- Email: [email protected]
Tolerance to antidepressant treatment may be overcome by ketoconazole. Report of two cases
Journal of Psychiatric Research 37 (2003) 171–173 www.elsevier.com/locate/jpsychires
Letter to the Editor
Tolerance to antidepressant treatment may be overcome by ketoconazole. Report of two cases Tolerance to antidepressant drugs treatment is an important clinical problem which may manifest as resistance or loss of clinical effect (Baldessarini et al., 2002). Resistance occurs when a patient, after a drug free-period, fails to respond to an antidepressant agent which yielded remission in a previous episode. It occurs in a third of patients in whom rechallenge is performed (Fava M et al., 2002). Another form of tolerance involves the return of depressive symptoms during maintenance antidepressant treatment, which was found to take place in 9–57% of patients in published trials (Byrne and Rotschild, 1998). Even though several pathophysiological mechanisms for the two phenomena have been suggested, there is no current satisfactory explanation or management (Fava, in press). We report here two cases in which ketoconazole, an inhibitor of steroid production employed for medical management of Cushing’s syndrome of various etiologies (Sonino, 1987; Sonino and Boscaro, 1999) and for treatment-resistant depression (Wolkowitz and Reus, 1999; Wolkowitz et al., 1999; Malison et al., 1999) was successfully introduced to overcome tolerance to antidepressant treatment. Patient 1. Mr. A. was a 51-year-old man with no previous history of mood disorders, who presented with a DSM-IV major depressive disorder with melancholic features (American Psychiatric Association, 1994). He was successfully treated with desipramine up to 200 mg per day. After 3 months, desipramine was tapered at the rate of 25 mg every other week. After discontinuation, Mr. A. was well for about 6 months, when he started presenting depressive symptoms again. Desipramine was used up to 250 mg per day, but unsuccessfully, even after lithium augmentation (600 mg per day for 1 month) or switch to fluoxetine (up to 60 mg per day, without lithium, for 6 weeks). He gave informed consent for further assessment and treatment. A clinical psychologist not involved in treatment administered the Change version of Paykel’s Clinical Interview for Depression (CID; Paykel, 1985). Mr. A., 2 weeks after discontinuation of fluoxetine, had a CID score of 62. His 24 h urinary free cortisol (UFC) was
331.9 nmol/day and plasma ACTH at 08.00 h was 20.7 pmol/l. Ketoconazole, 200 mg twice a day, was started. After 1 month of treatment, UFC decreased to 225 nmol/day and ACTH was 15.3 pmol/l. His CID score decreased to 25. After 2 months of treatment with ketoconazole, Mr. A. had a UFC of 174 nmol/day (ACTH level was unavailable). He was greatly improved. Ketoconazole was decreased at the rate of 100 mg per week. At 1 year-follow-up the patient was still well (CID=28) and drug free. His urinary cortisol was 183 nmol/day and ACTH was 12.7 pmol/l. There were no side effects from ketoconazole therapy. Patient 2. Mrs. B. was a 53-year-old woman, with one previous depressive episode 10 years earlier, who presented with major depression (American Psychiatric Association, 1994). She was treated with desipramine up to 200 mg per day, which improved both depressive and anxious symptoms. After 3 months of treatment, desipramine was tapered (at the rate of 25 mg every other week) and eventually discontinued. Three months later, she developed depressive symptoms again. Desipramine was used up to 200 mg per day, unsuccessfully. Mrs. B gave then informed consent for further assessment and treatment. While on desipramine, her CID score was 56. Her UFC was 565.6 nmol/day; her 08.00 h plasma ACTH was 9.7 pmol/l. Ketoconazole 200 mg twice a day was added to desipramine 150 mg per day. After 1 month of combined treatment, her CID score decreased to 23, her UFC to 471.7 nmol/day and ACTH was 5.3 pmol/l. Ketoconazole was then tapered (at the rate of 100 mg per week) and discontinued. One month later she was well, with a UFC of 353.1 nmol/day (ACTH was not available). She continued to take desipramine (150 mg per day). After 4 months, however, she developed a new depressive episode (CID=53; UFC 640 nmol/day; ACTH=10.4 pmol/l). Desipramine was increased to 200 mg, without any effects. Ketoconazole (200 mg twice a day) was added to 150 mg of desipramine and yielded remission in a month (CID=27; UFC=386 nmol/day; ACTH=4.9 pmol/l). Ketoconazole was then discontinued without any loss of effect. Desipramine was continued.
