Non-Approved Uses of Selected Psychotropic Drugs and Pharmacy Students' Understanding

A survey carried out among first year pharmacy students on their knowledge and opinions regarding the uses of non-FDA approved use of selected psychotropic drugs, namely duloxetine, escitalopram and quetiapine, revealed mixed results. Based on a set of five knowledge-based questions, an average of 39.5% of the survey participants scored correct answers on duloxetine. For escitalopram, the average correct response rate was 47.2%, and 32.2% for quetiapine. The highest correct response rate on a single question was 89.5% for duloxetine, 87.2% on two of the questions for escitalopram, and 77.1% for quetiapine. Comparison of each of the highest correct response to each of the responses within each drug showed significant differences ( p < 0.05). Conflicting opinions of survey participants were discerned regarding the off-label uses of duloxetine, with 65.8% expressing it should not be approved for urinary incontinence, and yet they are evenly divided (50% each) in their opinion on the use of non-approved drugs in general. More than 50% of the respondents held the opinion that escitalopram should not be used off-label for social phobia, while less than 41% were aware of its use for such non-approved indication. About 60% of respondents within the quetiapine survey group thought the drug should not be used for generalized anxiety disorder, which is in concordance with


Introduction
In the realm of mental health treatment, the medications duloxetine, escitalopram, and quetiapine are a few of the most effective drugs in mental health treatment.The first two are primarily used to treat depression, while quetiapine is used for schizophrenia and bipolar disorders.However, beyond their officially approved uses, these drugs sometimes find utility in off-label applications.Pharmacists have the unique responsibility to review the off-label uses of these medications, and thus weighing the evidence supporting their efficacy, the potential risks they carry, to reach informed decision-making.Duloxetine is an FDA-approved medication widely prescribed for major depressive disorder, generalized anxiety disorder, fibromyalgia, and chronic pain.In addition to these recognized uses, the drug has several additional benefits and used in off-label indications, 13 such as for premenstrual dysphoric disorder (PMDD) and stress urinary incontinence.As an extension of its mood-related applications, duloxetine has been studied for its potential to alleviate the emotional and physical symptoms associated with PMDD [1].This more severe form of premenstrual syndrome may respond to duloxetine's dual impact on serotonin and norepinephrine levels, targeting both mood and pain.Mazza, and colleagues explored the potential effectiveness of duloxetine in treating PMDD, a complex and challenging clinical syndrome [2].The research involved 55 women with PMDD who received a daily dosage of 60 mg of duloxetine over two menstrual cycles.Assessment of responses took place during the first and second treatment cycles.Various outcome measures, including visual analog scales and standardized rating scales for depression and anxiety, were used to evaluate the results.Out of fifty patients who completed the trial, all experienced significant improvement in depression and anxiety symptoms.Notably, 78% of patients showed a favorable response, defined as a 50% reduction in daily symptom scores.The positive effects of the treatment were most pronounced during the initial active cycle of menstruation.Despite limitations, such as the absence of placebo control and an open-label design, the consistent and robust results suggest the efficacy and tolerability of duloxetine 60 mg/day in alleviating PMDD symptoms.Beyond its primary applications, duloxetine's modulation of neurotransmitters has piqued interest in treating stress urinary incontinence.The potential reimagining of a medication for a distinct condition exemplifies the dynamic nature of medical research and practice.Studies have presented mixed findings, shedding light on both its potential and limitations in this context.Dmochowski et al conducted a study aimed to assess the efficacy and safety of duloxetine in the treatment of stress urinary incontinence in women [3].The study involved North American women with stress urinary incontinence who were randomly assigned to receive either duloxetine or placebo.The primary outcome was the change in the number of incontinence episodes.The study found that women who received duloxetine experienced a significant reduction in the number of stress urinary incontinence episodes compared to those who received placebo.Duloxetine was associated with improvements in incontinence severity and quality of life.The authors concluded that the study supports the efficacy of duloxetine in reducing stress urinary incontinence episodes and improving the quality of life in women with this condition.Escitalopram is an FDA-approved selective serotonin reuptake inhibitor (SSRI) predominantly employed for managing depression and anxiety disorders.However, its versatility extends to off-label possibilities.Escitalopram's effects on serotonin levels have led to investigations into its potential for managing obsessive compulsive disorder (OCD) symptoms.While not FDAapproved for this purpose, the shared mechanism of action with recognized OCD treatments makes it a candidate worth considering in certain cases.A study conducted by Pallanti and his colleagues aimed to assess the efficacy and tolerability of citalopram in the treatment of patients with treatment-resistant OCD.Patients with treatment-resistant OCD were treated with citalopram for 52 weeks in an open-label trial [4].The primary outcome measures included changes in the Y-BOCS score and the Clinical Global Impression-Severity (CGI-S) scale.The study found that citalopram led to significant reductions in OCD symptom