PHARMACOGENETICS AND THE MENTAL HEALTH CRISIS
Amid one of the most significant health crises of this century, we are witnessing an “echo pandemic” of escalating mental health issues sweeping through the Canadian population. A recent survey of more than 1800 Canadians conducted by Mental Health Research Canada revealed that over 60% of Canadians are currently experiencing anxiety, with the number reporting high levels of anxiety quadrupling and the number reporting high levels of depression having more than doubled since the beginning of the Covid-19 outbreak.1 Furthermore, experts across the mental healthcare community are predicting that the rate and severity of mental health issues will continue rising as social isolation measures persist, and warn of the high likelihood of concomitant increases in suicide rates due to economic stress and isolation.
The profound mental health related fallout of the pandemic is not unexpected. Large-scale disasters are almost always accompanied by increases in mental and behavioral disorders, with mental health issues surging after such crises as the 9/11 attacks and the SARS-CoV-1 epidemic.2,3 Since the Covid-19 pandemic began, calls to crisis centers and utilization of mental health services through apps and virtual means has increased exponentially, with companies offering these services struggling to meet the explosion in demand 4,5.
As this pandemic continues, Canadians are likely to be facing social, financial, and mental health-related consequences of COVID-19 for many months to come. These struggles will almost certainly have significant impact on our population’s productivity and ability to return to work, creating a sizeable and potentially persistent risk to the economy.
As the burden of mental health issues continues to grow, programs ensuring that people receive appropriate interventions and treatments as expeditiously as possible are urgently needed. Research continues to demonstrate that a combination of medication and psychotherapy is frequently key for recovery, and, accordingly, the Canadian government has responded to the current mental health crisis by investing in the “Wellness Together Campaign” (a virtual mental health support platform launched in April). To accelerate recovery and minimize the severe negative impacts of this crisis on mental health, these investments in non-pharmaceutical interventions should be leveraged by concerted efforts to optimize the medication component of treatment. This paper describes some of the challenges associated with drug treatments for mental health issues and the potential role for pharmacogenetics in addressing these challenges so as to ensure Canadians in need are offered timely access to treatments that are effective, safe, and well-tolerated.
The Mental Health Crisis and Drug Treatment
The mental health impact of the COVID 19 outbreak is widely recognized, with the Centers for Disease Control acknowledging the associated development and/or exacerbation of prior mental health conditions.6 People with chronic diseases and existing mental health conditions are at particularly high risk, especially front line healthcare workers and first responders .
Depression and anxiety are chronic psychiatric disorders with high prevalence and low treatment response rates, imposing significant burden to patients, health care providers, and society. Under “normal” (non-pandemic) circumstances, up to 25% of the population suffer from some type of mental health issue and up to one half of the population will experience some form of mental illness in their lifetime 7. Depression is associated with significantly reduced quality of life and is an independent risk factor for many chronic illnesses and for increased risk of all-cause mortality, leading to a 7–11 year reduction in life expectancy. 8-12 Increasing rates of depression and anxiety coupled with the availability of new medications have contributed to dramatic increases in antidepressant use in the last 20 years, ranking antidepressants as the third most commonly prescribed drugs among adults.13 Depression is also associated with a 50% – 75% increase in health care utilization 14. According to benefits consulting firm Willis Towers Watson, people with mental health disorders make six times more emergency room visits compared to the general population, and submit two to four times as many medical claims.15 The overall disease burden of mental illness has been estimated as 1.5 times higher than all cancers combined, and more than 7 times that of all infectious diseases. 16
An important consideration during the COVID 19 pandemic is that depression and stress may also increase the risk of viral infections, weaken the immune response to vaccines, increase inflammatory response, and make environmental toxins such as pesticides and air pollutants harder to tolerate. 17
The Labyrinth of Drug Treatment for Mental Health Conditions
Drug treatment for mental health issues is rarely straightforward; one size does NOT fit all, with individual varying significantly in their drug responses. With over 35 approved antidepressant/ antianxiety drugs on the market and multiple dosing possibilities, prescribers typically rely on the “trial and error” method to find a treatment that is well-tolerated and effective. This approach, however, is associated with treatment failure in as many as two-thirds of these patients due to lack of efficacy and/or unacceptable side effects.18, 19 Another third do not respond to the second treatment, and only 15% of those who progress to a third treatment will respond. 18, 19 With each treatment failure, the probability of remission diminishes and likelihood of relapse increases. Moreover, those who experience side effects with the first treatment(s) are less likely to achieve remission (almost 90% of those experiencing serious adverse effects are unable to achieve remission). Ultimately, remission rates are disappointingly low at 28 - 38%.20,21
Prescribing the correct medication is especially difficult when treating a mental illness because the full clinical effects of commonly used medications may not be achieved for several months. Further, discontinuing one of these medications usually requires weaning off the drug over a period of time while beginning the next drug, a process that can be associated with overlapping side effects and lack of clarity as to whether the new drug is working. In searching for an effective anti-depressant, patients on average need to try 2- 6 different medications and may therefore experience a very long period of ineffective treatment. Psychiatry medications often interact with each other as well as other medications, making it difficult to assess which one is working and which are causing side effects. For these reasons, it is not uncommon for patients to become discouraged and show poor adherence or discontinue medications altogether, leading to ongoing disability. Upon drug discontinuation, approximately 20% of patients will suffer withdrawal symptoms or “antidepressant discontinuation syndrome”, which is associated with significant discomfort, work absenteeism and other psychosocial problems.22
Recovery delays and absenteeism due to mental illness are also a concern for employers and add to the economic burden already imposed by significant drug costs and wastage. Epidemiological studies point to a consistent association between depression and loss of productivity, with depressed individuals being five times more likely to miss work due to illness 23. Poor mental health is also the leading cause of disability in Canada and depressed persons are nearly five times more likely to be on disability leave 24. Not surprisingly, depression is associated with a 50% – 75% increase in health care utilization, 25 with the costs of mental illness in Canada estimated at over $50 billion per year consequent to health care expenses, lost productivity, and reductions in health-related quality of life. 26,27 As employers work to find solutions that support increased productivity and decreased disability rates due to mental health issues, the emerging science of pharmacogenetics provides one avenue for beginning to address these challenges.