0022-3956/03/$ - see front matter # 2003 Elsevier Science Ltd. All rights reserved. PII: S0022-3956(02)00089-4
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Letter to the Editor / Journal of Psychiatric Research 37 (2003) 171–173
Six months later, she presented another depressive relapse, despite taking desipramine (CID=61; urinary cortisol=527 nmol/day; ACTH=4.9 pmol/l). Addition of ketoconazole up to 400 mg per day was unsuccessful. Ketoconazole was discontinued after a month and cognitive behavioral treatment (Fava GA et al., 2002) was provided by the treating psychiatrist (8 sessions of 30 min every other week). During treatment, desipramine was tapered and discontinued. After 4 months, the patients appeared to have remitted (CID=25; UFC =386 nmol/day; 08.00 plasma ACTH=4.7 pmol/l). She had no further episodes of depression at a 2-year followup. The patient did not report any side effects from ketoconazole therapy. UFC was measured by radioimmunoassay, (Diagnostic Products Corp, Los Angeles, California). The intra-assay CV was 6% (n=10) and the inter-assay CV was 8.2% (n=20). The normal range is 55–331 nmol/ day. Plasma ACTH was measured with an immunoradiometric assay (Nichols, San Juan Capistramo, CA). Intra- and inter-assay CVs were 5% (n=10) and 9% (n=20). Normal values at 08.00 h are up to 22 pmol/l. Even though spontaneous remission cannot be excluded, these two case reports suggest that ketoconazole may overcome resistance upon re-challenge with the same drug and loss of clinical effects during maintenance treatment in major depression. In both cases, after a month there was more than a 50% reduction in the CID score, and in the first case a 20–30% decrease in UFC and ACTH levels. On the basis of findings in Cushing’s disease (Sonino et al., 2000), Sonino and Fava (2002) have suggested that long-term treatment with antidepressant drugs in non-endocrine depression, after an initial phase of normalization of the HPA axis, may recruit different serotonin receptors leading to an increased ACTH production, which results in loss of clinical effect. The poor prognosis of remitted patients still displaying abnormalities of the HPA axis (Holsboer, 1989; Ribeiro et al., 1993) is in line with this hypothesis. These mechanisms may become more evident upon discontinuation of the drug, when they are unopposed, and lead to resistance after rechallenge. Interestingly, in Cushing’s syndrome the decrease of cortisol production by the use of ketoconazole was not found to be associated with changes in ACTH levels or escape phenomena during longterm treatment, except in occasional cases (Sonino et al., 1991). Ketoconazole may reset the HPA axis, more than simply decreasing cortisol production (Sonino and Boscaro, 1999). In the second case, a pharmacokinetic interaction boosting desipramine blood levels cannot be excluded (desipramine blood levels were not available). It is puzzling that, when a further relapse occurred, ketoconazole was no longer effective. A cognitive beha-
vioral approach was then successful and normalized the HPA axis. The findings suggest the clinical importance of pathophysiological mechanisms underlying HPA function during long-term treatment with antidepressant drugs (Holsboer, 2001).
Acknowledgements This work was supported in part by grants from the Ministero dell’Universita` e della Ricerca Scientifica e Tecnologica (MURST, Roma, Italy) to Drs. Sonino and Fava, and from the ‘‘Mental Health Evaluation Project’’ (Istituto Superiore di Sanita`, Roma) to Dr. Fava.