severity, as measured by the Y-BOCS and CGI-S scores, over the 52-week treatment period.The treatment was generally well tolerated, and improvements were sustained over time.Escitalopram's unique anxiolytic properties have positioned it as an off-label option for panic disorder, especially for individuals who may not respond optimally to other medications.Its role in reducing both anxiety and panic-related symptoms adds to its therapeutic potential.Furukawa et al conducted a Cochrane review aimed to assess the combined use of psychotherapy and escitalopram, in the treatment of panic disorder with or without agoraphobia [5].The review included randomized controlled trials that compared the combined therapy of psychotherapy and antidepressants with either treatment alone or placebo in patients with panic disorder.The outcomes assessed included the response rate and reduction in panic symptoms.The review found that the combined therapy of psychotherapy and citalopram was more effective in reducing panic symptoms and improving response rates compared to treatment with either modality alone or placebo.Quetiapine is an FDA-approved atypical antipsychotic, primarily prescribed for schizophrenia, bipolar disorder, and major depressive disorder.However, it has also shown efficacy in off-label applications.Its sedative qualities have led to its off-label utilization in managing insomnia, particularly in cases where conventional sleep aids have fallen short.While concerns exist regarding potential side effects, studies have shown that quetiapine may indeed improve sleep quality in certain populations.This literature review conducted by Sanger et al aimed to examine the evidence for the use of quetiapine in the treatment of insomnia [6].The review assessed relevant studies that investigated the use of quetiapine for insomnia treatment.It examined both the effectiveness and potential adverse effects of quetiapine.The results found that quetiapine was associated with 14 improvements in sleep parameters, including increased total sleep time and reduced wake after sleep onset.However, quetiapine was also associated with potential adverse effects, such as daytime sedation and weight gain.The authors suggested that quetiapine may have beneficial effects on improving sleep in individuals with insomnia.However, the potential adverse effects associated with quetiapine should be carefully considered in treatment decisions.The exploration of quetiapine's role in Generalized Anxiety Disorder (GAD) underscores the complexity of neurotransmitter systems in mental health.While offlabel use for anxiety disorders lacks FDA approval, its consideration demonstrates the medical community's pursuit of innovative solutions.The study conducted by Simon et al aimed to explore the efficacy of quetiapine as an augmentation strategy to paroxetine-controlled release (CR) in the treatment of refractory GAD [7].The study involved patients with refractory GAD who were treated with quetiapine in addition to paroxetine CR or placebo.The primary outcome measures were changes in anxiety symptom severity, assessed using the Hamilton Anxiety Rating Scale (HAM-A), and response rates.The study found that the quetiapine augmentation group showed greater reductions in anxiety symptom severity compared to the placebo augmentation group.Response rates were significantly higher in the quetiapine augmentation group.However, quetiapine was associated with a greater incidence of adverse events.The study suggests that quetiapine augmentation to paroxetine CR may be effective in reducing anxiety symptoms in patients with refractory GAD.However, the higher incidence of adverse events associated with quetiapine should be considered in the treatment decision-making process.Overall, the exploration of off-label uses for duloxetine, escitalopram, and quetiapine illustrates the dynamic nature of medical practice.While these medications demonstrate a potential beyond their approved indications, prudence, and careful consideration are crucial when contemplating off-label use.By embracing the principles of evidence-based medicine, patient safety, and holistic well-being, healthcare professionals navigate the complex landscape of mental health treatment.
In previous studies, we have surveyed the knowledge levels and opinions of Howard University (HU) first year pharmacy students on various drugs, such as cimetidine [8], metformin [9] and two non-steroidal antiinflammatory drugs celecoxib and indomethacin [10].In the current survey, we report results on the knowledge levels and opinions of these students on duloxetine, escitalopram, and quetiapine.

Methods
The survey was conducted among Howard University College of Pharmacy first-year professional students.
The questionnaires, comprising of five statements/questions, were formulated by one student for each drug.For each medication, there were five knowledge-based and five opinion-related statements/questions.The survey enrolled 38 student participants in the duloxetine group, 39 in the escitalopram group and 37 in the quetiapine group.The questionnaires were administered during a drug information course given by one of us, BH.For both the knowledge and opinion-based questions, a 4-point Likert scale (1=strongly agree; 2=agree; 3 = disagree; 4=strongly disagree) was utilized to score responses.The responses were then aggregated as 'agree" and "disagree," respectively.A mean Likert score was computed by dividing the respective scores by the total number of respondents.A 2-tailed Fisher test was used to compare knowledge-based scores within each group.A p value of <0.05 was considered statistically significant.

Statement of Informed Consent
This survey was conducted as part of HU College of Pharmacy drug information course.It did not require informed consent of survey participants.The survey was approved by Howard University IRB as part of a Drug Information course given by one of us (BH).

