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Follicular and late luteal phase serum fluoxetine levels in women suffering from late luteal phase dysphoric disorder
Follicular and Late Luteal Phase Serum Fluoxetine Levels in Women Suffering from Late Luteal Phase Dysphoric Disorder Donna E. Stewart, Margaret Fairman, Sandra Barbadoro, Patricia Zownir, and Meir Steiner
Key Words: Serum fluoxetine levels, menstrual cycle, late luteal phase dysphoric disorder Introduction
Methods
Gender-related differences in drug and alcohol pharmacokinetics have recently received more attention (Frezza et al 1990; Hamilton 1991; Jensvold 1993). One focus of this interest has been on the effects of the menstrual cycle on drug absorption, metabolism, clearance, efficacy, and side effects (Hamilton 1991; Jensvold ! 993; Sotheru et al 1993; Halionquist et al 1993; Gelenberg ! 993). Clinically significant effects in relation to gender or hormonal levels have been reported for lithium (Conrad and Hamilton 1986), antipsychotic drugs, phenytoin, diazepam, propranoiol, and alcohol (Hamilton 1991). Two recent reports have described women whose serum antidepressant levels (trazodone, desipramine) fell to subtherapeutic levels in the late luteal phase of the menstrual cycle (Kimmel et al 1992) or whose menstrual-cycle related depressive symptoms required variable antidepressant dosage of fluoxetine or nortriptyiinc to obtain an optimal therapeutic effect (Jensvold et al 1992). As the majority of information to date has been single case reports or a short series of patients, the purpose of this study was to compare follicular and late iuteai serum fluoxetine and norfluoxetine levels in a larger group of homogeneously selected women with prospectively documented severe late luteal phase dysphoric disorder (LLPDD).
Forty consecutive women were recruited into a double-blind, randomized, placebo-controlledtrial of fluoxetine for the treatment of prospectively confirmed LLPDD. The women were healthy, aged ! 8 to 45 years, had regular menstrual cycles greater than 24 days and less than 35 days, met all DSM-HI-R criteria for LLPDD and showed a 50% increase in severity of"tension," "irritability," and "depression" combined, or a 100% increase in one of these symptoms between the follicular and luteat phase over the baseline period. Women with irregular menstrual cycles, using oral contraceptives, unstable medical illnesses, not using reliable contraceptives, lactating, with psychiatric comorbidity, epilepsy, multiple adverse drug reactions, use of psychotropic medication within 2 months, use of medication to treat premenstraal symptoms within 2 months or prior use of fluoxetine were excluded from the study. ~A,, , study -V,u - ~u~.~F,u,~ : - : . . . . . ureter,vent ~ pao cycle .,,,as,,-,,u, . . . h ~.,, period. Subjects had blood withdrawn at follicular and cycle adjusted late iuteal phase (day 10 and 26 for most women) of a menstrual cycle at least two cycles after randomization to one of three conditions: daily placebo, fluoxetine 20 rag, or fluoxetine 60 rag. Compliance with medication taking was ascertained by twice monthly drug counts. The serum samples were matched for patient and cycle and a number assigned to each woman that precluded personal identification. The blood was collected in Vacutainer tubes (#6430 Becton, Dickinson Franklin Lakes NJ, USA) and the serum separated, frozen, and stored at -20°C. The matched pairs were analyzed for fluoxetine and norfluoxetine using the method of Gupta and Steiner (1990). The precision of the assay at the lower range throughout the study was as follows: intraassay variation 9.1%, interassay variation 10.4%, with the lower limit of detection at 66 nmol/L. The results of 13 women who received placebo medica-
From the Women's Health Concerns Clinic IMFL and Department of Clinical Biochemistry fSB), and the Department of Psychiatry IMS). St. Joseph's Hospital. Hamilton. Ontario; McMaster University (MS), Hamilton.Ontario. and Premenstmal Syndrome Clinic, Family Practice Unit, St. Michael's Hospital (i,rZ), and Department of Psychiatry(DES), University of Toronto, St. Michael's Hospital. Toronto, Ontario, Canada. Address reprint requests to Dr. Donna E. Stewart, Departmentof Psychiatry. University of Toronto. St. Michael's Hospital, 30 Bond Street, Toronto. ON MSB IW8 Canada. Received August 23, 1993; revised October 25, 1993. © 1994 Society of Biological Psychiatry
0006-3223/94/S07.00
BIOL I~YCltlATRY
tion were disc,~led. Paired t,tests (2.tailed) were done using SPSS.PC + statis,'ical package. (SPSS Inc., Chicago. [L).