References American Psychiatric Association. Diagnostic and statistical manual of mental disorders (DSM-IV). Washington, DC: APA; 1994. Baldessarini RJ, Ghaemi SN, Viguera AC. Tolerance in antidepressant treatment. Psychotherapy and Psychosomatics 2002;71:177–9. Byrne SE, Rotschild AJ. Loss of antidepressant efficacy during maintenance therapy. Journal of Clinical Psychiatry 1998;59:279– 88. Fava GA. Can long-term treatment with antidepressant drugs worsen the course of depression? Journal of Clinical Psychiatry (in press). Fava GA, Ruini C, Rafanelli C, Grandi S. Cognitive behavioral approach to loss of clinical effect during long-term antidepressant treatment. American Journal of Psychiatry 2002;2094–2095. Fava M, Schmidt ME, Zhang S, Gonzales J, Raute NJ, Judge R. Treatment approaches to major depressive relapse: II. Reinitiation of antidepressant treatment. Psychotherapy and Psychosomatics 2002;71:195–9. Holsboer F. Psychiatric implications of altered limbic-hypothalamicpituitary-adrenocortical activity. European Archives of Psychiatry and Neurological Sciences 1989;238:302–22. Holsboer F. Stress, hypercortisolism and corticosteroid receptors in depression: implications for therapy. Journal of Affective Disorders 2001;62:77–91. Malison RT, Anand A, Pelton GH, Kirwin P, Carpenter L, McDougle CJ, Heninger GR, Price LH. Limited efficacy of ketoconazole in treatment-refractory major depression. Journal of Clinical Psychopharmacology 1999;19:466–70. Paykel ES. The Clinical Interview for Depression. Journal of Affective Disorders 1985;9:85–96. Ribeiro SC, Tandon R, Grunhaus L, Greden JF. The DST as a predictor of outcome in depression. American Journal of Psychiatry 1993;150:1618–29. Sonino N. The use of ketoconazole as an inhibitor of steroid production. New England Journal of Medicine 1987;317:812–8. Sonino N, Boscaro M, Paoletta A, Mantero F, Ziliotto D. Ketoconazole treatment in Cushing’s syndrome. Clinical Endocrinology 1991; 35:347–52. Sonino N, Boscaro M. Medical therapy for Cushing’s disease. Endo-
Letter to the Editor / Journal of Psychiatric Research 37 (2003) 171–173 crinology and Metabolism Clinics of North America 1999;28:211– 22. Sonino N, Fava GA, Fallo F, Franceschetto A, Belluardo P, Boscaro M. Effect of serotonin antagonists ritanserin and ketanserin in Cushing’s disease. Pituitary 2000;3:55–9. Sonino N, Fava GA. CNS drugs in Cushing’s disease. Pathophysiological and therapeutic implications for mood disorders. Progress in Neuropsychopharmacology and Biological Psychiatry 2002;26:1011– 8. Wolkowitz OM, Reus VI. Treatment of depression with antiglucocorticoid drugs. Psychosomatic Medicine 1999;61:698– 711. Wolkowitz OM, Reus VI, Chan T, Manfredi P, Raum W, Johnson R, Garrick J. Antiglucocorticoid treatment of depression. Biological Psychiatry 1999;45:1070–4.
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Nicoletta Sonino Department of Statistical Sciences University of Padova and Department of Mental Health Padova, Italy E-mail address: [email protected] Giovanni A. Fava Affective Disorders Program Department of Psychology University of Bologna Bologna, Italy Accepted 7 November 2002
Letter to the Editor
Tolerance to antidepressant treatment may be overcome by ketoconazole. Report of two cases Tolerance to antidepressant drugs treatment is an important clinical problem which may manifest as resistance or loss of clinical effect (Baldessarini et al., 2002). Resistance occurs when a patient, after a drug free-period, fails to respond to an antidepressant agent which yielded remission in a previous episode. It occurs in a third of patients in whom rechallenge is performed (Fava M et al., 2002). Another form of tolerance involves the return of depressive symptoms during maintenance antidepressant treatment, which was found to take place in 9–57% of patients in published trials (Byrne and Rotschild, 1998). Even though several pathophysiological mechanisms for the two phenomena have been suggested, there is no current satisfactory explanation or management (Fava, in press). We report here two cases in which ketoconazole, an inhibitor of steroid production employed for medical management of Cushing’s syndrome of various etiologies (Sonino, 1987; Sonino and Boscaro, 1999) and for treatment-resistant depression (Wolkowitz and Reus, 1999; Wolkowitz et al., 1999; Malison et al., 1999) was successfully introduced to overcome tolerance to antidepressant treatment. Patient 1. Mr. A. was a 51-year-old man with no previous history of mood disorders, who presented with a DSM-IV major depressive disorder with melancholic features (American Psychiatric Association, 1994). He was successfully treated with desipramine up to 200 mg per day. After 3 months, desipramine was tapered at the rate of 25 mg every other week. After discontinuation, Mr. A. was well for about 6 months, when he started presenting depressive symptoms again. Desipramine was used up to 250 mg per day, but unsuccessfully, even after lithium augmentation (600 mg per day for 1 month) or switch to fluoxetine (up to 60 mg per day, without lithium, for 6 weeks). He gave informed consent for further assessment and treatment. A clinical psychologist not involved in treatment administered the Change version of Paykel’s Clinical Interview for Depression (CID; Paykel, 1985). Mr. A., 2 weeks after discontinuation of fluoxetine, had a CID score of 62. His 24 h urinary free cortisol (UFC) was
