Paroxetine plasma concentrations in adult and elderly depressed patients

Abstracts

INTRODUÇÃO: O efeito do envelhecimento nas concentrações plasmáticas em estado de equilíbrio da paroxetina foi investigado em 136 pacientes com depressão, tratados com doses variando entre 10 e 120 mg/dia de paroxetina. MÉTODOS: Os pacientes foram separados em três grupos: com idade até 64 anos (idade média ± desvio padrão: 41,7±12,6 anos; n = 44), entre 65 e 79 anos (72,8±4,7 anos; n = 64), e com mais de 80 anos (82,8±3,3 anos; n = 28). As doses de paroxetina foram normalizadas para 20 mg/dia. Amostras de sangue foram coletadas em condições de estado de equilíbrio. Os níveis plasmáticos de paroxetina foram medidos por cromatografia gasosa - espectrometria de massa. As funções hepática e renal foram medidas por testes laboratoriais clínicos estandardizados. RESULTADOS: Uma grande variabilidade interindividual dos níveis plasmáticos de paroxetina (37 vezes) foi medida para uma mesma dose. A média dos níveis plasmáticos de paroxetina corrigida para uma dose diária de 20 mg foi 87% maior no grupo com mais de 80 anos (56,4±64,1 ng/mL; p < 0,05) e 57% maior no grupo com idades entre 65 e 79 anos (46,7±33,4 ng/mL; p < 0,001) quando comparada com a média dos pacientes com menos de 64 anos (29,9±11,9 ng/mL). A idade foi correlacionada significativamente com os níveis plasmáticos de paroxetina (r = 0,21, p < 0,05) CONCLUSÃO: A redução de doses da paroxetina em pacientes idosos parece justificada.

Paroxetina; idosos; depressão; concentração plasmática; antidepressivos

ORIGINAL ARTICLE

Paroxetine plasma concentrations in adult and elderly depressed patients

Carlos Augusto de Mendonça Lima^I; Pierre Baumann^II; Chin Bin Eap^III

^IPhD. Professor, Instituto de Psiquiatria, Universidade Federal do Rio de Janeiro (UFRJ), Rio de Janeiro, RJ, Brazil

^IIPhD. Privat docent. Director, Unit of Biochemistry and Clinical Pharmacology, University Department of Psychiatry, University of Lausanne (UNIL), Lausanne, Switzerland

^IIIPhD. Biochemist, Unit of Biochemistry and Clinical Pharmacology, University Department of Psychiatry, UNIL

Correspondence

ABSTRACT

INTRODUCTION: The effect of aging on steady-state plasma concentrations of paroxetine was investigated in 136 depressive patients treated with paroxetine 10-120 mg/day.

METHODS: The patients were divided into three groups: aged up to 64 years (mean age ± standard deviation: 41.7±12.6 years; n = 44), between 65 and 79 years (72.8±4.7 years; n = 64), and 80 years or older (82.8±3.3 years; n = 28). Paroxetine doses were normalized to 20 mg/day. Blood samples were collected under steady-state conditions. Paroxetine plasma levels were measured by gas chromatography/mass spectrometry. Hepatic and renal functions were measured by standardized clinical laboratory tests.

RESULTS: A large interindividual variability of paroxetine plasma levels (37-fold) was measured for a given dose. The mean plasma levels of paroxetine corrected for a 20 mg daily dose were 87% higher in the very elderly (≥ 80 years) patients (56.4±64.1 ng/mL; p < 0.05) and 57% higher in the elderly (65-79 years) patients (46.7±33.4 ng/mL; p < 0.001) when compared to the adult patients (< 64 years) (29.9±11.9ng/mL). Age correlated significantly with paroxetine plasma levels (r = 0.21, p < 0.05).

CONCLUSION: Recommended dose reduction of paroxetine in elderly patients seems therefore justified.

Keywords: Paroxetine, elderly, depression, plasma levels, antidepressants.

