
==== Front
Indian J Psychiatry
Indian J Psychiatry
IJPsy
Indian J Psychiatry
Indian Journal of Psychiatry
0019-5545
1998-3794
Wolters Kluwer - Medknow India

IJPsy-66-660
10.4103/indianjpsychiatry.indianjpsychiatry_330_24
Viewpoint
Advocating for the inclusion of therapeutic drug monitoring in the national essential diagnostic list: Perspectives from psychiatrists
Parmar Arpit
Pal Arghya 1
Department of Psychiatry, All India Institute of Medical Sciences, Bhubaneswar, Odisha, India
1 Department of Psychiatry, All India Institute of Medical Sciences, Kalyani, West Bengal, India
Address for correspondence: Dr. Arghya Pal, Department of Psychiatry, All India Institute of Medical Sciences, Kalyani, West Bengal, India. E-mail: drarghyamb@gmail.com
7 2024
17 7 2024
66 7 660664
15 4 2024
27 6 2024
29 6 2024
Copyright: © 2024 Indian Journal of Psychiatry
2024
https://creativecommons.org/licenses/by-nc-sa/4.0/ This is an open access journal, and articles are distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as appropriate credit is given and the new creations are licensed under the identical terms.
India published its first edition of the National Essential Diagnostics List in 2019. The list depicts the list of diagnostic tests that can ensure affordable and quality healthcare delivery by removing barriers toward accessibility and reducing out-of-pocket expenditure. In 2024, the Indian Council of Medical Research has invited suggestions for revision of the list. Therapeutic drug monitoring (TDM) has been a promising modality and has been useful for a range of indications like monitoring medication adherence, diagnosing suboptimal treatment, detecting drug interactions, and guiding initiation or withdrawal of therapy. In this article, the authors make a case for inclusion of TDM for certain psychotropic drugs like lithium, sodium valproate, carbamazepine, and clozapine at the district hospital level. The authors have tried to justify the inclusion backed by recent evolving evidence.

National List of Essential Diagnostics
therapeutic drug monitoring
serum level
toxicity
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pmcINTRODUCTION

Diagnostics play an elementary role in the process of providing quality healthcare services to patients. It is essential that diagnostic measures remain accurate, reliable, and valid so that the rather complex task of diagnosing diseases is achieved at the earliest. Diagnostics, however, is an essential component of the expenditure incurred during the management of disorders. Thus, it is imperative to state that the appropriate use of diagnostics is essential to ensure the affordable delivery of healthcare services. Appropriate use of diagnostics can also play an important role in dealing with other important issues like treatment resistance and determining medication adherence.

The National List of Essential Medicines (NLEM) of India was published for the first time in 1996 and has been revised four times, the latest being in 2022.[1] However, a similar effort for diagnostics, which has been christened as the National Essential Diagnostics List (NEDL), was first published only in 2019.[2] This effort was a complement to the World Health Organization’s (WHO) Essential Diagnostics List (EDL), which is updated biannually, and the latest version, which was released in 2023.[3] An editorial on this topic highlighted the unavailability of essential diagnostic tests in various low- and middle-income countries and highlighted that the major reasons behind this were lack of trained human resource, inadequate education, poor infrastructure, and lack of quality standards.[4] The NEDL thus complements the commitment of the government in their attempt to achieve affordable and quality healthcare delivery by removing barriers toward accessibility and reducing out-of-pocket expenditure, as mentioned in the Sustainable Development Goal 3.8.

