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Excess Mortality from Desipramine and Dosage Recommendations
- Yona Amitai, Henry Frischer (11 May 2003)
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Although SSRIs are with less side effects,but are they really as effective as the TCAs?
- AK Al-Sheikhli (12 May 2003)
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Re: Although SSRIs are with less side effects,but are they really as effective as the TCAs?
- vineet kumar singh, Leyland Preston PR25 3ED (13 May 2003)
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Pharmacological heterogeneity within antidepressant classes
- Anthony S Hale (17 May 2003)
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Inadequacy of antidepressant therapy.
- Alexander SD Spiers (29 May 2003)
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Why should primary care patients have a different response to antidepressants?
- Francois Curtin, Pierre Schulz (7 June 2003)
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ECONOMIC APPROPRIATENESS OF THE EXPENDITURE FOR SELECTIVE SEROTONIN REUPTAKE INHIBITORS IN DEPRESSIVE DISORDER: ANALYSIS OF NATIONAL PRESCRIPTION DATA IN ITALY
- Benedetta Santarlasci, Giulia Burchini, and Andrea Messori (14 February 2004)
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Yona Amitai, Director, Department of Mother Child and Adolescent Health, Ministry of Health, Israel Ministry of Health, 2o King David St. Jerusalem 91010 Israel, Henry Frischer
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The conclusion of MacGillivray et al. (1) of comparable efficacy between serotonin reuptake inhibitors and tricyclic antidepressants (TCA), may result in increase usage of TCA. This raises again the question of TCA safety, with particular reference to desipramine. Higher fatality rate from desipramine compared with that of other TCA has been documented based on national data in the UK (2,3) and the US (4,5). Additionally, unexpected and unexplained death has been reported in several children treated with therapeutic doses of desipramine. We have suggested an explanation for this excessive mortality rate. Desipramine and nortriptyline are desmethyl metabolites of their parent compounds; imipramine and amitriptyline, respectively. Desipramine and nortriptyline share similar pharmacokinetic profiles, and differ from their parent compounds by having higher distribution volumes, erythrocyte/plasma ratio, and higher fraction of unbound drug (5). Thus, desipramine and nortriptyline would have higher tissue concentrations than imipramine and amitriptyline, for a given plasma level. Consequently, the recommended therapeutic plasma levels for nortriptyline is 30-150 ng/mL, compared with 150-300 ng/mL of amitriptyline. The recommended daily dose of nortriptyline (30-150 mg) and the maximum pill strength (75 mg) are half of that of amitriptyline. Indeed, with these dosage adjustments, the mortality index for nortriptyline and amitriptyline are similar. By contrast, similar adjustments have not been done for desipramine. The therapeutic desipramine plasma level listed in the US Pharmaceutical Drug Index (USPDI) is 125-300 ng/mL, the daily dose recommended by the USPDI and the PDR are identical with that of imipramine (50-300 mg), as is the maximum pill strength (150 mg). Of note, therapeutic plasma levels of 40- 160 ng/mL were listed for desipramine in the Goodman and Gilman’s textbook of Pharmacology since 1990. To obtain such plasma levels, desipramine dose should be reduced to half. We have suggested limiting the maximum pill strength of desipramine to 75 mg, reducing its therapeutic plasma levels and to consider downscaling of the recommended dose (5). Yet, eight years elapsed since our suggestions were made, and dosage recommendations, therapeutic plasma levels and maximal pill strength of desipramine remained unchanged. Compilation of the Annual Reports from the Toxic Exposure Surveillance System of the American Association of Poison Control Centers for the years 1983-2001, show high mortality index for desipramine which exceeds that of amitriptyline, imipramine, and nortriptyline by 2.28, 2.67 and 2.35, respectively (Table). We urge for prompt revision of desipramine dosage regime to improve its safety. Yona Amitai, M.D.
Henry Frischer, MD. Ph.D.
