example, it is perceived that use of Escitalopram has the highest chance of showing anxiety as a side effect, which is not the case based on the literature. Due to this incorrect perception, a large market of patients suffering from both anxiety and depression are not reached. Firms could thus realign their strategies to better suit the market needs.

Conclusion
There exists a gap between the theoretical evidence and the practical observations about the pharmacokinetics, uses and side effects of the 5 SSRIs under study. For example, sertraline, a drug proven to be useful in the treatment of depression, has an incorrect bias of causing anxiety as a side effect. This results in psychiatrists not prescribing an effective drug due to a bias with no theoretical basis, thus resulting in poorer treatment outcomes for the patient. For healthcare organizations, it means that they are losing out on almost half the potential patient population. Therefore, it would be useful for them to undertake communication campaigns that revolved around thwarting such biases, thus resulting in better treatment choices for patients and improved health outcomes.

Limitations of the Study
The study was conducted with the help of 49 psychiatrists, of 186 psychiatrists practicing in Mumbai region. Due to constraint of resources psychiatrists practicing in other metros and Tier 2 & 3 cities could not be included in the study. Psychiatrist perceptions and practice may differ significantly based on the location of their practice.