Notification Issue Date:

Medical Policy Bulletin

Title:Therapeutic Drug Monitoring for Antidepressants, Antipsychotics, or Antiepileptics

Policy #:06.02.55

This policy is applicable to the Company’s commercial products only. Policies that are applicable to the Company’s Medicare Advantage products are accessible via a separate Medicare Advantage policy database.

The Company makes decisions on coverage based on Policy Bulletins, benefit plan documents, and the member’s medical history and condition. Benefits may vary based on contract, and individual member benefits must be verified. The Company determines medical necessity only if the benefit exists and no contract exclusions are applicable.

When services can be administered in various settings, the Company reserves the right to reimburse only those services that are furnished in the most appropriate and cost-effective setting that is appropriate to the member’s medical needs and condition. This decision is based on the member’s current medical condition and any required monitoring or additional services that may coincide with the delivery of this service.

This Medical Policy Bulletin document describes the status of medical technology at the time the document was developed. Since that time, new technology may have emerged or new medical literature may have been published. This Medical Policy Bulletin will be reviewed regularly and be updated as scientific and medical literature becomes available. For more information on how Medical Policy Bulletins are developed, go to the About This Site section of this Medical Policy Web site.


Coverage is subject to the terms, conditions, and limitations of the member's contract. The Company reserves the right to reimburse only those services that are furnished in the most appropriate and cost-effective setting that is appropriate to the member’s medical needs and condition.


Therapeutic drug monitoring (TDM) for antidepressants, antipsychotics, and antiepileptic medications is considered medically necessary, and, therefore, covered for any of the following reasons when a plan is in place to use the test findings clinically:
  • Dose optimization after initial prescription or dose change
  • Suspected complete or partial non-adherence or non-compliance to prescribed medication
  • Lack of clinical improvement under recommended dose
  • Clinical improvement under recommended dose but with adverse effects
  • Initiation of combination therapy with a drug known for its interaction potential or suspected drug interaction
  • Relapse prevention under maintenance treatment


When the above criteria are met, TDM is considered medically necessary, and, therefore, covered for the following number of units:
  • Antidepressants to a combined maximum of up to 15 units of tests per calendar year (CPT codes 80332, 80333, 80334, 80335, 80336, 80337, 80338)
  • Antiepileptics to a combined maximum of up to 15 units of tests per calendar year (CPT codes 80339, 80340, 80341, 80355, 80366, 80156, 80157, 80164, 80165, 80168, 80171, 80175, 80177, 80183, 80184, 80185 , 80186, 80188, 80199, 80201, 80203)
  • Antipsychotics to a combined maximum of up to 15 units of tests per calendar year (CPT codes 80342, 80343, 80344, 80159, 80173, 80178)

Specimen validity/adulteration testing is not eligible for separate reimbursement, as this is considered part of the laboratory quality control practice.


TDM is considered not medically necessary and, therefore, not covered, when the above criteria are not met for testing including, but not limited to, routine testing (e.g., testing at every visit, without consideration for specific member risk factors, or without consideration for whether therapeutic testing is required for clinical decision making). Testing of the same drug with both a blood and a urine specimen simultaneously is considered not medically necessary and, therefore, not covered. Testing in addition to the medically necessary limits described above in a calendar year, will be considered not medically necessary and, therefore, not covered.


The individual's medical record must reflect the medical necessity for the care provided. These medical records may include, but are not limited to, records from the physician's office, hospital, nursing home, home health agencies, therapies, other health care professionals, and test reports.

The Company may conduct reviews and audits of services to our members, regardless of the participation status of the provider. All documentation is to be available to the Company upon request.


Subject to the terms and conditions of the applicable benefit contract, drug testing for employment purposes is a standard benefit contract exclusion for most products of the Company. Therefore, drug testing for employment purposes may be considered a benefit contract exclusion and is not eligible for reimbursement consideration.


Inclusion of a code in this policy does not imply reimbursement. Eligibility, benefits, limitations, exclusions, precertification/referral requirements, provider contracts, and Company policies apply.