Results The serum fluoxetine and norltuoxetine levels of the 27 women at follicular and late luteal phase of the menstrual cycle showed no statistically significant difference~ (fluoxetine t = 0.36, df = 26, p = 0.72, mean difference 26.45 +_ 149.63, 95% confidence imerval 123,15-176.1 i): norfluoxetine t = 9.51, df = 26, p = 0.61. mean difference 46.26 -+ 186.02, 95% confidence interval 139.75232.29, The statistical power of the sample size was calculated using the statistical shareware package PC-Size. Usir,g a delta of 500, sd 378, paired t-test, two tailed with alpha set at 0.05, the sample size of 27 has a statistical power of 1.00 (100%).
Discussion We were unable to demonstrate any differences in serum fluoxefine or nodluoxetinc levels in 27 women'with prospectively confirmed LLPDD whose levels were measured in the follicular and late luteal phases of the menstrual cycle at least two cycles after the initiation of fluoxetine. Limitations to our study are our failure to control for weight, smoking, or diet, although clearly anorectic or obese subjects were not included. The long half life of fluoxetinc and norfluoxetine probably makes this drug less vulnerable to menstrual cycle changes, It may be that luteal phase decreases in serum antidepressant levels are unusual and occur only in small subsets of women, but considering that previous reports suggested that increased extracellular fluid volume might he one mechanism (Kimmel et al 1992) and that this phenomenon might be more common in women with dysphoric premenstrual syndrome (Jensvoid et al 1992), our lack of confirmation ofa luteal decline is even more surprising, Another possible consideration is that oral contraceptive medications have been found to alter the clearance of antidepressants
Brief Reports
(Teichman 1990). A condition ofourstudy was that women refrain from using other drugs including oral contraceptives and undergo a two-cycle washout period. If oral contraceptives or other drugs play a critical role in late luteal antidepressant serum level declines, this would explain our negative findings. It is of interest that a number of other drugs including salicylates, antipyrine, nitrazepam and paracetamol do not show significant menstrual cycle variability (Hamilton 1991; Reister et al 1980). To our knowledge, only one paper (Kimmel et al 1992), which reported the need for an increased dose of antideptcssam in the late luteal phase of the menstrual cycle has documented an actual decline in serum antidepressant levels from follicular to luteal phase. Serum antidepressant measurements were performed in only two women in that report and questions arise about patient noncompliance, poor absorption, or decreased protein binding of the drug. Clearly, more frequent sampling points in this work and our study are desirable. Other repoRs have relied only on clinical assessment of the need for a greater ar,tidepressant dose premenstrually, thus raising the possibility of an etiologic mechanism independent of serum drug levels. Proposed explanations include competition between antidepressants and sex hormones for the same metabolic sites, involvement of the P-450 oxygenase system, individual differences in the use of alternative metabolic pathways, or in levels of, or sensitivity to, endogenous sex hormones (Hamilton 1991). Clearly, further work is required to elucidate possible effects of menstrual-cycle variables on depressive symptoms and antidepressant action.
The authors wish to thank Dr. R.L. Patten, Dr. R.N. GulRa,M. Coote, M, Jaszek,and Rose lantoscafor their assistancewith this study. Supportedby a grant in aid from the Eli Lilly Canada, Ltd. and St. Joseph's Hospital Research Foundation, Hamilton,Ontario.