Introduction

Paroxetine (PARO), a phenylpiperidine derivative, is a selective serotonin reuptake inhibitor (SSRI) and a widely used antidepressant.^1,2 When compared with other SSRI antidepressants, PARO is two to 23 times more potent.³ It can be administered at a single dose, between 20-50 mg. Its metabolism during the first hepatic passage is approximately 60%. Plasma peak occurs between 2-4 hours after administration.⁴ It is biotransformed by the liver into inactive metabolites. Its high affinity with the cytochrome P450 isoenzyme CYP2D6 suggests it can interact with other substances.^5-8

Its use in the elderly proved to be as efficacious as other antidepressants, with a profile of undesirable effects comparable to its use in adults.⁹ PARO has been included in the list of antidepressants recommended for the elderly proposed by a consensus declaration of experts.¹ Its use by elderly patients with depression significantly reduces the number of recurrences and relapses.² In spite of that, there are few pharmacokinetic studies on PARO in this group of patients, especially those including patients 80 years or older.

In a study by Lundmark et al.,¹⁰ it was observed that, in a sample of 21 elderly patients, there was a considerable interindividual variability in their plasma levels in steady state and elimination half-life. The authors considered that these results were insufficient to justify a reduction in PARO dose for the elderly. This same wide interindividual variability in plasma levels was confirmed by Sindrup et al., who observed a 25-fold variation in steady-state concentrations for a daily dose of 30 mg/day (25-670 µmol/L).¹¹ This variability has been explained by presence of slow and extensive metabolizers of sparteine in the population studied, confirming that the main PARO metabolism is dependent on isoenzyme CYP2D6. The fact that PARO is bonded to this isoenzyme may reduce the clearance of other concomitantly administered drugs, bringing the risk of its accumulation and increase in adverse effects.¹²

This study aimed at assessing the effect of aging - including very elderly patients (> 80 years) - on PARO plasma levels, considering gender and hepatic and renal functions.

Methods

Inclusion and exclusion criteria

Inclusion criteria were patients living in the community belonging to the Department of Adult Psychiatry and Geriatric Psychiatry Service at the University of Lausanne treated with PARO and for whom a clinical routine dose of this antidepressant was performed in the steady state (at least 2 weeks after the last modification in PARO dose and 12 hours after administration of the last drug dose) from January 1998 through December 2002. The patients should meet the diagnostic criteria of the International Classification of Diseases (ICD-10) for depressive episode (F32) or recurrent depressive disorder (F33), as established by their physician.

Patients who were not receiving concomitant drugs that could interfere with the PARO metabolism were not excluded (in particular, patients with other drugs metabolized by cytochrome P450 CYP2D6 were not included).

Data were collected from 136 patients with depression (44 men; depressive episode ICD-10 F32: 48 patients; ICD-10 F33: 88 patients). The patients were divided into three groups according to age group: patients aged 65 years or younger; patients aged 65-79 years; and patients aged 80 years or older.

As PARO doses administered orally ranged between 10-120 mg/day, they were (mathematically) normalized, as well as respective values of plasma concentrations (rule of three) for 20 mg/day, so that statistical comparisons could be performed between the plasma levels of the antidepressant.

Biochemical dosage, statistics

PARO plasma levels were measured by gas chromatography/mass spectrometry, as described in other studies.^13,14 Hepatic and renal functions were measured by standardized clinical laboratory tests using Integra 400 (Roche Diagnostics, Basel, Switzerland). Comparisons of variables between groups were performed using Student's t test and the chi-square test when appropriate. P < 0.05 was considered as statistically significant.

Ethics

The research protocol was approved by the Ethics Committee of the Department of Adult Psychiatry at the University of Lausanne in December 1997. Dosages were performed as part of treatment course routine to investigate the antidepressant plasma levels and correlate them with respective therapeutic responses; therefore, the patient's written consent for blood collection was not deemed necessary, and only oral consent was obtained.