Recognizing the need for quality diagnostics at affordable prices and ensuring accessibility and equitable distribution, the Government of India initiated the Free Diagnostics Service Initiative in 2015 under the aegis of the National Health Mission. Subsequently, the WHO published the first edition of EDL in 2018. In the background of these developments, the NEDL of India was published in 2019. The NEDL was prepared keeping in mind the challenges and requirements expected according to the Indian context. The list was prepared with the guiding principle of building over the existing infrastructure and to be in sync with the ongoing national programs, like the Pradhan Mantri Jan Arogya Yojana. The endeavor also included the best practices from the NLEM while identifying the diagnostic tests. The tests were included in the EDL if they satisfied the following criteria. The tests must deal with conditions with high disease burden and public health relevance and enable the safe and rational use of drugs included in NLEM. In 2024, the Indian Council of Medical Research (ICMR) has also invited suggestions regarding changes to be made to the NEDL. The criteria proposed by the council to ascertain the suitability of the tests essentially remain the same as of NEDL 2018.

PREREQUISITES OF INCLUDING THERAPEUTIC DRUG MONITORING IN THE NATIONAL ESSENTIAL DRUG LIST

Therapeutic drug monitoring (TDM) refers to the practice of measuring the levels of a drug in body fluids, which, when interpreted with necessary caution, is likely to influence clinical decision-making. TDM is beneficial in the practice of personalized medicine because it helps to collate the theoretical knowledge of pharmacokinetics and pharmacodynamics of a drug with the practical challenges of prescribing a drug by ensuring its efficacy and safety. Though the initial advent of the TDM in the 1960s championed its use in the determination and early identification of adverse drug reactions (ADRs), the later studies identified its manifold implications in clinical practice like monitoring medication adherence, diagnosing suboptimal treatment, detecting drug interactions, and guiding initiation or withdrawal of therapy. TDM requires the creation of a team consisting of clinicians, pharmacists, and laboratory attendants and involves the use of techniques like radioimmunoassay, fluorescence polarization immunoassay (FPIA), enzyme immunoassay (EMIT), enzyme-linked immunosorbent assay (ELISA), and high-performance liquid chromatography.

The authors of the current manuscript believe that TDM is an essential diagnostic modality, especially in the context of psychiatric practice, and should be included following the upcoming revision of NEDL. The authors wish to highlight the following points pertaining to psychiatric practice to justify the inclusion of TDM in NEDL.

Monitoring treatment adherence:

Adherence to treatment is among the few modifiable factors for relapse of psychiatric disorders. TDM plays an essential role in the monitoring of treatment adherence. Emsley et al.,[5] in their review, have highlighted the need to ensure good medication adherence to prevent relapse of psychiatric disorders because strategies like identifying at-risk patients or the use of rescue medications have shown dismal results. In a study conducted in the psychiatric emergency services among relapsed patients receiving antipsychotics or antidepressant drugs, it was found that 73% of the patients had their drug levels clearly below or above the expected level. The authors concluded that nonadherence was the likely cause of the relapse.[6] The current evidence shows that self-reported and clinician-rated measures of assessing adherence were unreliable.[78] TDM is a better method of monitoring drug compliance.[9] Multiple studies have established the fact that psychotropic drugs like antipsychotics, antidepressants, ionic mood stabilizers, and antiepileptic mood stabilizers are all good candidate drugs for TDM.[7810]

Promotes practice of personalized medicine:

Personalized medicine is the emerging practice of using knowledge of a patient’s genetic profile to guide treatment decisions. Appropriate knowledge of a person’s genetic profile can be helpful in choosing the appropriate drugs at appropriate doses. TDM can be a useful arsenal in the practice of personalized medicine.[11] Other than the genetic profile, the drug’s pharmacokinetics are also governed by patients’ physiological status, and they can change in certain special groups of patients like pregnant patients, children and adolescents, and geriatric patients. The data clearly show that there is a decrease in the serum levels of all groups of psychotropics in pregnant females.[1213] The evidence in the child and adolescent population and geriatric population is hindered by the lack of enough studies and unpredictable pharmacokinetics.[14] Evidence has shown that TDM can be useful in customizing the treatment approach in such patients.[15]

Early detection of toxicity:

There are certain psychotropics that have a relatively narrow therapeutic index, like lithium, which also has a relatively linear dose–response curve. For such drugs, TDM is a recommended modality for monitoring the appropriate dose and deciding on treatment optimization.[16] The issues become a bit more complex yet promising for drugs like clozapine. It has active metabolites and has multiple idiosyncratic adverse effects. There have been studies that have used TDM to detect the chances of agranulocytosis and neurological adverse effects (like seizures and myoclonus) following being initiated on clozapine.[1718] Clozapine levels also seem to have a relationship with insulin resistance and other metabolic side effects attributed to it.[19] There is also some evidence that clozapine levels are correlated to sialorrhea.[20]

Detection of drug interactions:

In psychiatric practice, polypharmacy is often required due to various compulsions. The other medical comorbidities in patients with mental disorders may necessitate the administration of other drugs, raising the possibility of drug–drug interactions. In such situations, TDM can be very helpful in supporting treatment decisions to ensure efficacy and tolerability. The complex permutations of the interactions have been comprehensively reviewed in other articles. However, in this context, drugs that are metabolized by the cytochrome enzymes (like aripiprazole or quetiapine) can be readily influenced by the coadministration of enzyme inducers like carbamazepine or inhibitors like valproate. Habits like smoking can also influence the hepatic cytochrome enzymes, and monitoring of the drug levels may be required to achieve the target dose of the drugs.

Attempting to justify the inclusion according to the NEDL guidelines

The NEDL criteria for inclusion of tests in the EDL mandate the following points. In the following section, we will attempt to justify why TDM should be included in NEDL.

Conditions with high disease burden/high public health relevance:

Though the current manuscript primarily deals with TDM in the context of psychopharmacology, it is redundant to state that TDM is useful for pharmacotherapy across disorders of all specialties. But even in the context of mental disorders, the burden of psychiatric disorders remains substantial and is of high public health relevance.[2122] According to the National Mental Health Survey of India (2016), the lifetime prevalence of morbidity arising from mental disorders was 13.7%, whereas about 10.6% of the sample examined reported of current morbidity due to mental disorders.[22] This was also ratified by the Global Burden of Disease study, which showed that about 1 in 7 persons from India is affected by some psychiatric disorder.[21]

Priority conditions with weaker support programs:

The most important program that supports the treatment of psychiatric disorders in India is the National Mental Health Program (NMHP). However, the performance of the program has received a lukewarm response from the critics.[23] The NMHP has been repeatedly subject to scrutiny, and it has been seen that though it has been partly successful in its objective expanding the reach of mental health services to the community, it has been constantly plagued by issues like financial and manpower crunch. Thus, providing external support to the program should be beneficial for all stakeholders associated with mental health treatment.

Tests that enable safe and rational use of NLEM medicine:

In the previous section, we have tried to justify the enormous scope of the use of TDM in psychopharmacology. This should also be considered in light of the fact that the psychotropics included in the NLEM are limited and, unsurprisingly, first-line drugs for most disorders (certainly with exceptions like clozapine).[24] The rates of nonresponse to treatment with first-line drugs are often high, and TDM has the promise of improving their response rates by providing critical information. In this way, the rates of prescription of the drugs listed in NLEM can be encouraged.

For a drug like clozapine, TDM can also ensure better utilization of the drug. There is rising evidence of the fact that clozapine is underutilized in India because of fear among clinicians about life-threatening adverse effects and the need for close monitoring.[25] Often, there is a delay of 1.5–2 years before its initiation, even when indicated. A similar concern was also found among Indian clinicians toward lithium in another study.[26] Access to TDM can help assuage the clinician’s concerns about the use of these drugs and improve its prescription rates.

Conditions prone to outbreaks:

In most contexts, this subheading refers to disorders with infective etiology. However, the recent COVID-19 outbreak has highlighted the fact that even mental disorders are prone to outbreaks in critical periods like pandemics. Moreover, testing times like pandemics also can wreak havoc in the management of chronic disorders, and TDM can be helpful in informed decision-making.