References Conrad C, Hamilton J (1986): Recurrent premenstrual decline in serum lithium concentration; clinical correlates and treatment implications. JAm Acad Child Psychiatr 26:852-853. F,~,,za M, ~adova C, ~ssato G, Terpin M, Baraona E, Lieber C (1990): High blood alcohol levels in women. N Engl J Med 322:95-99, Gelenherg AJ (I 993): Symptoms, drugs and the menstrual cycle. Biolog 2"herPsychiatry ! 6: i 7-20. Gupta RN, Steiner M (1990): Determination of fluoxetine and nonfluoxetine in serum by liquid chromatography with fluorescence detection. J Liquid Chromatog ! 3:3785-3797. Hallonquist YD, Seemen MV, Lang M, Rector NA (1993): Variation in symptom severity over the menstrual cycle of schizophrenics. Biol Psychiatry 33:207-209. Hamilton J (1991): Clinical pharmacology panel report. In Blumenthal SJP, Parry B, Hamilton I (eels), Forging a Women's Health Research Agenda, Conference Proceedings. Washington DC: National Women's Health Resource Center, pp 1-27. Jensvold MF ( 1993): Psychiatric Aspects of the Menstrual Cycle.
In Stewart DE, Stotland N (eds), Psychological Aspects of
Women's Health Care; The Interface Between Psychiatry and Obstetrics and Gynecology. Washington DC: American Psychiatric Press, pp 199-228. Jensvold MF, Reed K, Jarrett DB, Hamilton JA (1992): Menstrual cycle--related depressive symptoms treated with variable antidepressant dosage. J Women's Health !: 109-115. Kimmel S, Gonsalves L, Youngs D, Gidwani G (1992): Fluctuating levels of antidepressants premenstrually. J Psychosomatic Obstet Gynecol 13:277-280. Reister EF, Pantuck EJ, Pantuck CB, Passamanti GT, Veselli ES, Conney AH 0980): Antipyrine metabolism during the menstrual cycle. Clin Pharmacol Ther 28:384-391. Sothern RB, Slover Girl", Morris RW (1993): Circannual anO. menstrual rhythm characteristics in manic episodes and body temperature. Biol Psychiatry 33:194-203. Teichmann A (1990): Influence of oral contraceptives on drug therapy. Am J Obstet Gynecol 163:2208-22 ! 3.
Key Words: Serum fluoxetine levels, menstrual cycle, late luteal phase dysphoric disorder Introduction
Methods
Gender-related differences in drug and alcohol pharmacokinetics have recently received more attention (Frezza et al 1990; Hamilton 1991; Jensvold 1993). One focus of this interest has been on the effects of the menstrual cycle on drug absorption, metabolism, clearance, efficacy, and side effects (Hamilton 1991; Jensvold ! 993; Sotheru et al 1993; Halionquist et al 1993; Gelenberg ! 993). Clinically significant effects in relation to gender or hormonal levels have been reported for lithium (Conrad and Hamilton 1986), antipsychotic drugs, phenytoin, diazepam, propranoiol, and alcohol (Hamilton 1991). Two recent reports have described women whose serum antidepressant levels (trazodone, desipramine) fell to subtherapeutic levels in the late luteal phase of the menstrual cycle (Kimmel et al 1992) or whose menstrual-cycle related depressive symptoms required variable antidepressant dosage of fluoxetine or nortriptyiinc to obtain an optimal therapeutic effect (Jensvold et al 1992). As the majority of information to date has been single case reports or a short series of patients, the purpose of this study was to compare follicular and late iuteai serum fluoxetine and norfluoxetine levels in a larger group of homogeneously selected women with prospectively documented severe late luteal phase dysphoric disorder (LLPDD).