Results

Clinical data

Table 1 presents a summary of clinical data and plasma dosages. The proportion of men and women in the three groups of patients (group A: ≤ 64 years; group B: 65-79 years; group C: ≥ 80 years) is equivalent (χ² = 1.23, nonsignificant). Mean age (± standard deviation) of patients in the three groups was 41.7±12 years, 72.8±4.7 years and 82.8±3.3, respectively; there was no difference in distribution of number of patients as to gender between all three groups. There was no difference in creatinine plasma levels, which was used to assess renal function, between the three age groups. In addition, there was no significant difference in pyruvic transaminase (ALT), oxalacetic transaminase (AST) and gamma-glutamyl transpeptidase (Υ-GT), used to assess hepatic function between the three age groups. ALT levels were significantly higher (p < 0.02) in men (33.7±26.7 IU/L) when compared with women (22.4±26.2 IU/L), and mean value of Υ-GT was also significantly higher (p < 0.05) in men (61.7±97.8 IU/L) than in women (28.9±33.2 IU/L). These differences, however, were not relevant and were within normality levels for each substance. Hence, it can be estimated that in general hepatic and renal functions were equivalent in all three age groups and of little relevance between both genders.

Table 1 - Click to enlarge

PARO doses and plasma levels

Mean PARO doses administered to all patients was 34.3±20.1 mg. Equivalent doses administered to adults (51.4±23.5 mg/day) were significantly higher (p < 0.001) than doses given to elderly (26.3±10.3 mg/day) and to very elderly (22.1±6.9 mg/day) patients. The difference between mean doses administered to elderly and very elderly patients was also significant (p < 0.05).

Table 1 shows that mean PARO plasma levels (corrected for a daily oral dose of 20 mg) in the 136 patients was 43.2±39.1 ng/mL. For a single dose, there was a 37-fold interindividual variability in PARO plasma levels (maximal concentration/minimal concentration). Mean plasma levels of PARO were significantly (87%) higher in elderly patients compared with adult patients. Mean plasma levels in elderly patients was significantly (57%) higher when compared with adult patients. On the other hand, mean plasma levels of PARO were not significantly different between the group of very elderly and elderly patients. The result of high PARO levels in elderly patients is in accordance with the significant correlation observed between age and PARO plasma levels (r = 0.21, p < 0.05).

Finally, gender did not influence PARO plasma levels, since these values were not significantly different between both genders, neither for the adult nor for the elderly group. There was a significant difference (t = 2.45; p < 0.05) in the group of very elderly patients, but the small number of representatives of the male gender in this group (n = 4) prevents a more definitive conclusion.

Discussion

As the population grows old, there is a high risk of increasing the number of elderly people with mental health problems. Among these problems, depression is the most frequent, with severe consequences for the individual's health as a whole, implying risk of premature death.¹⁵ Although there are therapeutic resources easily available, depression is still underdiagnosed, and above all poorly treated in the elderly. In this context, it is crucial to avoid a bad choice of antidepressants to obtain the best, fastest and most long-lasting therapeutic result as possible. Among determining factors to choose an antidepressant are the following (in decreasing order of importance):¹⁵ 1) pharmacokinetic aspects associated with aging; 2) profile of potential collateral effects; 3) drug interactions.

As a consequence, pharmacokinetic studies in elderly people are needed to have a more precise knowledge of how these drugs behave in old organisms. In the USA, a report by a group of experts¹⁶ recommended that tertiary tricyclic antidepressants - amitriptyline (AMI), imipramine and doxepine - should be avoided in the elderly. SSRI are today the most widely prescribed antidepressant for this age group.

The elderly are characterized for having a wide interindividual variability of drug metabolism. As a consequence, there is a great difficulty in predicting the target-dose for the patient: this can be demonstrated by interindividual variability in plasma levels found for a same standard dose of the antidepressant. In a previous study, applying the same methodology used in this study, the authors found that interindividual variability of AMI plasma levels in the elderly ranged up to 18 times (for its main metabolite, nortriptyline, it ranged 13 times).¹⁷ In a similar study, the authors reported that, for a 20 mg dose of citalopram (CIT), interindividual variability for plasma rates could reach up to 16 times.¹⁸ These results are quite lower than the 37-fold variability found in the present study for PARO, which had been confirmed by previous studies,^10,11 but that did not include important data from very elderly patients.

In the present study, gender did not account for such variability - the difference in PARO levels between both genders was not significant, and renal and hepatic functions were equivalent in all three groups.