References: 1. MacGillivary S, Arroll B, Hatcher S, Ogston S, Reid I, Sullivan F et al. Efficacy and tolerability of selective serotonin reuptake inhibitors compared with tricyclic antidepressants in depression treated in primary care: systematic review and meta-analysis. BMJ;2003:326:1014-7. 2. Cassidy S, Henry J. Fatal toxicity of antidepressant drugs in overdose. BMJ 1987:295: 1021-4. 3. Buckley NA, McManus PR. Can the fatal toxicity of antidepressant drugs be predicted with pharmacological and toxicological data? Drug Safety 1998; 18; 369-81. 4. Kapur S, Mieczkowski T, Mann J. Antidepressant medications and the relative risk of suicide attempt and suicide. JAMA 1992: 268: 3441-5. 5. Amitai Y, Frischer H. The toxicity and dose of desipramine hydrochloride. JAMA 1994: 272: 1719-20. Table: Mortality Index of Four Tricyclic Antidepressant Medications During the Years 1983-2001 (the period 1995-2001 is since our report in 1994) Mortality Index: No. of Death / No. of Exposures (%)*_ 1983-8 1989-94 1995-2001 Total for 1983-2001 Amitriptyline 121/17,302 256/38,347 387/56,100 764/111,749 (0.70) (0.67) (0.69) (0.68) Imipramine 68/9,9596 110/19,961 85/15,678 263/45,235 (0.71) (0.55) 0.54) (0.58) Nortriptyline 28/2,904 110/15,173 58/11,485 196/29,562 (0.96) (0.72) (0.50) (0.66) Desipramine 83/4,113 143/9,869 53/4,050 279/18,032 (2.02)* 1.44)** (1.31) *** (1.55)**** Chi2=(df=3)*70;p<.001**79;p<.001 ***34;p<.001 **183:p<.001 * Source of data: the Annual Reports of the American Association of Poison Control Centers Toxic Exposure Surveillance System for the years 1983 -2001 Competing interests: None declared |
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AK Al-Sheikhli, Loc.Consultant Psychiatrist Medical Centre,2Manor Court Avenue,Nuneaton CV11 5HX,England.
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Dear Sir, MacGillivray etal(BMJ 2003)did show in their review article similar effectiveness for the SSRIs and TCAs in primary care depressive illness, also they did show that SSRIs are better tolerated. But from clinical experience, although SSRIs are better tolerated than TCAs, they tend to be of similar effectiveness for mild and moderate depressive illness. For severe depressive illness with or without psychotic features, TCAs tend to be better. With my best regards, A.K.Al-Sheikhli,MB;ChB,MRCPsych DPM. Competing interests: None declared |
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vineet kumar singh, SHO Level 2 Child and Adolescent Psychiatry CAMHS shawbrook House Balcaress Road, Leyland Preston PR25 3ED
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Dear Sir/Madam We all agree that SSRI`S have greater tolerability and reach therapeutic potential sooner but evidence does slightly favour Tricyclics in terms of efficacy.Tricyclics can be very useful for resistant and severe depression in inpatient setting because of wider recepter profile.If the risk of suicide is minimal and there are no contraindications tricyclics can be tried as a first change antidepressant in place of trying other SSRI,all of which have the same receptor profile. Thanks Dr Singh Competing interests: None declared |
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Anthony S Hale, Professor of Psychiatry KIMHS, University of Kent, CT2 7NZ
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The paper by MacGillivray et al (BMJ 2003; 326: 1014) potentially makes a huge contribution to the understanding of the relative utility of serotonin selective reuptake inhibitors (SSRIs) and older antidepressants in primary care. Sadly, the usefulness of this meta-analysis is limited by the original data, as is so often the case. These results are very difficult to interpret, not least because the comparitors used in the key studies are pharmacologically heterogeneous. Two studies, including one of the key three crucial studies providing data in an unambiguous format, used mianserin as a comparitor. Mianserin is a tetracyclic, not a tricyclic as the paper’s title might imply. It is not a potent reuptake inhibitor and is a potent and thus sedative antihistamine. A third study used lofepramine as a comparitor, more ‘modern’ tricyclic with a much more benign anticholinergic side effect profile than its older cousins, with an adverse event rate similar to the SSRIs (1). Two of the three studies providing unambiguous data for the efficacy analysis were of paroxetine against amitriptyline. Paroxetine may be considered an ‘atypical’ SSRI, in that is has some adrenergic reuptake inhibition and anticholinergic properties, so that pharmacologically is has a profile lying between the more selective SSRIs and the classic tricyclics, as does lofepramine (2). As an underlying principle of meta-analysis is homogeneity of the material, it is no surprise that a clear answer does not emerge from this work, given the pharmacological heterogeneity. References: 1. Katona CL, Abou-Saleh MT, Harrison DA, Nairac BA, Edwards DR, Lock T, Burns RA, Robertson MM. Placebo-controlled trial of lithium augmentation of fluoxetine and lofepramine. Br J Psychiatry. 1995 Jan;166(1):80-6. 2. Hale A S. The treatment of depression: the reuptake inhibitors. In: Honig A, van Praag HM. Depression: Neurobiological, Psychopathological and Therapeutic Advances. 1997. John Wiley & Sons Chichester UK. Competing interests: Past investigator and speaker for companies producing all the drugs concerned |