Is Pharmacogenetic Testing a Critical Part of the Solution?
The significant contribution of genetic factors to the differences in individual responses to specific medications is now well established. Genetic studies have shown that over 98% of the population carry gene variants that can cause differential responses to drugs and that the use of such information to inform the choice of medication prescribed can improve clinical outcome. 28,29,30, 31. Genetics accounts for between 20 – 95% of individual variability in drug response in general, 24,25 but for 42 - 50% of variability in antidepressant drug response rates 26,27.
Pharmacogenetics is the study of the specific genetic variants which influence an individual’s ability to process or metabolize certain medications. Pharmacogenetic tests are genetic tests that predict how an individual will respond to specific medications based on the composite of gene variants they carry/have inherited. These tests provide a valuable clinical tool that have supported improved patient outcomes in real-world settings and are strongly positioned to help reduce the medical and economic burden of psychiatric disorders. Many studies have demonstrated increased treatment efficacy, lower health care utilization costs, and increased adherence rates with pharmacogenetic-guided treatment, and decreased adverse drug events, when depression treatment is guided by pharmacogenetic testing. 17,30-34,40-43
Therapeutic drug monitoring” of drug plasma levels has long been used in psychiatry to assess response and guide treatment adjustments, but can only be performed after the drug reaches steady state in the bloodstream and the patient has already been exposed to potential side effects while awaiting a response. In contrast, pharmacogenetic testing can be done before a drug is initiated and used shortly thereafter to guide treatment. In recognition of the significant role for genetic variation in individual response to medications, the FDA has now labelled more than 280 drugs with pharmacogenetic guidance. While the evidence supporting pharmacogenetic recommendations and the number of drugs including such recommendations in their labels continue to increase, the rate of introduction of new high impact drugs in psychiatry has been relatively slow in recent years. In this context, pharmacogenetically-enabled treatment personalization is particularly important, enabling the best use of currently available medications.
Five Benefits of Pharmacogenetic Testing in Mental Health
1) Patients feel better sooner.
Multiple studies have demonstrated that pharmacogenetic testing allows clinicians to personalize treatment so as to increase the chances of response to the first drug tried, optimize symptom improvement, and increase remission rates in mental health conditions. Medication management guided by pharmacogenetic testing insights has been shown to achieve up to double the response rates of “standard care” and drive up to four-fold improvement in symptoms, and up to 1.7 times symptom remission rates in patients diagnosed with depression 34,35.
2) Potential for harmful side-effects is reduced
Drug related adverse events are the fourth largest cause of death in Canada, leading to about one third of hospitalizations, 20% of in-hospital injuries/deaths, and significant increases in length of disability/hospital stay.36 About 98% of the population carry gene variants associated with increased risk for drug related adverse events (AEs), which in turn contributes very significantly to health care costs (with 69% higher healthcare costs and 67% more medical visits 14). Pharmacogenetic testing has been shown to cut AE rates by about 60% and reduce hospitalizations by more than 30% overall 38. A 2018 study of over 3,000 patients with mood and anxiety disorders by Perlis and colleagues showed that individuals who underwent pharmacogenetic testing experienced 40% fewer all-cause emergency room visits and 58% fewer all-cause hospitalizations 39.
3) Willingness to take medications and adherence
It is estimated that some 50% of patients do not use medications as prescribed, and one third of prescriptions are never used. Fear of side effects and/or lack of perceived effect (often driven by previous disappointing experience with medications) are among the main factors underlying drug non adherence 40. Poor adherence can be more pronounced among patients with mental health illness, at least in part due to stigma associated with taking medication for such issues. These problems may be alleviated at least in part by providing patients with data predicting a medicine will be a “good fit”. In one study, for example, medication adherence was improved by 17% by citing data showing genetic testing might save an average of USD$1036 per patient per year in total medication costs 14. Another study exploring the impact of pharmacogenetic testing demonstrated a 40% increase in medication adherence and 30% increase in treatment persistence among those tested33, and in one other study, over 70% of study participants subjected to pharmacogenetic testing said this testing would make them “much more likely” to adhere to treatment32.
4) Health care costs decrease:
Health care costs decrease when patients receive an effective and tolerable medication at the time of first treatment; such success results in less failed drug trials and fewer health care professional visits and /or hospitalizations. Providing pharmacogenetic information in advance of treatment allows patients to forgo months of trial-and-error and can have a significant impact on drug wastage/costs, health care utilization, and disability.
5) Patients may be able to return to work more quickly:
Depression is the leading cause of disability, with depressed individuals being five times more likely to miss work due to illness7and 4.78 times more likely to be on disability. 45,46 A retrospective chart review by Winner et al demonstrated that patients who were using medications that should have been avoided based on their genetic profiles had a 69% increase in total healthcare visits, four times the number of disability claims, and three - fold increase in medical absences.
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