331.9 nmol/day and plasma ACTH at 08.00 h was 20.7 pmol/l. Ketoconazole, 200 mg twice a day, was started. After 1 month of treatment, UFC decreased to 225 nmol/day and ACTH was 15.3 pmol/l. His CID score decreased to 25. After 2 months of treatment with ketoconazole, Mr. A. had a UFC of 174 nmol/day (ACTH level was unavailable). He was greatly improved. Ketoconazole was decreased at the rate of 100 mg per week. At 1 year-follow-up the patient was still well (CID=28) and drug free. His urinary cortisol was 183 nmol/day and ACTH was 12.7 pmol/l. There were no side effects from ketoconazole therapy. Patient 2. Mrs. B. was a 53-year-old woman, with one previous depressive episode 10 years earlier, who presented with major depression (American Psychiatric Association, 1994). She was treated with desipramine up to 200 mg per day, which improved both depressive and anxious symptoms. After 3 months of treatment, desipramine was tapered (at the rate of 25 mg every other week) and eventually discontinued. Three months later, she developed depressive symptoms again. Desipramine was used up to 200 mg per day, unsuccessfully. Mrs. B gave then informed consent for further assessment and treatment. While on desipramine, her CID score was 56. Her UFC was 565.6 nmol/day; her 08.00 h plasma ACTH was 9.7 pmol/l. Ketoconazole 200 mg twice a day was added to desipramine 150 mg per day. After 1 month of combined treatment, her CID score decreased to 23, her UFC to 471.7 nmol/day and ACTH was 5.3 pmol/l. Ketoconazole was then tapered (at the rate of 100 mg per week) and discontinued. One month later she was well, with a UFC of 353.1 nmol/day (ACTH was not available). She continued to take desipramine (150 mg per day). After 4 months, however, she developed a new depressive episode (CID=53; UFC 640 nmol/day; ACTH=10.4 pmol/l). Desipramine was increased to 200 mg, without any effects. Ketoconazole (200 mg twice a day) was added to 150 mg of desipramine and yielded remission in a month (CID=27; UFC=386 nmol/day; ACTH=4.9 pmol/l). Ketoconazole was then discontinued without any loss of effect. Desipramine was continued.
0022-3956/03/$ - see front matter # 2003 Elsevier Science Ltd. All rights reserved. PII: S0022-3956(02)00089-4
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Letter to the Editor / Journal of Psychiatric Research 37 (2003) 171–173
Six months later, she presented another depressive relapse, despite taking desipramine (CID=61; urinary cortisol=527 nmol/day; ACTH=4.9 pmol/l). Addition of ketoconazole up to 400 mg per day was unsuccessful. Ketoconazole was discontinued after a month and cognitive behavioral treatment (Fava GA et al., 2002) was provided by the treating psychiatrist (8 sessions of 30 min every other week). During treatment, desipramine was tapered and discontinued. After 4 months, the patients appeared to have remitted (CID=25; UFC =386 nmol/day; 08.00 plasma ACTH=4.7 pmol/l). She had no further episodes of depression at a 2-year followup. The patient did not report any side effects from ketoconazole therapy. UFC was measured by radioimmunoassay, (Diagnostic Products Corp, Los Angeles, California). The intra-assay CV was 6% (n=10) and the inter-assay CV was 8.2% (n=20). The normal range is 55–331 nmol/ day. Plasma ACTH was measured with an immunoradiometric assay (Nichols, San Juan Capistramo, CA). Intra- and inter-assay CVs were 5% (n=10) and 9% (n=20). Normal values at 08.00 h are up to 22 pmol/l. Even though spontaneous remission cannot be excluded, these two case reports suggest that ketoconazole may overcome resistance upon re-challenge with the same drug and loss of clinical effects during maintenance treatment in major depression. In both cases, after a month there was more than a 50% reduction in the CID score, and in the first case a 20–30% decrease in UFC and ACTH levels. On the basis of findings in Cushing’s disease (Sonino et al., 2000), Sonino and Fava (2002) have suggested that long-term treatment with antidepressant drugs in non-endocrine depression, after an initial phase of normalization of the HPA axis, may recruit different serotonin receptors leading to an increased ACTH production, which results in loss of clinical effect. The poor prognosis of remitted patients still displaying abnormalities of the HPA axis (Holsboer, 1989; Ribeiro et al., 1993) is in line with this hypothesis. These mechanisms may become more evident upon discontinuation of the drug, when they are unopposed, and lead to resistance after rechallenge. Interestingly, in Cushing’s syndrome the decrease of cortisol production by the use of ketoconazole was not found to be associated with changes in ACTH levels or escape phenomena during longterm treatment, except in occasional cases (Sonino et al., 1991). Ketoconazole may reset the HPA axis, more than simply decreasing cortisol production (Sonino and Boscaro, 1999). In the second case, a pharmacokinetic interaction boosting desipramine blood levels cannot be excluded (desipramine blood levels were not available). It is puzzling that, when a further relapse occurred, ketoconazole was no longer effective. A cognitive beha-
vioral approach was then successful and normalized the HPA axis. The findings suggest the clinical importance of pathophysiological mechanisms underlying HPA function during long-term treatment with antidepressant drugs (Holsboer, 2001).