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Alexander SD Spiers, Professor of Medicine (Retired) Home SL6 9TR
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The valuable article by MacGillivray and his colleagues serves to underline the general inadequacy of therapy with antidepressant drugs. Frequently they are ineffective, and relatively often they are employed to commit suicide, and in this setting they are quite lethal (1,2). Studies of their efficacy are frequently small, methodologically flawed, and all too often are sponsored by the manufacturers of the drug under study. As the article points out, the majority of patients with depression are treated in a primary care setting, but many of the drug studies are conducted in a secondary care setting and their results - even when reliable - cannot safely be extrapolated to the patient population that is encountered in primary care. The authors found no significant difference in effectiveness when tricyclic antidepressants were compared with selective serotonin reuptake inhibitors, although there was a significant advantage for the latter in terms of greater tolerability and lower withdrawal rates. This might imply that the serotonin reuptake inhibitors are actually inferior, as the lower withdrawal rate was not accompanied by greater efficacy. Perhaps the best conclusion is that none of the currently available drugs is of sovereign value. I recall prescribing amitriptyline - then a relatively new drug - as a house officer in 1961. Since then we have seen a multitude of new antidepressants introduced - each one reported to be superior to all preceding drugs - but after more than forty years, amitriptyline remains on the market and many of the newer drugs are no longer prescribed. Amitriptyline is not a very good drug, but its persistence on the market surely indicates that there has been no dramatic advance in antidepressant drug therapy. 1.Hawton K, Simkin S, Deeks J. Co-proxamol and suicide: a study of national mortality statistics and local non-fatal self poisonings. BMJ 2003;326:1006-8. 2. Hall DW, Mant A, Mitchell PB, Rendle VA, Hickie IB, McManus P. Association between antidepressant prescribing and suicide in Australia, 1991-2000: trend analysis. BMJ 2003;326:1008-11. Competing interests: None declared |
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Francois Curtin, Consultant Clinical Psychopharmacology Unit, Geneva University Hospital, CH-1225 Geneva, Switzerland, Pierre Schulz
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MacGillivray et al (1) published a meta-analysis on antidepressant treatments for primary care depressed patients. They compared the efficacy and tolerability of selective serotoninergic reuptake inhibitors (SSRI) to those of tricyclics. Studying primary care patients was taken as the criteria for selecting studies. We question the validity of this criteria. First, it is not sure that the patients treated in a primary care setting are similar between the UK, Greece and South Africa, for example, in terms of diagnosis of depression, depression severity, comorbidities or general health care. One could expect a large heterogeneity in the population of patients defined by primary care depressed patients. Second, we wonder to which extent primary care depressed patients differ from the secondary care population of patients. We would like to know according to what clinical parameters differences should be observed and, according to the hypothesized differences, what differences in efficacy and safety should be expected between the two antidepressant classes. When an antidepressant, whose efficacy has been demonstrated in clinical trials, is used in a patient with a depression, why should one expect that the patient will respond to tricyclics or SSRI in a comparatively different manner simply because the clinical setting is different? Do patients become psychiatric patients only when in secondary care? Did the authors select studies where patients received a prescription for an antidepressant while not being psychiatric patients? A difference that might exist between primary and secondary care patients might be a lesser comorbidity of other psychiatric disorders but a greater comorbidity of physical disorders. This might impact on the efficacy of antidepressants as well as on their tolerability. One could also expect that secondary care patients would be managed in a more careful way by psychiatrists aware of psychotropic drug administration than by GPs who are less familiar with these treatments. It is therefore surprising to read the conclusion that the drop-out rate could be lower in primary care patients compared to secondary care patients. The results of the meta-analysis by Gillivray et al (1) are in line with what is known about antidepressant treatments (2) but the patients included might be quite heterogenous. 1.MacGillivray S, Arroll B, Hatcher S, Ogston S, Reid I, Sullivan F, Williams B, Crombie I. Efficacy and tolerability of selective serotonin reuptake inhibitors compared with tricyclic antidepressants in depression treated in primary care: systematic review and meta-analysis. BMJ 2003;323:1014 2.Anderson IM. Selective serotonin reuptake inhibitors versus tricyclic antidepressants: a meta-analysis of efficacy and tolerability. J Affect Disord 2000;58:19-36 Competing interests: None declared |
