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Successful antidepressive treatment with mirtazapine following lung transplantation
Progress in Neuro-Psychopharmacology & Biological Psychiatry 32 (2008) 1745-1746
Contents lists available at ScienceDirect
Progress in Neuro-Psychopharmacology & Biological Psychiatry j o u r n a l h o m e p a g e : w w w. e l s e v i e r. c o m / l o c a t e / p n p b p
Letter to the Editor (Case report)
Successful antidepressive treatment with mirtazapine following lung transplantation
1. Introduction Over the last years, lung transplantation has become a well established intervention in the management of patients with an endstage pulmonary disease. In addition to survival benefits (Trulock et al., 2007), it has the potential to enhance the health-related quality of life and the overall functioning in patients who would have otherwise become medically disabled and functionally impaired (Lanuza et al., 2000; Vasiliadis et al., 2006). However, depression and anxiety related disorders are commonly reported either in a patient awaiting a lung transplant (Parekh et al., 2003) or in patients who had received an organ (Chacko et al., 1996). Causes of depression after lung transplantation may include personality disorders, dysfunctional coping strategies, stressful events, physical complications, side effects of immunosuppressant medications, limitations in job performance, sexual dysfunctions and lack of psychosocial support (Fusar-Poli et al., 2007). No effective and safe psychological or psychopharmacological antidepressive interventions are currently approved for this population. This case report aims to: (i) acknowledge the relevance of major depression in the clinical management of lung-transplant recipients, (ii) encourage clinicians to evaluate post-operative lung-transplanted patients for depression, and (iii) describe the putative role of mirtazapine as a first-choice antidepressant in such population.
anorexia and insomnia. No formal thought disorders, delusions, obsessions, compulsions or phobias were clinically elicited. He explicitly added that “it would have been better not to do such an intervention”. Although he did not report any thoughts of self-harm, death wishes or suicidal thoughts on purpose, he showed a complete lack of interest and a minimal compliance on the rehabilitation programme. Depressive symptoms scored 45 on the Beck Depression Inventory (BDI) (Beck et al., 1974), while the Karnofsky index (Karnofsky and Burchenal, 1949) was 40. He was diagnosed with ICD-10 Major Depression and treated with mirtazapine 30 mg/day, with the aim to improve the mood level, the anorexic behaviour and to normalise the irregular sleeping patterns. He was also offered a daily psychological support by the consultant psychiatrist. The patient remained in the intensive care unit and, after 4 weeks his mood significantly improved. His sleep regularised, his appetite normalised and he felt more relaxed and engaged in the daily activities and in the rehabilitation programme. His BDI and Karnofsky scores at this time were respectively 9 and 65. Fig. 1 s the daily dosage of immunosuppressive medication (mean 323.33 mg; d.s. 130 mg) and the following hematic cyclosporine (mean 225 ng/ml; s.d. 51.78 ng/ml) during the follow-up. No pharmacological interactions between mirtazapine and cyclosporine were observed, since the plasmatic level of cyclosporine remained in the therapeutical range (150–375 ng/ml) for the whole duration of treatment.