Results
The average correct response rate for knowledgebased questions on duloxetine was 39.5%, with the correct highest rate (89.5%) being for respondents who agreed that urinary incontinence is very common among childbearing women.The second highest correct response rate (65.8%) was obtained for a question dealing with whether duloxetine is considered a narrow therapeutic index medication.The lowest correct response of 10.8% was registered on the adverse effects of duloxetine (Table 1).The opinions of 65.8% of the survey participants expressed agreement on the use duloxetine outside of FDA approved indications and 57.9% stated that they believe there is enough evidence for its use in treating stress-related urinary incontinence in women.Respondents were split (50% each) on the general appropriateness of the use of non-approved drugs (Table 2).The total correct response rate for knowledge-based questions on escitalopram was 47.2%.The highest correct response rate was 87.2%, with the lowest being 10.3% (Table 3).Sixteen respondents (41%) believed that they knew enough about the use of escitalopram for social phobia.46.2% held an opinion that social phobia has many approved treatment options, and that they did not believe it should be treated by a nonapproved escitalopram (Table 4).About 77% of the quetiapine group respondents had the correct knowledge that military or harsh working environments, troubled childhood and traumatic events cause generalized anxiety disorders (GAD).Only 15 8.1% know that the common dosage form of quetiapine is tablet.Ten respondents (27%) were aware that this drug is used to treat schizophrenia (Table 5).In the opinion panel of the questionnaire, 22 students (61.1%) thought that are effective drugs to treat GAD and that quetiapine should not be promoted for use for such indications.Five of the respondents (13.9%) supported the use of quetiapine if there is adequate evidence in the literature.About 36% agree that it should not be promoted for non-approved indications (Table 6). 1 Abbreviations: SA=strongly agree; A=agree; DA=disagree; SDA=strongly disagree; LKS=Likert Score; S.D.= standard deviation. 2The average correct response rate is 39.5%. 1 Abbreviations: SA=strongly agree; A=agree; DA=disagree; SDA=strongly disagree; LKS=Likert Score; S.D.= standard deviation. 2The average correct response rate is 32.2%.Comparisons of individual knowledge-based questions are given in Tables 7-9.Survey participants scored high on one or two knowledge-based questions, while they failed in most of them.The paired scores are compared for significance in each category.As shown in Tables 7  to 9, the highest knowledge-based scores for each category were significantly higher relative to the lower scores.

Discussion
Comparison of each of the highest correct response with the responses within each drug showed significant differences (p< 0.05) (Tables 7,8,9).In the duloxetine group, the correct responses (65.5% and 89.5%) were significantly higher than the other correct response rates (Table 7).It is noteworthy that only 4 respondents (10.8%) were aware of the common adverse effects of duloxetine.This knowledge level contributed significantly to the average low correct response rate of 39.5% on duloxetine.Also, only seven respondents (18.4%) were aware that it is approved for the treatment of major depressive disorders.Conflicting opinions of survey participants were noted regarding the off-label uses of duloxetine, with 25 (65.8%)expressing disapproval for its use in urinary incontinence, while they were evenly divided (50% each) in their opinion on the use of non-approved drugs in general.
In the escitalopram group, 34 of the respondents (87.2%) correctly answered questions on the maximum daily dose, and the use of antidepressants to treat social phobia.These correct response rates were significantly higher than the other response rates within this group (Table 8).In their opinion on the treatment of social phobia, more than 50% of the respondents expressed that escitalopram should not be used off-label for this condition, while less than 41% were aware of its use for such non-approved indication.
The average correct response rate for escitalopram (47.2%) (Table 1) was higher than the corresponding rates for duloxetine (39.5%) (Table 3) and quetiapine (32.2%) (Table 5).About 77.1% of respondents within the Quetiapine had the correct knowledge about the causes of generalized anxiety disorders (Table 5).This response rate was significantly higher than those of the others in the group (Table 9).About 60% of respondents within the quetiapine survey group thought the drug should not be used for generalized anxiety disorder, which agreed with the low 36%-40% who believed it should be promoted for non-approved uses.

Conclusion
A survey among Howard University College of Pharmacy first-year professional students showed low knowledge levels on duloxetine, escitalopram, and quetiapine.The average score was 39.5% for duloxetine, 47.2% for escitalopram and 32.2% for quetiapine.Among the five knowledge-based questions, two of the questions scored relatively high at 89.5% and 65.8%, respectively.The students scored high at 87.2% each on two of the five questions.In the quetiapine group, students scored 77.1% on one question.Overall, the average score on each of the three drugs survey was low.

Limitations
The limitation of this study is the small sample size, with only 37 to 39 students participating in the survey.For this reason, the findings cannot be extrapolated to future incoming pharmacy students at HU, or other first-year pharmacy students in other institutions.