Acknowledgements This work was supported in part by grants from the Ministero dell’Universita` e della Ricerca Scientifica e Tecnologica (MURST, Roma, Italy) to Drs. Sonino and Fava, and from the ‘‘Mental Health Evaluation Project’’ (Istituto Superiore di Sanita`, Roma) to Dr. Fava.
References American Psychiatric Association. Diagnostic and statistical manual of mental disorders (DSM-IV). Washington, DC: APA; 1994. Baldessarini RJ, Ghaemi SN, Viguera AC. Tolerance in antidepressant treatment. Psychotherapy and Psychosomatics 2002;71:177–9. Byrne SE, Rotschild AJ. Loss of antidepressant efficacy during maintenance therapy. Journal of Clinical Psychiatry 1998;59:279– 88. Fava GA. Can long-term treatment with antidepressant drugs worsen the course of depression? Journal of Clinical Psychiatry (in press). Fava GA, Ruini C, Rafanelli C, Grandi S. Cognitive behavioral approach to loss of clinical effect during long-term antidepressant treatment. American Journal of Psychiatry 2002;2094–2095. Fava M, Schmidt ME, Zhang S, Gonzales J, Raute NJ, Judge R. Treatment approaches to major depressive relapse: II. Reinitiation of antidepressant treatment. Psychotherapy and Psychosomatics 2002;71:195–9. Holsboer F. Psychiatric implications of altered limbic-hypothalamicpituitary-adrenocortical activity. European Archives of Psychiatry and Neurological Sciences 1989;238:302–22. Holsboer F. Stress, hypercortisolism and corticosteroid receptors in depression: implications for therapy. Journal of Affective Disorders 2001;62:77–91. Malison RT, Anand A, Pelton GH, Kirwin P, Carpenter L, McDougle CJ, Heninger GR, Price LH. Limited efficacy of ketoconazole in treatment-refractory major depression. Journal of Clinical Psychopharmacology 1999;19:466–70. Paykel ES. The Clinical Interview for Depression. Journal of Affective Disorders 1985;9:85–96. Ribeiro SC, Tandon R, Grunhaus L, Greden JF. The DST as a predictor of outcome in depression. American Journal of Psychiatry 1993;150:1618–29. Sonino N. The use of ketoconazole as an inhibitor of steroid production. New England Journal of Medicine 1987;317:812–8. Sonino N, Boscaro M, Paoletta A, Mantero F, Ziliotto D. Ketoconazole treatment in Cushing’s syndrome. Clinical Endocrinology 1991; 35:347–52. Sonino N, Boscaro M. Medical therapy for Cushing’s disease. Endo-
Letter to the Editor / Journal of Psychiatric Research 37 (2003) 171–173 crinology and Metabolism Clinics of North America 1999;28:211– 22. Sonino N, Fava GA, Fallo F, Franceschetto A, Belluardo P, Boscaro M. Effect of serotonin antagonists ritanserin and ketanserin in Cushing’s disease. Pituitary 2000;3:55–9. Sonino N, Fava GA. CNS drugs in Cushing’s disease. Pathophysiological and therapeutic implications for mood disorders. Progress in Neuropsychopharmacology and Biological Psychiatry 2002;26:1011– 8. Wolkowitz OM, Reus VI. Treatment of depression with antiglucocorticoid drugs. Psychosomatic Medicine 1999;61:698– 711. Wolkowitz OM, Reus VI, Chan T, Manfredi P, Raum W, Johnson R, Garrick J. Antiglucocorticoid treatment of depression. Biological Psychiatry 1999;45:1070–4.
173
Nicoletta Sonino Department of Statistical Sciences University of Padova and Department of Mental Health Padova, Italy E-mail address: [email protected] Giovanni A. Fava Affective Disorders Program Department of Psychology University of Bologna Bologna, Italy Accepted 7 November 2002