Subject to the terms and conditions of the applicable benefit contract, drug testing is covered under the medical benefits of the Company’s products when the medical necessity criteria listed in this medical policy are met.

Subject to the terms and conditions of the applicable benefit contract, drug testing for employment purposes may be a standard benefit contract exclusion for all products of the Company.

Health Maintenance Organization (HMO) and Health Maintenance Organization Point-of-Service (HMO-POS) products require that the member obtain medically necessary laboratory services at the primary care provider's (PCP's) designated capitated laboratory site*. In most cases, laboratory services that are rendered at a non-capitated site for members enrolled in HMO or HMO-POS products are not eligible for reimbursement consideration by the Company.
    *Members who are enrolled in New Jersey products may choose to receive routine laboratory services authorized by their PCP from a participating individual laboratory provider other than the PCP’s capitated laboratory provider. This requires the member to have a referral issued by their PCP.


Clinical laboratories may develop and validate tests in-house and market them as laboratory service; laboratory developed tests (LDTs) must meet the general regulatory standards of the Clinical Laboratory Improvement Act (CLIA).

Gas chromatography/mass spectrometry (GC/MS) tests and some immunoassays are performed in laboratory settings. Laboratories that offer LDTs must be licensed by CLIA for high-complexity testing.



Therapeutic drug monitoring (TDM) is the measurement of the concentration of drugs in body fluids, usually plasma, which can be used for treatment management. For select drugs, TDM may assist with enhancing drug efficacy, monitoring compliance, or identifying toxicity. Routine monitoring is not advocated for most drugs, and only clinically meaningful tests that would aid clinical decision making should be performed.

TDM for measuring plasma concentrations of neuropsychiatry medications is typically performed for dose optimization, dose change, suspected non-adherence to medication, lack of clinical improvement to prescribed dose, adverse effects under recommended dose, changing medication, suspected drug interactions, or drug toxicity. Clinical evidence evaluating the frequency of TDM in neuropsychiatry practice is scarce; however, generally, regular monitoring of plasma concentrations under maintenance therapy is recommended every 3-6 months to prevent relapse in the typical individual population, with increased monitoring in non-adherent individuals or in cases of co-medication alterations.

Commonly monitored medications in neuropsychiatry are: antidepressants, antipsychotics, and antiepileptics.

Antidepressants are used to treat depression, major depressive disorder (MDD), obsessive-compulsive disorder, bulimia nervosa, panic disorder, social anxiety disorder, generalized anxiety disorder (GAD), posttraumatic stress disorder (PTSD), premenstrual dysphoric disorder (PMDD), diabetic peripheral neuropathy, fibromyalgia, chronic musculoskeletal pain, and seasonal affective disorder (SAD).

Classes of antidepressant medication include selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), norepinephrine and dopamine reuptake inhibitors (NDRIs), tricyclic antidepressants, and monoamine oxidase inhibitors (MAOIs). SSRIs are commonly used as first-line treatment because they cause fewer side effects. Common SSRIs include fluoxetine, paroxetine, sertraline, citalopram, and escitalopram.

Tricyclic antidepressants tend to cause more side effects than the newer antidepressants and are therefore generally not prescribed unless SSRIs have failed to show improvement.

When an individual responds poorly to an antidepressant medication or exhibits side effects, an antidepressant within the same class or another class is generally indicated. Similarly, if an individual does not show improvement with one antidepressant, he or she may be prescribed combination therapy, with one or two antidepressants in addition to other medications, such as mood stabilizers or antipsychotics.

The standard approach to switching antidepressants is cross-tapering, where a dose of the currently prescribed antidepressant is gradually reduced and then stopped, while simultaneously the new antidepressant is started and titrated to the therapeutic range. For most antidepressant medications, cross-tapering occurs at various time frames ranging from 2 to 4 weeks. For example, tricyclic antidepressants are generally tapered over 2 to 4 weeks, while MAOIs are generally tapered for at least 4 weeks.

Cross-tapering is typically contraindicated if the two antidepressants can cause drug--drug interaction, in which case the current antidepressant is tapered and stopped before the new medication is started. In certain situations, when the new drug prescribed is within the same drug class, the current medication may be stopped without cross-tapering, and the new medication may be switched and started the next day.