Forty consecutive women were recruited into a double-blind, randomized, placebo-controlledtrial of fluoxetine for the treatment of prospectively confirmed LLPDD. The women were healthy, aged ! 8 to 45 years, had regular menstrual cycles greater than 24 days and less than 35 days, met all DSM-HI-R criteria for LLPDD and showed a 50% increase in severity of"tension," "irritability," and "depression" combined, or a 100% increase in one of these symptoms between the follicular and luteat phase over the baseline period. Women with irregular menstrual cycles, using oral contraceptives, unstable medical illnesses, not using reliable contraceptives, lactating, with psychiatric comorbidity, epilepsy, multiple adverse drug reactions, use of psychotropic medication within 2 months, use of medication to treat premenstraal symptoms within 2 months or prior use of fluoxetine were excluded from the study. ~A,, , study -V,u - ~u~.~F,u,~ : - : . . . . . ureter,vent ~ pao cycle .,,,as,,-,,u, . . . h ~.,, period. Subjects had blood withdrawn at follicular and cycle adjusted late iuteal phase (day 10 and 26 for most women) of a menstrual cycle at least two cycles after randomization to one of three conditions: daily placebo, fluoxetine 20 rag, or fluoxetine 60 rag. Compliance with medication taking was ascertained by twice monthly drug counts. The serum samples were matched for patient and cycle and a number assigned to each woman that precluded personal identification. The blood was collected in Vacutainer tubes (#6430 Becton, Dickinson Franklin Lakes NJ, USA) and the serum separated, frozen, and stored at -20°C. The matched pairs were analyzed for fluoxetine and norfluoxetine using the method of Gupta and Steiner (1990). The precision of the assay at the lower range throughout the study was as follows: intraassay variation 9.1%, interassay variation 10.4%, with the lower limit of detection at 66 nmol/L. The results of 13 women who received placebo medica-
From the Women's Health Concerns Clinic IMFL and Department of Clinical Biochemistry fSB), and the Department of Psychiatry IMS). St. Joseph's Hospital. Hamilton. Ontario; McMaster University (MS), Hamilton.Ontario. and Premenstmal Syndrome Clinic, Family Practice Unit, St. Michael's Hospital (i,rZ), and Department of Psychiatry(DES), University of Toronto, St. Michael's Hospital. Toronto, Ontario, Canada. Address reprint requests to Dr. Donna E. Stewart, Departmentof Psychiatry. University of Toronto. St. Michael's Hospital, 30 Bond Street, Toronto. ON MSB IW8 Canada. Received August 23, 1993; revised October 25, 1993. © 1994 Society of Biological Psychiatry
0006-3223/94/S07.00
BIOL I~YCltlATRY
tion were disc,~led. Paired t,tests (2.tailed) were done using SPSS.PC + statis,'ical package. (SPSS Inc., Chicago. [L).
Results The serum fluoxetine and norltuoxetine levels of the 27 women at follicular and late luteal phase of the menstrual cycle showed no statistically significant difference~ (fluoxetine t = 0.36, df = 26, p = 0.72, mean difference 26.45 +_ 149.63, 95% confidence imerval 123,15-176.1 i): norfluoxetine t = 9.51, df = 26, p = 0.61. mean difference 46.26 -+ 186.02, 95% confidence interval 139.75232.29, The statistical power of the sample size was calculated using the statistical shareware package PC-Size. Usir,g a delta of 500, sd 378, paired t-test, two tailed with alpha set at 0.05, the sample size of 27 has a statistical power of 1.00 (100%).
