Levels, Labs, and Lessons

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As discussed in last month’s editorial,¹ serum drug levels deliver a treasure trove of information to guide decision-making in a patient’s treatment plan. Specifically, several commonly used psychiatric medications—eg, lithium, valproic acid, and carbamazepine—have well-established serum levels that should be monitored, as suggested by current guidelines.²

To explore how serum levels work in the real world, this column discusses 2 fictional scenarios in which the results of a serum drug level frame the clinical picture and inform next steps in each patient’s ongoing treatment. (Although fictional, the cases are based on real patient vignettes gleaned over decades of treating primarily outpatients.) In the first case, we see how clozapine serum levels can be helpful in fine-tuning the treatment course of a woman with schizophrenia who has received multiple antipsychotic trials. The second case demonstrates how sertraline levels can bring clarity to a puzzling case of treatment nonresponse in a man with obsessive compulsive disorder (OCD).

Case 1: Clozapine Conundrum

“Ms Smith,” a 29-year-old woman, received a diagnosis of schizophrenia, paranoid type, at age 21 years. Her first psychotic episode responded reasonably well to risperidone 4 mg by mouth at bedtime; it resulted in a resolution of auditory hallucinations and an approximately 80% reduction in paranoia. After 8 months she abruptly self-discontinued the risperidone due to muscle rigidity, cognitive fog, and akathisia. Four months later her psychotic symptoms recurred, interfering with her ability to live independently. She ultimately required psychiatric hospitalization as a result of agitation and interpersonal conflicts directly related to the auditory hallucinations and paranoia.

During the next 4 years, Ms Smith underwent trials of 3 atypical antipsychotic medications, each presumed to be of adequate dose and duration as evidenced by expected adverse events. Two years ago, she agreed to a trial of clozapine for what then was termed treatment-resistant schizophrenia. However, after 5 months into the clozapine trial and 12 weeks of clozapine 300 mg by mouth, she reported persistent auditory hallucinations and paranoia.

A 12-hour post-clozapine level returned at 378 ng/mL. Over the next 3 months her clozapine dose was slowly increased to 600 mg by mouth at bedtime, with a steady-state 12-hour postdose clozapine level documented at 546 ng/mL. After 6 weeks on 600 mg at bedtime, her auditory hallucinations significantly decreased in frequency and intensity, as did her paranoia. The positive trajectory continued, and after 6 months of oral clozapine 600 mg at bedtime, Ms Smith’s auditory hallucinations fully resolved and her paranoia was minimal. She became more engaged in her treatment with supportive psychotherapy and case management, and she participated in a psychoeducation group as well as vocational rehabilitation.

One year later, she remained on the 600-mg dose and was at her stable baseline. She also began a part-time job and reported satisfaction with her quality of life. Her repeat 12-hour postdose clozapine level was documented as 517 ng/mL.

Discussion. Clozapine remains our only medication with demonstrated efficacy for treatment-resistant schizophrenia. Arguably, clozapine should be used earlier in treatment for patients whose conditions have failed at least 2 or more other antipsychotics of adequate dose and duration. With the decision by the US Food and Drug Administration to end the Risk Evaluation and Mitigation Strategy, while still recommending the same monitoring as defined in the product insert by the prescriber, it is likely clozapine will experience a renaissance of use. This is great news for individuals with treatment-resistant schizophrenia.

In my experience, psychiatric providers have historically underutilized clozapine serum levels to optimize its efficacy. The 12-hour postdose serum level determines the adequacy of a clinical clozapine trial, not the dosage. An extensive literature exists to guide the clinician in monitoring a clozapine trial.^3,4 The Table lists the current evidence-based parameters extracted from this literature.

TABLE. Tips for Obtaining Accurate Clozapine Levels

Case 2: Sertraline Stumper

“Mr Reginald” is a 23-year-old man in treatment for severe OCD. When he entered treatment a year ago, his psychiatric history indicated the onset of severe symptoms of OCD in his early childhood. His symptoms varied over the years to include compulsive checking, excessive fear of contamination, and obsessive thoughts that some minor act toward another person could have catastrophic consequences. At times of stress, these symptoms exacerbated, most recently during his years away from home while in college. He had assumed these obsessions and compulsions were common to everyone but through a recent intimate relationship realized they were excessive and might benefit from treatment. Mr Reginald reported a family history of anxiety and depression in siblings, his mother, and several aunts and uncles.