2. Case presentation 3. Discussion A 35 year old baker presented to the emergency service with shortness of breath on exertion. Following an admission to a pulmonary service he was diagnosed with “severe pulmonary hypertension, right ventricular dilatation with myocardial hypertrophy”. He then underwent a number of investigations, including perfusion scintigraphy and TC, which confirmed that his pulmonary hypertension occurred in the absence of a known cause (“primary pulmonary hypertension”, PPH). He completed the psychosocial screening assessment which did not evidence any previous psychiatric problems or illicit drug abuse. Three years later he received a bilateral lung transplantation, followed by a standard immunosuppressive therapy (cyclosporine, see below). During the post-surgery period in the intensive care service, he was referred to the liaison psychiatrist because of an episode of severe psychomotor agitation, when he dislodged the tracheal cannula screaming at anyone who was attempting to help him. The mental status examination evidenced a subject awake and oriented to self and place, lucid but minimally cooperative. Conversation was particularly difficult since he showed a significant latency in his answers and made few eyes contacts. His speech was monotonous and low in volume. He subjectively described his mood as “low”. He was objectively sad, tearful and hopeless. He also complained a number of somatic feelings: severe chest pain, 0278-5846/$ – see front matter © 2008 Elsevier Inc. All rights reserved. doi:10.1016/j.pnpbp.2008.05.019
This case report has addressed: (i) the close link between depression and non-adherence to treatment (Di Matteo, 2000), and (ii) the potential importance of having effective and reliable interventions for major depression following lung transplantation. The treatment of such cases is often felt to be problematic and physicians usually remain uncertain about which course of treatment is most beneficial. Transplanted patients are prescribed numerous medications for their illnesses, making the addition of psychiatric medications more difficult, since these may increase the risk of serious drug interactions. On the other side, the favourable general safety profile of the newer antidepressant drugs recently introduced has lead to their increased use in lung-transplant recipients. However, most of these medications inhibit one or more hepatic microsomal cytochrome p450 isoenzymes. Because cyclosporine is metabolised predominantly by CYP3A3/4 isoenzymes, inhibition of this system can lead to the build-up of toxic levels. For example, some cases of cyclosporine toxicity attributable to interactions with the novel antidepressants nefazodone and fluvoxamine are reported (Vella and Sayegh, 1998). To our best knowledge, this is the first case report addressing a safe mirtazapine usage in lung-transplantation population. Its anxiolytic effect, its benefit effect on sleep and its 5-HT3
1746
Letter to the Editor (Case report)
Acknowledgements Patient consent has been received for the manuscript to be published. References
Fig. 1. Hematic cyclosporine during the treatment with mirtazapine (therapeutic range: 150–375 ng/ml).
blockade-mediated activity to prevent nausea and vomiting could be extremely useful in the management of lung-transplant recipients with anxiety, depression, insomnia or inappetence. Its side effects usually include sedation and drowsiness (via its H1 blockade) and weight gain, although there is evidence to suggest that these problems are not significant during long-term treatment (Nutt, 2002). Limitations of this manuscript include the methodological design and the lack of any long-term assessment to monitor the behavioural and psychopathological improvements over time. Given these considerations it is impossible to draw firmer conclusions about the efficacy or safety of antidepressive therapies in the lung-transplant population and intensive monitoring of the serum creatinine and cyclosporine level is always recommended. Moreover, although mirtazapine may present a favourable profile, other antidepressants (i.e. Citalopram) have been used in this population with successful results (Silvertooth et al., 2004) and without significant interactions with the immunodepressant medication (Markowitz et al., 1998). Future research should clarify: (i) the clinical efficacy of the new antidepressants in this specific population, (ii) the P450-interaction between new antidepressants and immunosuppressive drugs, and (iii) the side-effect profile of antidepressants best fitting the clinical characteristics of lung-transplanted recipients. 4. Author contribution list This paper is unpublished and it is not being considered for publication elsewhere. All co-authors have agreed to the submission of the paper in this form. Dr. Martinelli and Hobson assessed the subject and collected the data. Dr. Fusar-Poli and Prof. Politi prepared the first draft of the manuscript. 5. Competing interests The author(s) declare that they have no competing interests.