Discussion We were unable to demonstrate any differences in serum fluoxefine or nodluoxetinc levels in 27 women'with prospectively confirmed LLPDD whose levels were measured in the follicular and late luteal phases of the menstrual cycle at least two cycles after the initiation of fluoxetine. Limitations to our study are our failure to control for weight, smoking, or diet, although clearly anorectic or obese subjects were not included. The long half life of fluoxetinc and norfluoxetine probably makes this drug less vulnerable to menstrual cycle changes, It may be that luteal phase decreases in serum antidepressant levels are unusual and occur only in small subsets of women, but considering that previous reports suggested that increased extracellular fluid volume might he one mechanism (Kimmel et al 1992) and that this phenomenon might be more common in women with dysphoric premenstrual syndrome (Jensvoid et al 1992), our lack of confirmation ofa luteal decline is even more surprising, Another possible consideration is that oral contraceptive medications have been found to alter the clearance of antidepressants
Brief Reports
(Teichman 1990). A condition ofourstudy was that women refrain from using other drugs including oral contraceptives and undergo a two-cycle washout period. If oral contraceptives or other drugs play a critical role in late luteal antidepressant serum level declines, this would explain our negative findings. It is of interest that a number of other drugs including salicylates, antipyrine, nitrazepam and paracetamol do not show significant menstrual cycle variability (Hamilton 1991; Reister et al 1980). To our knowledge, only one paper (Kimmel et al 1992), which reported the need for an increased dose of antideptcssam in the late luteal phase of the menstrual cycle has documented an actual decline in serum antidepressant levels from follicular to luteal phase. Serum antidepressant measurements were performed in only two women in that report and questions arise about patient noncompliance, poor absorption, or decreased protein binding of the drug. Clearly, more frequent sampling points in this work and our study are desirable. Other repoRs have relied only on clinical assessment of the need for a greater ar,tidepressant dose premenstrually, thus raising the possibility of an etiologic mechanism independent of serum drug levels. Proposed explanations include competition between antidepressants and sex hormones for the same metabolic sites, involvement of the P-450 oxygenase system, individual differences in the use of alternative metabolic pathways, or in levels of, or sensitivity to, endogenous sex hormones (Hamilton 1991). Clearly, further work is required to elucidate possible effects of menstrual-cycle variables on depressive symptoms and antidepressant action.
The authors wish to thank Dr. R.L. Patten, Dr. R.N. GulRa,M. Coote, M, Jaszek,and Rose lantoscafor their assistancewith this study. Supportedby a grant in aid from the Eli Lilly Canada, Ltd. and St. Joseph's Hospital Research Foundation, Hamilton,Ontario.
References Conrad C, Hamilton J (1986): Recurrent premenstrual decline in serum lithium concentration; clinical correlates and treatment implications. JAm Acad Child Psychiatr 26:852-853. F,~,,za M, ~adova C, ~ssato G, Terpin M, Baraona E, Lieber C (1990): High blood alcohol levels in women. N Engl J Med 322:95-99, Gelenherg AJ (I 993): Symptoms, drugs and the menstrual cycle. Biolog 2"herPsychiatry ! 6: i 7-20. Gupta RN, Steiner M (1990): Determination of fluoxetine and nonfluoxetine in serum by liquid chromatography with fluorescence detection. J Liquid Chromatog ! 3:3785-3797. Hallonquist YD, Seemen MV, Lang M, Rector NA (1993): Variation in symptom severity over the menstrual cycle of schizophrenics. Biol Psychiatry 33:207-209. Hamilton J (1991): Clinical pharmacology panel report. In Blumenthal SJP, Parry B, Hamilton I (eels), Forging a Women's Health Research Agenda, Conference Proceedings. Washington DC: National Women's Health Resource Center, pp 1-27. Jensvold MF ( 1993): Psychiatric Aspects of the Menstrual Cycle.
In Stewart DE, Stotland N (eds), Psychological Aspects of
Women's Health Care; The Interface Between Psychiatry and Obstetrics and Gynecology. Washington DC: American Psychiatric Press, pp 199-228. Jensvold MF, Reed K, Jarrett DB, Hamilton JA (1992): Menstrual cycle--related depressive symptoms treated with variable antidepressant dosage. J Women's Health !: 109-115. Kimmel S, Gonsalves L, Youngs D, Gidwani G (1992): Fluctuating levels of antidepressants premenstrually. J Psychosomatic Obstet Gynecol 13:277-280. Reister EF, Pantuck EJ, Pantuck CB, Passamanti GT, Veselli ES, Conney AH 0980): Antipyrine metabolism during the menstrual cycle. Clin Pharmacol Ther 28:384-391. Sothern RB, Slover Girl", Morris RW (1993): Circannual anO. menstrual rhythm characteristics in manic episodes and body temperature. Biol Psychiatry 33:194-203. Teichmann A (1990): Influence of oral contraceptives on drug therapy. Am J Obstet Gynecol 163:2208-22 ! 3.