In order to decide whether an antidepressant is sufficiently treating symptoms, a 6 to 12 week trial is generally considered adequate. However, trial duration may be as little as 4 to 6 weeks for individuals who show little improvement (e.g., reduction of baseline symptoms <25 percent).

Antidepressant treatment is typically carried out for a minimum of 4 weeks before determination of ineffectiveness and beginning the next step (e.g., dose adjustment, change in medication). In individuals who are non-responsive, TDM may be a useful tool and may be required sooner than every 3 to 6 months.

The following guidelines provide some recommendations for treatment with antidepressants.

The National Institute for Health and Care Excellence (NICE) guidelines for antidepressant treatment recommend verifying whether the initial drug has been taken as prescribed if improvement is not seen after 2 to 4 weeks.

The American Academy of Family of Physicians recommendation for pharmacological management of depression includes the following:
  • Treat depression at adequate antidepressant doses for a minimum of 4 to 8 weeks before labeling a treatment regimen ineffective.
  • Consider a change in therapy if there is no improvement after 4 to 12 weeks of antidepressant treatment.
  • After treatment failure with an antidepressant, the next option may be a different medication of the same class, a medication from a different class, or augmentation with a second agent.

The following strategies to address non-response are recommended by the American Psychiatric Association for treatment of individuals with major depressive disorder:
  • If at least a moderate improvement in symptoms is not observed within 4 to 8 weeks of treatment initiation, the diagnosis should be reappraised, side effects assessed, complicating co-occurring conditions and psychosocial factors reviewed, and the treatment plan adjusted.
  • If medications are prescribed, the treating provider should determine whether pharmacokinetic or pharmacodynamic factors suggest a need to adjust medication doses. With some tricyclic antidepressants, such as amitriptyline and doxepin, a drug blood level can help determine whether additional dose adjustments are required.
  • After an additional 4 to 8 weeks of treatment, if the individual continues to show minimal or no improvement, the treating provider should conduct another thorough review of possible contributory factors and make additional changes in the treatment plan.

Antipsychotic medications manage psychosis. Psychotic states include delusions, hallucinations, and disordered thoughts, which are seen in conditions such as schizophrenia and bipolar disorder. Common antipsychotics include amisulpride, aripiprazole, asenapine, bromperidol, clozapine, flupenthixol, iloperidone, lurasidone, olanzapine, pipamperone, quetiapine, risperidone, and ziprasidone.

Antipsychotic medication can be classified as first-generation and second-generation medications. Generally, it takes several weeks after initiation of antipsychotic medication to improve symptoms. Varying dosage or a combination of medication may be tried over time to achieve the desired result.

Serum concentrations of specific antipsychotic drugs may be obtained to explain treatment failure or nonresponse, or to check compliance. While TDM is well established for certain antipsychotic medications (e.g., clozapine), it is generally not standard for the newer antipsychotics such as ziprasidone and ariprazole. TDM should therefore be restricted to monitor compliance with, or to evaluate side effects of, specific medications at the therapeutically recommended dose.

According to clinical practice guidelines for treatment of individuals with schizophrenia, during the stable phase, in assessing treatment resistance or partial response to schizophrenia medication, an initial trial of 4 to 6 weeks is needed to determine whether the individual will have any symptomatic response. Guidelines further state that symptom improvement from pharmacologic treatment can continue to be seen after 6 months or longer. Therefore, TDM of antipsychotic medications should be conducted at a minimum of 4 to 6 week intervals.

Antiepileptic drugs, also known as anticonvulsants or antiseizure drugs, are the main form of treatment for individuals with epilepsy. However, some antiepileptic drugs can be prescribed for other indications such as bipolar affective disorder, migraine prophylaxis, major depressive disorder, and neuropathic pain. Common antiseizure medications include carbamaepine, gabapentien, phenobarbital, phenytoin, pregabalin and tiagabine.