Beck A, Rial W, et al. Short-form of depression inventory: cross validation. Psychol Rep 1974;34:1184–6. Chacko RC, Harper RG, et al. Relationship of psychiatric morbidity and psychosocial factors in organ transplant candidates. Psychosomatics 1996;37:100–7. Di Matteo M. Depression is a risk factor for noncompliance with medical treatment: meta-analysis of the effects of anxiety and depression on patients adherence. Arch Inter Med 2000;160:2101. Fusar-Poli P, Lazzaretti M, et al. Depression after lung transplantation: causes and treatment. Lung 2007;185:55–65. Karnofsky D, Burchenal J. Evaluation of chemotherapeutic agents. Columbia University: New York; 1949. Lanuza D, Lefaiver C, et al. Prospective study of functional status and quality of life before and after lung transplantation. Chest 2000;118:115–22. Markowitz J, Gill H, et al. Lack of antidepressant-cyclosporine pharmacokinetic interactions. J Clin Psychopharmacol 1998;18:91–3. Nutt DJ. Tolerability and safety aspects of mirtazapine. Hum Psychopharmacol 2002;17 (Suppl 1):S37–41. Parekh PI, Blumenthal JA, et al. Psychiatric disorder and quality of life in patients awaiting lung transplantation. Chest 2003;124:1682–8. Silvertooth EJ, Doraiswamy PM, et al. Citalopram and quality of life in lung transplant recipients. Psychosomatics 2004;45:271–2. Trulock EP, Christie JD, et al. Registry of the International Society for Heart and Lung Transplantation: twenty-fourth official adult lung and heart–lung transplantation report—2007. J Heart Lung Transplant 2007;26:782–95. Vasiliadis HM, Collet JP, et al. Health-related quality-of-life determinants in lung transplantation. J Heart Lung Transplant 2006;25:226–33. Vella JP, Sayegh MH. Interactions between cyclosporine and newer antidepressant medications. Am J Kidney Dis 1998;31:320–3.
Paolo Fusar-Poli⁎ Valentina Martinelli Pierluigi Politi DSSAeP, Sezione di Psichiatria, Università di Pavia and Servizio Psichiatrico di Diagnosi e Cura, IRCCS Policlinico San Matteo, Pavia, Italy ⁎ Corresponding author. Department of Applied and Psychobehavioural Sciences, University of Pavia, via Bassi 21, 27100 Pavia, Italy. Tel.: +39 349 6053229; fax: +39 0374 78067. E-mail address: [email protected] (P. Fusar-Poli). Paolo Fusar-Poli Neuroimaging Section, Department of Psychological Medicine, Institute of Psychiatry, King's College London, UK Ryan Hobson Barts and the London School of Medicine, London, UK 18 February 2008
Contents lists available at ScienceDirect
Progress in Neuro-Psychopharmacology & Biological Psychiatry j o u r n a l h o m e p a g e : w w w. e l s e v i e r. c o m / l o c a t e / p n p b p
Letter to the Editor (Case report)
Successful antidepressive treatment with mirtazapine following lung transplantation
1. Introduction Over the last years, lung transplantation has become a well established intervention in the management of patients with an endstage pulmonary disease. In addition to survival benefits (Trulock et al., 2007), it has the potential to enhance the health-related quality of life and the overall functioning in patients who would have otherwise become medically disabled and functionally impaired (Lanuza et al., 2000; Vasiliadis et al., 2006). However, depression and anxiety related disorders are commonly reported either in a patient awaiting a lung transplant (Parekh et al., 2003) or in patients who had received an organ (Chacko et al., 1996). Causes of depression after lung transplantation may include personality disorders, dysfunctional coping strategies, stressful events, physical complications, side effects of immunosuppressant medications, limitations in job performance, sexual dysfunctions and lack of psychosocial support (Fusar-Poli et al., 2007). No effective and safe psychological or psychopharmacological antidepressive interventions are currently approved for this population. This case report aims to: (i) acknowledge the relevance of major depression in the clinical management of lung-transplant recipients, (ii) encourage clinicians to evaluate post-operative lung-transplanted patients for depression, and (iii) describe the putative role of mirtazapine as a first-choice antidepressant in such population.