Tests encompassing care pathways of diseases:

As has already been highlighted, the promise of TDM transcends the boundaries of psychopharmacology. In a country like India, where allopathic practice is complemented with other systems like Ayurveda and Homeopathy, often a fear is seen among the patients regarding the adverse effects of allopathic medications.[27] Additionally, in many pockets of the countries, prescribers of the drugs may not have received adequate medical training.[28] In such situations, the availability of TDM by allowing better detection of treatment-emergent adverse effects can also be helpful in removing the stigma and fear associated with the prescription of psychotropics.

Tests which are not mainstay of diagnosis but are critical supporting tests:

TDM should be considered as a critical supporting test because of its immense potential in assisting in monitoring medication adherence, diagnosing suboptimal treatment, detecting drug interactions, and guiding initiation or withdrawal of therapy. The report of the fourth meeting of the WHO Strategic Advisory Group of Experts on In Vitro Diagnostics (2022) (SAGE IVD) has considered the use of TDM for five drugs (amikacin, gentamicin, phenytoin, methotrexate, and lithium) to be of high priority, whereas TDM for drugs like carbamazepine and sodium valproate was categorized under low-priority tests.[2930] Though this decision particularly pertains to the WHO-EDL list, the decision ratifies the status of TDM as a critical supporting test.

CONCERNS RELATED TO IMPLEMENTATION OF THERAPEUTIC DRUG MONITORING IN THE NATIONAL ESSENTIAL DRUG LIST

One of the criticisms that the authors expect to receive is whether TDM is going to be cost-effective at a tertiary level. In this context, it is imperative to state that TDM for antibacterial and antifungal drugs is already recommended at the district hospital level in the NEDL 2019.[2] Thus, we can expect the basic infrastructure to be present at the district level. Additionally, it must be reiterated that TDM facilities, once established, are going to be used across all specialties for most drugs where TDM is possible. Additionally, including TDM in NEDL can also be useful in the regulation of the price of the infrastructure by capping the price of essential instruments that are required for establishing TDM services.

TDM is also known to be influenced by many other factors like ethnic differences, interferences due to nutritional deficiencies, and quality of medications.[3132] All such issues can be investigated in much greater detail if we are able to invest in TDM.

RECOMMENDATION

The NEDL has separate lists for various healthcare levels, from subcenters and primary health centers to district hospitals. The authors recommend that TDM services should be established at the level of the district hospital. Initially, the TDM services ought to be initiated for lithium, sodium valproate, carbamazepine, and clozapine. All these drugs are already included in NLEM 2022.[33] Lithium, carbamazepine, and sodium valproate are included for the management of mood disorders, and clozapine is included for the management of psychotic disorders. Thereafter, the scope of TDM can be extended to other psychotropics included in the NLEM. Our choices were governed by the presence of the drug in the NLEM, evidence from the decisions taken by SAGE IVD, and the potential benefits of TDM in ensuring the safe and effective prescription of a drug.[293033]

Additionally, with the better implementation of the National Mental Health Program and the District Mental Health Program, along with other National Health Programs for communicable and noncommunicable diseases, we expect better availability of skilled manpower and experts at the district level, which can be convenient for the initiation of TDM services.

CONCLUSION

TDM has been a promising approach in the effort of providing safe and effective pharmacotherapy to patients. Its benefits have been highlighted in all recent publications on the topic. Its applicability has also been highlighted in many treatment guidelines. However, its practical use in clinical settings has been rudimentary and largely sporadic. The NEDL revision, which is scheduled to take place soon, provides us with a golden opportunity to revise our outlook toward this promising modality. We recommend that it should be included in the next amendment of the NEDL, and it should be available at the district level across the country. Initially, the TDM services ought to be initiated for lithium, sodium valproate, carbamazepine, and clozapine as all these drugs are also included in the NLEM. This development should also be supported with greater intersectoral collaboration with related programs like the NMHP.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.
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