There are several types of antiseizure drugs, and combination therapy using multiple antiseizure drugs is possible. However, monotherapy, using only one antiseizure drug, is generally recommended as the initial treatment for epilepsy; a second antiseizure drug trial is recommended if the first antiseizure drug is unsuccessful.

Therapeutic drug ranges of antiepileptic drugs are often associated with seizure control. Serum concentrations may be used to guide an individual’s response; however, they should not be substituted for assessing the individual's clinical response because serum levels that are associated with neurotoxicity vary between individuals, and toxicity can occur even when measured levels are considered to be within the appropriate therapeutic range.

TDM for antiepileptic drugs may be used to guide optimal dosing, identify toxicity, or assess medication adherence. To reflect accurate medication concentration, blood levels are checked once the medication has reached a stable level, also called steady state. The time required to reach steady state for different antiseizure medications varies from less than 1 week to up to 4 weeks. For example: Time to steady state for carbamazepine is 3 weeks; phenobarbital 3 weeks; phenytoin 3 weeks; and abapentine 2 days.

Individuals whose seizures do not successfully respond to antiseizure medication are typically considered to have drug-resistant epilepsy (DRE), also known as intractable, medically refractory, or pharmacoresistant epilepsy. A task force for the International League against Epilepsy recommends drug-resistant epilepsy be defined as the failure of adequate trials of two tolerated, appropriately chosen and administrated antiseizure drugs (whether as monotherapy or in combination) to achieve seizure freedom.


"To produce its characteristic effects, a drug must be present in appropriate concentrations at its sites of action. The latter is not only a function of the dose administered, but also of the extent and rate of drug absorption, distribution, tissue binding, biotransformation, and excretion, which can vary markedly between individuals due to differences in gender, age, morbidity, smoking or eating habits, differential expression of drug metabolizing enzymes or drug transporters or other factors. Therefore, drug concentrations in blood resulting after a given dose differ by tenfold or more between individuals. For psychoactive drugs, animal studies have shown that plasma concentrations of psychotropic drugs correlate well with concentrations in the target organ, the brain. In the brain of individuals treated with antipsychotic or antidepressant drugs, clear-cut relationships were found between plasma concentrations of the drug and occupancy of dopamine receptors or serotonin uptake sites by positron emission tomography (PET). Monitoring concentrations of psychoactive drugs in plasma of individuals, so called therapeutic drug monitoring (TDM), is therefore useful for adjusting dosages for optimal "receptor" blockade. TDM is well established for mood stabilizers and anticonvulsant drugs. For other neuropsychiatric drugs, however, 'routine' TDM is rare. Optimal target concentrations are unclear for many drugs, and the number of laboratories that use reliable methods to measure the low concentrations of the drugs within a single day is quite limited. Moreover, the use of TDM in practice is far from optimal. The TDM group of the Arbeitsgemeinschaft für Neuropsychopharmakologie und Pharmakopsychiatrie (AGNP see has published literature-based guidelines for optimal use of TDM in psychiatry. TDM can be most informative to solve problems underlying the treatment of an individual. It can be clarified if suggested non-compliance or insufficient response in spite of recommended doses is due to rapid metabolism of the drug. Moreover, many drug interactions have been detected by using TDM. In conclusion, TDM is a reliable tool to optimize psychopharmacotherapy. When used adequately, it is helpful for many psychiatric individuals and in many situations." (Hiemke C, March 2008).


Urine specimen testing to ensure consistency with normal human urine and to verify that the urine has not been adulterated or substituted may include, but is not limited to, pH, specific gravity, oxidants, and creatinine.

Urine for clinical drug testing is the specimen of choice because of its high drug concentrations and well-established testing procedures. Nevertheless, urine is one of the easiest specimens to adulterate. Urine samples can be diluted, swapped for another individual’s, or tampered with using commercially available or homemade products that change the chemical profile of the urine. If the clinician suspects that a sample has been adulterated, substituted, swapped, or otherwise altered in attempt to defeat evaluation and monitoring, the clinician may choose to evaluate specimen validity using built-in validity tests such as temperature, creatinine, and pH readings; or witness collection (if no alternative matrix sampling is available such as blood or saliva). Most basic urine immunoassays have specimen validity checks built into the screening process and allow for a basic determination of potential urine sample tampering (dilution, substituted specimen, etc.). Pain management laboratories may have specimen validity testing protocols. However, these too are deemed quality control measures.

