Closer Monitoring Needed to Combat Poor Antidepressant Adherence

Liam Davenport

June 19, 2017

COPENHAGEN, Denmark — About half of patients treated with antidepressants do not adhere to their regimen, and a little more than 40% achieve recommended plasma levels of the drugs even when treated at the correct dose, say Czech researchers, who recommend that more patients undergo therapeutic drug monitoring.

The study, which included patients with depressive disorders and anxiety disorders who were hospitalized for inadequate therapeutic response, showed that a little less than 50% of patients adhered to their medication regimen. There was no significant differences between drugs.

Moreover, the findings, presented here at the 13th World Congress of Biological Psychiatry, indicated that in only 43% of patients were plasma concentrations within the therapeutic range after 4 days of recommended treatment. Paroxetine (multiple brands) was associated with a significantly higher rate of plasma drug inadequacy than other medications.

Study presenter Eva Ceskova, MD, PhD, professor of psychiatry at the Central European Institute of Technology, Masaryk University, Brno, Czech Republic, said that patients who respond only partially or who do not respond to antidepressant therapy "are frequently underdosed or nonadherent."

Consequently, she believes that therapeutic drug monitoring "is not sufficiently used in outpatients treated with antidepressants" to identify patients whose responses are inadequate.

"Outpatient determination of plasma concentrations of antidepressants, with their interpretation performed by a clinical pharmacologist prior to referring the patients for hospitalization, thus should be a more frequently used diagnostic tool," she added.

The researchers conducted an open, prospective pilot study of patients with anxiety disorder or depressive disorder who were prescribed selective serotonin reuptake inhibitors (SSRIs) or serotonin-norepinephrine reuptake inhibitors as either monotherapy or in combination with other psychotropic or somatic drugs.

The patients had to have taken the drugs for at least 2 weeks to achieve a stable clinical state. This made it possible to administer of the same medication at the same dose for the first 4 days of hospitalization. Patients were excluded if they had also received valproate or carbamazepine or were heavy smokers.

Tandem mass spectrometry was used to assess antidepressant plasma levels in blood samples taken on the day of admission, after medication administration, and on the fourth day of hospitalization, both prior to drug administration (Tmin) and 2 to 6 hours after administration (Tmax).

Patients were deemed to be adherent to antidepressant medication if their plasma level on the day of admission was within the range Tmin to Tmax ± 10%.

This additional 10% margin was chosen to eliminate variations in plasma levels resulting from the analytic technique and from pharmacokinetic factors, such as diet, patients' sex, age, and individual metabolism.

The researchers also examined the adequacy of the administered antidepressant doses by comparing Tmin with the recommended therapeutic reference range defined in the 2011 update to the AGNP Consensus Guidelines for Therapeutic Drug Monitoring in Psychiatry.

High Rate of Nonadherence

Overall, 83 patients hospitalized between March and November 2011 met the inclusion criteria. Of these, 40% had depressive disorder and 60% had anxiety or stress disorders. The mean age of the patients was 40.3 years, and 77% were women.

They were treated with paroxetine, escitalopram (Lexapro, Forest Labs), sertraline (Zoloft, Pfizer), citalopram (multiple brands), and venlafaxine extended release (Effexor XR, Wyeth).

The analysis revealed that 49% of the patients were adherent to their medication prior to admission. In 35%, antidepressant plasma levels were lower than Tmin minus 10% on admission; in 16%, plasma levels higher than Tmax plus 10% on admission.

The lowest level of adherence was with citalopram, at 33%; the highest, at 55%, was with paroxetine, although there were no significant differences between the individual drugs.

Of the 81 patients in whom antidepressant plasma levels were detectable on admission, 43% were within the therapeutic reference range of day 4 of hospitalization. A further 43% reached the reference range, and 14% exceeding the range.

The highest proportions of patients with inadequate plasma drug levels on hospitalization day 4 were seen with citalopram, at 73% on an average daily dose of 21.8 mg, and paroxetine, at 82% on an average daily dose of 24.5 mg. The rate of plasma drug inadequacy with paroxetine was significantly higher than that for other drugs (P < .05).

The proportional difference in the maximum and minimum mean plasma drug levels ranged from 5.2-fold with citalopram to 28.0-fold with sertraline. This was markedly higher than the proportional difference in the maximum and minimum mean daily drug doses, which ranged from 2.0-fold for escitalopram and 4.0-fold for all other drugs studied.

Dr Ceskova noted that this difference was in line with the published literature; identical drug doses have resulted in more than 20-fold interindividual differences in steady state plasma concentrations.

She went on to acknowledge that the study was relatively small, had a diagnostically heterogeneous patient population, and that the short period between the taking of blood samples and the use of only one method to measure adherence may have affected the results.

Nevertheless, she said, the 50% adherence rate with antidepressants revealed by the analysis "corresponds with published data."

She added that only two patients in whom plasma drug levels were undetectable were fully noncompliant with their medication. The results showed that "partial noncompliance is more frequent."

Dr Ceskova said that following the analysis, "problematic adherence was discussed with patients individually." This included talking about the ongoing clinical strategy for those patients.

"Forty percent of the patients were treated with doses which, even though taken regularly, resulted in lower than therapeutic concentrations; these results should encourage psychiatrists to increase the dose in the range of recommended doses in nonresponders," she said.

Plasma Monitoring Feasible?

Session cochair Tom Bolwig, MD, PhD, professor emeritus of psychiatry, University Hospital of Copenhagen, Denmark, described the study as "very interesting" and noted that the researchers' recommended use of plasma monitoring is at a level that is "probably more than is usual in Europe or in other countries."

In the discussion following the presentation, Dr Bolwig asked Dr Ceskova why the patients included in the study were not treated with tricyclic antidepressants. She pointed that SSRIs are the first-line treatment in outpatient departments, "so we don't use tricyclics very much in the Czech Republic, only as a second or third line."

Zhang-Jin Zhang, MD, PhD, professor and associate director (clinical affairs), School of Chinese Medicine, the University of Hong Kong, China, asked whether all patients received antidepressant monotherapy.

Dr Ceskova confirmed that the patients were treated with antidepressant monotherapy. She added that, although there was "maybe some comedication with other drugs," the rates and types of comedication were comparable across the cohort.

No funding for the study or relevant financial relationships have been disclosed.

13th World Congress of Biological Psychiatry. Abstract 948, presented June 18.

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