After establishing the diagnosis of OCD, Mr Reginald was referred to an exposure-response prevention behavioral psychotherapist, where he also expressed a strong preference to initiate medication treatment. He was prescribed sertraline 25 mg by mouth daily and instructed to increase the dose by 25 mg/week to a target dose of 100 mg. After 8 weeks on 100 mg daily, he reported minimal improvement in his symptoms as well as the absence of any adverse events. The sertraline was increased by 25 mg/week to the maximum FDA-approved dose of 200 mg daily; this dose is commonly needed to achieve benefit in individuals with OCD. At follow-up 3 months later, Mr Reginald reported full adherence with the sertraline but frustratingly reported no notable benefit in his OCD symptoms, with the exception of some targeted improvements he attributed to the tools learned in behavior therapy. Significantly, he denied any adverse effects.

A 12-hour postdose sertraline level was ordered, which resulted in a curiously low level of 14 ng/mL. Although no therapeutic sertraline level has been determined, a reasonable range has been established as 10 to 150 ng/mL.⁵

There are numerous factors that could singularly or synergistically result in poor absorption or rapid metabolism for any medication, resulting in a lower serum level than expected.¹ For instance, a person who genotypically is an ultrarapid metabolizer at cytochrome P450 2C19 (CYP2C19) would likely require a higher sertraline dose than the average person due to the hypermetabolism of sertraline by CYP2C19, one of its primary metabolic pathways. However, many other variables can contribute to a nontherapeutic sertraline level on 200 mg daily.⁵

Mr Reginald insisted he had been adherent with the 200 mg daily, and his frustration over his lack of benefit supported the likelihood of this. With a baseline low sertraline level at 200 mg daily and lack of any adverse effects, the sertraline was increased by 25 mg/week to 300 mg, and ultimately 400 mg. After 2 months of 400 mg daily, Mr Reginald reported a notable decrease in his checking behaviors and that his thoughts were “less sticky,” which in turn greatly improved his quality of life. A 12-hour postdose sertraline level at steady state on 400 mg returned at 97 ng/mL.

Mr Reginald continues in monthly therapy with his behavioral therapist and has maintained his improvement in his OCD symptoms.

Discussion. Sertraline is a selective serotonin reuptake inhibitor (SSRI) that was approved by the FDA in 1991 as an antidepressant. As with most of the SSRIs, sertraline was demonstrated to be effective in the treatment of a wide range of psychiatric disorders, and leaving the term antidepressant a misnomer. Unsurprisingly, various psychiatric disorders respond to different dosages of sertraline. The usual dosage range for sertraline is 25 to 200 mg, with patients with unipolar major depression responding in the range of 25 to 100 mg daily; those with anxiety disorders commonly require a higher dosage of 100 to 200 mg daily; and I typically dose patients with OCD at 200 mg daily.

Mr Reginald’s lack of response to sertraline 200 mg could have been the result of many unique factors. Regardless, in the presence of high confidence that he was adherent with the sertraline, obtaining the serum sertraline level provided a meaningful result that was immediately actionable. If his serum sertraline level was in the usual range for a person on 200 mg daily, the medication trial could have been concluded as a failed trial and the next step would have included cross-titration to a different medication. Because his serum sertraline level was notably lower than expected at 200 mg daily, and with a lack of any adverse events, a reasonable next step was to increase the dose until either efficacy was achieved or poor tolerability was reported. Following up with another sertraline level once efficacy was achieved, or before discontinuing due to poor tolerability or lack of efficacy, creates another important data point in the patient’s medical record.

Concluding Thoughts

Critics in and out of psychiatry often note that there is a lack of good objective tools. Yet, I suggest that serum levels of many psychiatric drugs provide us with such a tool. A handful of psychiatric medications have therapeutic ranges that are well established, and these are important to monitor during treatment. Serum levels of most other psychiatric medications are readily available to us, albeit with a 1- to 2-week wait for results after blood is drawn. These levels, coupled with the bigger clinical variables and picture, can shed significant light on the next step in a patient’s treatment.

Dr Miller is Medical Director, Brain Health, Exeter, New Hampshire; Editor in Chief, Psychiatric Times; Staff Psychiatrist, Seacoast Mental Health Center, Exeter; Consulting Psychiatrist, Insight Meditation Society, Barre, Massachusetts.

References

1. Miller JJ. Using serum drug levels. Psychiatric Times. 2025;42(7):4-5.

2. Jacobson SA. Laboratory Medicine in Psychiatry and Behavioral Science. 2nd ed. American Psychiatric Association Publishing; 2023.

3. Meyer JM, Stahl SM. The Clozapine Handbook. Cambridge University Press; 2019. Stahl’s Handbooks.

4. Meyer JM, Stahl SM. The Clinical Use of Antipsychotic Plasma Levels. Cambridge University Press; 2021. Stahl’s Handbooks.

5. Huddart R, Hicks JK, Ramsey LB, et al. PharmGKB summary: sertraline pathway, pharmacokinetics. Pharmacogenet Genomics. 2020;30(2):26-33.