Adams SM, Miller KE, Zylstra RG. Pharmacologic management of adult depression. Am Fam Physician. 2008;77(6):785-92.

American Psychiatric Association Practice Guidelines for the Psychiatric Evaluation of Adults. 3rd Edition. Available at: Accessed on March 1st 2017.

Armstrong C. APA Updates Guidelines on Psychiatric Evaluation in Adults. Am Fam Physician. 2016;94(1):62-4.

CADTH Rapid Response Reports. Source Ottawa (ON): Canadian Agency for Drugs and Technologies in Health; 2016 Sep. Combination Atypical Antipsychotics in Adolescents or Adults with Bipolar Disorder with Psychotic Features: A Review of Clinical and Cost-Effectiveness and Guidelines [Internet].

Dold M, Kasper S. Evidence-based pharmacotherapy of treatment-resistant unipolar depression. Int J Psychiatry Clin Pract. 2017;21(1):13-23.

Fountoulakis KN, Yatham L, Grunze H, et al. International College of Neuro-Psychopharmacology (CINP) Treatment Guidelines for Bipolar Disorder in Adults (CINP-BD-2017), Part 2: Review, Grading of the Evidence, and a Precise Algorithm. Int J Neuropsychopharmacol. 2016 Dec 22.

Fountoulakis KN, Grunze H, Vieta E, et al. International College of Neuro-Psychopharmacology (CINP) treatment guidelines for Bipolar disorder in adults (CINP-BD-2017), part 3: The clinical guidelines. Int J Neuropsychopharmacol. 2016 Dec 10.

Hiemke C. Therapeutic drug monitoring in neuropsychopharmacology: does it hold its promises? Eur Arch Psychiatry Clin Neurosci. 2008;258 Suppl 1:21-7.

Hiemke C, Baumann P, Bergemann N, et al. AGNP Consensus Guidelines for Therapeutic Drug Monitoring in Psychiatry: Update 2011. Pharmacopsychiatry. 2011;44(6):195-235.

Hiemke C. Consensus Guideline Based Therapeutic Drug Monitoring (TDM) in Psychiatry and Neurology. Curr Drug Deliv. 2016;13(3):353-61.

Keating D, McWilliams S, Schneider I, et al. Pharmacological guidelines for schizophrenia: a systematic review and comparison of recommendations for the first episode. BMJ Open. 2017;7(1):e013881.

Kovich H, DeJong A. Common questions about the pharmacologic management of depression in adults. Am Fam Physician. 2015;92(2):94-100.

León Ruiz M, Rodríguez Sarasa ML, Sanjuán Rodríguez L, et al. Guidelines for seizure management in palliative care: Proposal for an updated clinical practice model based on a systematic literature review. Neurologia. 2017. pii: S0213-4853(17)30003-8.

Laux G, Baumann P, Hiemke C; TDM group of the Arbeitsgemeinschaft Neuropsychopharmakologie und Pharmakopsychiatrie. Therapeutic drug monitoring of antidepressants--clinical aspects. J Neural Transm Suppl. 2007;(72):261-7.

Mancia K, Paola M, Dawson E. Specimen Validity Testing, Focus on Screens looks at interpreting urine drug assay results. Available at: Accessed on March 1st 2017.

Martin RC, Faught E, Szaflarski JP, et al. What does the U.S. Medicare administrative claims database tell us about initial antiepileptic drug treatment for older adults with new-onset epilepsy? Epilepsia. 2017 Feb 7.

Miller KE, Adams SM, Miller MM. Antidepressant medication use in palliative care. Am J Hosp Palliat Care. 2006;23(2):127-33.

Parker GB, Graham RK, Tavella. Is there consensus across international evidence-based guidelines for the management of bipolar disorder? Acta Psychiatr Scand. 2017 Mar 5.

Poolos NP, Castagna CE, Williams S, et al. Association between antiepileptic drug dose and long-term response in patients with refractory epilepsy. Epilepsy Behav. 2017;69:59-68.