Age was significantly correlated with PARO plasma levels (r = 0.21; p < 0.05). PARO plasma levels were 87% higher in the group of patients aged 80 years or older when compared with the same levels in adult patients, while they were 57% higher in patients aged 65-79 years compared with adult patients. These results suggest that PARO levels increase with age, which has been confirmed by other authors.

Kaye et al.⁵ verified that there is an important interindividual variation in the elderly in terms of pharmacokinetic parameters in the steady state, with statistically significant increase in plasma concentrations and decrease in elimination.

Lundmark et al.¹⁰ conducted a clinical study in 21 patients with mean age of 72 years. They found considerable variability in PARO plasma levels in the steady state, with higher concentrations in very elderly patients. There was also significant variability in elimination half-life in the elderly. The authors concluded that these results did not justify the need for reducing PARO doses in the elderly and that further studies were needed.

In the study on CIT, plasma levels were 55% higher in the group of patients aged 80 years or older when compared with the same levels in adult patients, and 38% higher in patients aged 65-79 years compared with adult patients. These results suggest that CIT levels also increase with age, but at a lower proportion than PARO. However, only a study particularly designed to compare both antidepressants may find a significant difference as to interindividual variability.

In the study on AMI, plasma levels were 9% higher in the group of patients aged 80 years or older when compared with the same levels in adult patients, and equivalent when compared with patients aged 65-79 years. In conclusion, AMI plasma levels were not significantly changed as a whole by the aging process.

Possible explanatory mechanisms for the increase in PARO with age include (1) presence of a prescribed co-medication (often multiple in the elderly), (2) reduction in PARO extraction and/or (3) the age process itself, whether alone or in association with reduction in PARO extraction through the process of PARO demethylation (mediated by CYP2D6).¹⁹ For the first hypothesis, which considers prescribed co-medication, the authors did not report concomitant medication, which may reduce the value of obtained results. However, only patients receiving drugs that did not interfere with the PARO metabolism were included.

The present study presents limitations that may reduce the impact of conclusions. Firstly, it is a retrospective study using data measured for clinical, and not for research purposes. A prospective study could increase the significance of possible conclusions. The lack of parameters about intensity of the depressive state is also a limiting factor. A correlation between obtained plasma rates and therapeutic outcome could have been useful. The same can be said about the lack of a record of undesirable effects. Such record could be valuable to know, for instance, whether there was an increase in undesirable effects simultaneously to the increase in PARO plasma levels. Finally, a reliable record of the co-medication could have facilitated the study of potential drug interaction risks, especially in the context of increase in plasma levels.

Conclusion

The present study confirms the observation of the existence of a significant interindividual variability in PARO plasma levels for a given dose. Age partly contributed to this variability, while gender has no influence on it. A mean increase of 57-87% in PARO plasma levels was measured in elderly and very elderly patients in comparison with these levels in younger levels. A reduction in PARO dose in elderly patients (aged 65 years or older) is recommended, but there is no consensus for this issue. Although there is no evidence of the existence of a relationship between an ideal plasma concentration interval and the maximal therapeutic response or between critical plasma concentration and increased risk of adverse effects, monitoring of plasma levels seems justified considering the findings of this study, in addition to the likely increased sensitivity to drugs in elderly patients, also caused by pharmacodynamic factors. The limitations of this study leads to the proposal of new research studies using a more rigorous methodology, but also including an expressive number of patients aged 80 years or older.

Acknowledgments

The authors thank Dr. Michel Gaillard for his support in the execution of this study.