anorexia and insomnia. No formal thought disorders, delusions, obsessions, compulsions or phobias were clinically elicited. He explicitly added that “it would have been better not to do such an intervention”. Although he did not report any thoughts of self-harm, death wishes or suicidal thoughts on purpose, he showed a complete lack of interest and a minimal compliance on the rehabilitation programme. Depressive symptoms scored 45 on the Beck Depression Inventory (BDI) (Beck et al., 1974), while the Karnofsky index (Karnofsky and Burchenal, 1949) was 40. He was diagnosed with ICD-10 Major Depression and treated with mirtazapine 30 mg/day, with the aim to improve the mood level, the anorexic behaviour and to normalise the irregular sleeping patterns. He was also offered a daily psychological support by the consultant psychiatrist. The patient remained in the intensive care unit and, after 4 weeks his mood significantly improved. His sleep regularised, his appetite normalised and he felt more relaxed and engaged in the daily activities and in the rehabilitation programme. His BDI and Karnofsky scores at this time were respectively 9 and 65. Fig. 1 s the daily dosage of immunosuppressive medication (mean 323.33 mg; d.s. 130 mg) and the following hematic cyclosporine (mean 225 ng/ml; s.d. 51.78 ng/ml) during the follow-up. No pharmacological interactions between mirtazapine and cyclosporine were observed, since the plasmatic level of cyclosporine remained in the therapeutical range (150–375 ng/ml) for the whole duration of treatment.
2. Case presentation 3. Discussion A 35 year old baker presented to the emergency service with shortness of breath on exertion. Following an admission to a pulmonary service he was diagnosed with “severe pulmonary hypertension, right ventricular dilatation with myocardial hypertrophy”. He then underwent a number of investigations, including perfusion scintigraphy and TC, which confirmed that his pulmonary hypertension occurred in the absence of a known cause (“primary pulmonary hypertension”, PPH). He completed the psychosocial screening assessment which did not evidence any previous psychiatric problems or illicit drug abuse. Three years later he received a bilateral lung transplantation, followed by a standard immunosuppressive therapy (cyclosporine, see below). During the post-surgery period in the intensive care service, he was referred to the liaison psychiatrist because of an episode of severe psychomotor agitation, when he dislodged the tracheal cannula screaming at anyone who was attempting to help him. The mental status examination evidenced a subject awake and oriented to self and place, lucid but minimally cooperative. Conversation was particularly difficult since he showed a significant latency in his answers and made few eyes contacts. His speech was monotonous and low in volume. He subjectively described his mood as “low”. He was objectively sad, tearful and hopeless. He also complained a number of somatic feelings: severe chest pain, 0278-5846/$ – see front matter © 2008 Elsevier Inc. All rights reserved. doi:10.1016/j.pnpbp.2008.05.019
This case report has addressed: (i) the close link between depression and non-adherence to treatment (Di Matteo, 2000), and (ii) the potential importance of having effective and reliable interventions for major depression following lung transplantation. The treatment of such cases is often felt to be problematic and physicians usually remain uncertain about which course of treatment is most beneficial. Transplanted patients are prescribed numerous medications for their illnesses, making the addition of psychiatric medications more difficult, since these may increase the risk of serious drug interactions. On the other side, the favourable general safety profile of the newer antidepressant drugs recently introduced has lead to their increased use in lung-transplant recipients. However, most of these medications inhibit one or more hepatic microsomal cytochrome p450 isoenzymes. Because cyclosporine is metabolised predominantly by CYP3A3/4 isoenzymes, inhibition of this system can lead to the build-up of toxic levels. For example, some cases of cyclosporine toxicity attributable to interactions with the novel antidepressants nefazodone and fluvoxamine are reported (Vella and Sayegh, 1998). To our best knowledge, this is the first case report addressing a safe mirtazapine usage in lung-transplantation population. Its anxiolytic effect, its benefit effect on sleep and its 5-HT3
1746
Letter to the Editor (Case report)
Acknowledgements Patient consent has been received for the manuscript to be published. References
Fig. 1. Hematic cyclosporine during the treatment with mirtazapine (therapeutic range: 150–375 ng/ml).