National Institute for Health and Care Excellence (NICE) Guidelines for Depression in adults: recognition and management. Available at: Accessed on March 1st 2017.

National Institute for Health and Care Excellence (NICE) Pathways for Antidepressant treatment in adults. Available at: Accessed on March 1st 2017.

Practice Guideline for the Treatment of Patients With Major Depressive Disorder. 3rd Edition. Available at: Accessed on March 1st 2017.

Samalin L, Garnier M, Auclair, Llorca PM. Clinical decision-making in the treatment of schizophrenia: focus on long-acting injectable antipsychotics. Int J Mol Sci. 2016;17(11).

Shih JJ, Whitlock JB, Chimato N, et al. Epilepsy treatment in adults and adolescents: Expert opinion, 2016. Epilepsy Behav. 2017 Feb 22.

Specimen Validity Testing. Prepared by: Division of Workplace Programs. Available at: Accessed on March 1st 2017.

Treating Major Depressive Disorder, A Quick Reference Guideby the American Psychiatric Association. Available at: Accessed on March 1st 2017.

Wade M, Tai S, Awenat Y, Haddock G. A systematic review of service-user reasons for adherence and nonadherence to neuroleptic medication in psychosis. Clin Psychol Rev. 2017 Feb;51:75-95.


Inclusion of a code in this table does not imply reimbursement. Eligibility, benefits, limitations, exclusions, precertification/referral requirements, provider contracts, and Company policies apply.

The codes listed below are updated on a regular basis, in accordance with nationally accepted coding guidelines. Therefore, this policy applies to any and all future applicable coding changes, revisions, or updates.

In order to ensure optimal reimbursement, all health care services, devices, and pharmaceuticals should be reported using the billing codes and modifiers that most accurately represent the services rendered, unless otherwise directed by the Company.

The Coding Table lists any CPT, ICD-9, ICD-10, and HCPCS billing codes related only to the specific policy in which they appear.

CPT Procedure Code Number(s)

80156, 80157, 80159, 80164, 80165, 80168, 80171, 80173, 80175, 80177, 80178, 80183, 80184, 80185, 80186, 80188, 80199, 80201, 80203, 80299, 80332, 80333, 80334, 80335, 80336, 80337, 80338, 80339, 80340, 80341, 80342, 80343, 80344, 80355, 80366


82570, 83986, 84311, 84315, 82542

Professional and outpatient claims with a date of service on or before September 30, 2015, must be billed using ICD-9 codes. Professional and outpatient claims with a date of service on or after October 1, 2015, must be billed using ICD-10 codes.

Facility/Institutional inpatient claims with a date of discharge on or before September 30, 2015, must be billed with ICD-9 codes. Facility/Institutional inpatient claims with a date of discharge on or after October 1, 2015, must be billed with ICD-10 codes.

ICD - 10 Procedure Code Number(s)


Professional and outpatient claims with a date of service on or before September 30, 2015, must be billed using ICD-9 codes. Professional and outpatient claims with a date of service on or after October 1, 2015, must be billed using ICD-10 codes.

Facility/Institutional inpatient claims with a date of discharge on or before September 30, 2015, must be billed with ICD-9 codes. Facility/Institutional inpatient claims with a date of discharge on or after October 1, 2015, must be billed with ICD-10 codes.

ICD -10 Diagnosis Code Number(s)


HCPCS Level II Code Number(s)


Revenue Code Number(s)


Coding and Billing Requirements

Policy History

Revisions from 06.02.55
03/25/2020This policy has been reissued in accordance with the Company's annual review process.
05/08/2019This policy has been reissued in accordance with the Company's annual review process.
08/29/2018The policy has been reviewed and reissued to communicate the Company’s continuing position on Therapeutic Drug Monitoring for Antidepressants, Antipsychotics, or Antiepileptics.

Effective 10/05/2017 this policy has been updated to the new policy template format.

Version Effective Date: 04/07/2017
Version Issued Date: 04/07/2017
Version Reissued Date: 03/25/2020

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