References

• 1. Alexopoulos GS, Katz IR, Reynolds CF 3rd, Carpenter D, Docherty JP. Pharmacotherapy of depressive disorders in older patients. Postgrad Med. 2001;Spec N° Pharmacotherapy:1-86.
• 2. Reynolds CF 3rd, Dew MA, Pollock BG, Mulsant BH, Frank E, Miller MD, et al. Maintenance treatment of major depression in old age. N Engl J Med. 2006;354(11):1130-8.
• 3. Hiemke C. [Paroxetine: pharmacokinetics and pharmacodynamics]. Fortschr Neurol Psychiatr. 1994;62(Suppl 1):2-8.
• 4. Bayer AJ, Roberts NA, Allen EA, Horan M, Routledge PA, Swift CG, et al. The pharmacokinetics of paroxetine in the elderly. Acta Psychiatr Scand Suppl. 1989;350:85-6.
• 5. Kaye CM, Haddock RE, Langley PF, Mellows G, Tasker TC, Zussman BD, et al. A review of the metabolism and pharmacokinetics of paroxetine in man. Acta Psychiatr Scand Suppl. 1989;350:60-75.
• 6. Dechant KL, Clissold SP. Paroxetine: a review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential in depressive illness. Drugs. 1991;41(2):225-53.
• 7. Tulloch IF, Johnson AM. The pharmacologic profile of paroxetine, a new selective serotonin reuptake inhibitor. J Clin Psychiatry. 1992;53(Suppl):7-12.
• 8. Bloomer JC, Woods FR, Haddock RE, Lennard MS, Tucker GT. The role of cytochrome P4502D6 in the metabolism of paroxetine by human liver microsomes. Br J Clin Pharmacol. 1992;33(5):521-3.
• 9. Dunner DL. An overview of paroxetine in the elderly. Gerontology. 1994;40(Suppl 1):21-7.
• 10. Lundmark J, Scheel Thomsen I, Fjord-Larsen T, Manniche PM, Mengel H, Moller-Nielsen EM, et al. Paroxetine: pharmacokinetic and antidepressant effect in the elderly. Acta Psychiatr Scand Suppl. 1989;350:76-80.
• 11. Sindrup SH, Brosen K, Gram LF. Pharmacokinetics of the selective serotonin reuptake inhibitor paroxetine: nonlinearity and relation to the sparteine oxidation polymorphism. Clin Pharmacol Ther. 1992;51(3):288-95.
• 12. Catterson ML, Preskorn SH. Pharmacokinetics of selective serotonin reuptake inhibitors: clinical relevance. Pharmacol Toxicol. 1996;78(4):203-8.
• 13. Eap CB, Baumann P. Analytical methods for the quantitative determination of selective serotonin reuptake inhibitors for therapeutic drug monitoring purposes in patients. J Chromatogr B Biomed Appl. 1996;686(1):51-63.
• 14. Eap CB, Bouchoux G, Amey M, Cochard N, Savary L, Baumann P. Simultaneous determination of human plasma levels of citalopram, paroxetine, sertraline, and their metabolites by gas chromatography-mass spectrometry. J Chromatogr Sci. 1998;36(7):365-71.
• 15. Baldwin RC, Chiu E, Katona C, Graham N. Guidelines on depression in older people. Practising the evidence. London: Martin Dunitz; 2002.
• 16. Mulsant BH, Alexopoulos GS, Reynolds CF III, Katz IR, Abrams R, Oslin D, et al. Pharmacological treatment of depression in older primary care patients: the PROSPECT algorithm. Int J Geriatr Psychiatry. 2001;16(6):585-92.
• 17. Lima CAM. Efeitos da idade, do sexo e do índice de massa corporal nas concentrações plasmáticas de amitriptilina e nortriptilina em pacientes adultos e idosos. Arq Bras Psiquiatr Neurol Med Legal. 2006;100(2):17-23.
• 18. de Mendonça Lima CA, Baumann P, Brawand-Amey M, Brogli C, Jacquet S, Cochard N, et al. Effect of age and gender on citalopram and desmethylcitalopram steady-state plasma concentrations in adults and elderly depressed patients. Prog Neuropsychopharmacol Biol Psychiatry. 2005;29(6):952-6.
• 19. Feng Y, Pollock BG, Ferrell RE, Kimak MA, Reynolds CF 3rd, Bies RR. Paroxetine: population pharmacokinetic analysis in late-life depression using sparse concentration sampling. Br J Clin Pharmacol. 2006;61(5):558-69.

Publication Dates

• Publication in this collection
  01 Dec 2008
• Date of issue
  Apr 2008

History

• Accepted
  10 Dec 2007
• Received
  24 Oct 2007