blockade-mediated activity to prevent nausea and vomiting could be extremely useful in the management of lung-transplant recipients with anxiety, depression, insomnia or inappetence. Its side effects usually include sedation and drowsiness (via its H1 blockade) and weight gain, although there is evidence to suggest that these problems are not significant during long-term treatment (Nutt, 2002). Limitations of this manuscript include the methodological design and the lack of any long-term assessment to monitor the behavioural and psychopathological improvements over time. Given these considerations it is impossible to draw firmer conclusions about the efficacy or safety of antidepressive therapies in the lung-transplant population and intensive monitoring of the serum creatinine and cyclosporine level is always recommended. Moreover, although mirtazapine may present a favourable profile, other antidepressants (i.e. Citalopram) have been used in this population with successful results (Silvertooth et al., 2004) and without significant interactions with the immunodepressant medication (Markowitz et al., 1998). Future research should clarify: (i) the clinical efficacy of the new antidepressants in this specific population, (ii) the P450-interaction between new antidepressants and immunosuppressive drugs, and (iii) the side-effect profile of antidepressants best fitting the clinical characteristics of lung-transplanted recipients. 4. Author contribution list This paper is unpublished and it is not being considered for publication elsewhere. All co-authors have agreed to the submission of the paper in this form. Dr. Martinelli and Hobson assessed the subject and collected the data. Dr. Fusar-Poli and Prof. Politi prepared the first draft of the manuscript. 5. Competing interests The author(s) declare that they have no competing interests.
Beck A, Rial W, et al. Short-form of depression inventory: cross validation. Psychol Rep 1974;34:1184–6. Chacko RC, Harper RG, et al. Relationship of psychiatric morbidity and psychosocial factors in organ transplant candidates. Psychosomatics 1996;37:100–7. Di Matteo M. Depression is a risk factor for noncompliance with medical treatment: meta-analysis of the effects of anxiety and depression on patients adherence. Arch Inter Med 2000;160:2101. Fusar-Poli P, Lazzaretti M, et al. Depression after lung transplantation: causes and treatment. Lung 2007;185:55–65. Karnofsky D, Burchenal J. Evaluation of chemotherapeutic agents. Columbia University: New York; 1949. Lanuza D, Lefaiver C, et al. Prospective study of functional status and quality of life before and after lung transplantation. Chest 2000;118:115–22. Markowitz J, Gill H, et al. Lack of antidepressant-cyclosporine pharmacokinetic interactions. J Clin Psychopharmacol 1998;18:91–3. Nutt DJ. Tolerability and safety aspects of mirtazapine. Hum Psychopharmacol 2002;17 (Suppl 1):S37–41. Parekh PI, Blumenthal JA, et al. Psychiatric disorder and quality of life in patients awaiting lung transplantation. Chest 2003;124:1682–8. Silvertooth EJ, Doraiswamy PM, et al. Citalopram and quality of life in lung transplant recipients. Psychosomatics 2004;45:271–2. Trulock EP, Christie JD, et al. Registry of the International Society for Heart and Lung Transplantation: twenty-fourth official adult lung and heart–lung transplantation report—2007. J Heart Lung Transplant 2007;26:782–95. Vasiliadis HM, Collet JP, et al. Health-related quality-of-life determinants in lung transplantation. J Heart Lung Transplant 2006;25:226–33. Vella JP, Sayegh MH. Interactions between cyclosporine and newer antidepressant medications. Am J Kidney Dis 1998;31:320–3.
Paolo Fusar-Poli⁎ Valentina Martinelli Pierluigi Politi DSSAeP, Sezione di Psichiatria, Università di Pavia and Servizio Psichiatrico di Diagnosi e Cura, IRCCS Policlinico San Matteo, Pavia, Italy ⁎ Corresponding author. Department of Applied and Psychobehavioural Sciences, University of Pavia, via Bassi 21, 27100 Pavia, Italy. Tel.: +39 349 6053229; fax: +39 0374 78067. E-mail address: [email protected] (P. Fusar-Poli). Paolo Fusar-Poli Neuroimaging Section, Department of Psychological Medicine, Institute of Psychiatry, King's College London, UK Ryan Hobson Barts and the London School of Medicine, London, UK 18 February 2008