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Benedetta Santarlasci, researcher Laboratorio SIFO di Farmacoeconomia, c/o U.O. Farmaceutica, Azienda Careggi, 50132 Firenze, Italy, Giulia Burchini, and Andrea Messori
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The systematic review by MacGillivray et al. (1) discusses the efficacy and tolerability of selective serotonin reuptake inhibitors (SSRIs) compared with tricyclic antidepressants. While this review is almost exclusively focused on clinical effectiveness, the high cost of these agents raises the need to evaluate also their cost-effectiveness ratio. In Italy, SSRIs are widely prescribed to patients with depressive disorder. To interpret the data of yearly national expenditure (EXPEND) for a drug class, the method recently proposed by Messori et al. (2-10) assigns an index of “economic appropriateness” to the treatment(s) under examination. This analysis is based on the comparison between the health gain theoretically expected from EXPEND according to current cost effectiveness benchmarks (expected health gain, EHG) and the amount of health that is estimated to be gained in the "real" patients (real health gain, RHG). The final index is calculated as RHG/EHG. Considering the Italian expenditure for SSRIs in 2002 (372 million Euros) along with the average cost of a DDD (12), the number of DDDs administered over the year under examination can be calculated to be 323,478,269. If one designs this economic analysis as a comparison between SSRIs and tricyclic antidepressants, the increase in cost related to the use of SSRIs is 356,958,261 Euros in 2002 (assumptions: cost of 1 DDD = 1.15 Euros for SSRIs and 0.0465 Euros for tricyclic antidepressants). What is the "economic appropriateness" of this expenditure? The value of EHG is 35,696 quality-adjusted life years (QALYs) or 7,139 QALYs using the benchmark of either 10,000 or 50,000 Euros per QALY gained, respectively. To calculate the value of RHG, since the average duration of the treatment with these agents is around 2 years per patient (13), the number of patients who have been started on these drugs in 2002 is calculated as 443,121. The lifetime gain per patient is 0.25 QALYs (13), and so 443,121 patients are thought to gain a total of 110,780 QALYs. Comparing EHG (either 35,696 or 7,139 QALYs depending on which benchmark is chosen) with RHG (110,780 QALYs) yields a ratio RHG/EHG of 3.10 or 15.5, respectively. In summary, our analysis produces a pharmacoeconomic profile of SSRIs (RHG much greater than EHG) more favourable than the findings previously published in the literature (13). There are some important approximations in our analysis: firstly the uncertainties about the average duration of treatment and secondly the methodological quality of the study by Revicki et al. (13) (which is flawed by the large number of unproven assumptions). Both of these approximations might have contributed to overestimating the value of RHG. REFERENCES 1. MacGillivray S, Arroll B, Hatcher S, Ogston S, Reid I, Sullivan F, Williams B, Crombie I. Efficacy and tolerability of selective serotonin reuptake inhibitors compared with tricyclic antidepressants in depression treated in primary care: systematicreview and meta-analysis. 2. Messori A et al. Economic appropriateness of the expenditure for alendronate: cost-effectiveness analysis of national prescription data in Italy. http://bmj.com/cgi/eletters/327/7406/89#40333 3. Santarlasci B, Trippoli S, Messori A. Economic appropriateness of the expenditure for beta-interferon in multiple sclerosis: analysis of national prescription data in Italy. http://bmj.bmjjournals.com/cgi/eletters/326/7388/522#46835 4. Cecchi M, Pelagotti F, Santarlasci B, Trippoli S, Brutti C, Messori A. Economic appropriateness of the expenditure for infliximab in rheumatoid arthritis : analysis of national prescription data in Italy. http://bmj.com/cgi/eletters/324/7333/312#44561 5. Santarlasci B, Brutti C, Messori A. Economic appropriateness of the expenditure for aromatase inhibitors: analysis of national prescription data in Italy. http://bmj.com/cgi/eletters/327/7420/885#47864 6. Messori A et al. Economic appropriateness of the expenditure for coxibs: cost-effectiveness analysis of national prescription data in Italy. http://bmj.com/cgi/eletters/327/7420/933-b#39700 7. Santarlasci B. Economic appropriateness of national drug expenditures: improved estimation of cost-effectiveness ranking for coxibs. http://bmj.com/cgi/eletters/327/7420/933-b#42273 8. Messori A et al. Spending on statins. http://bmj.com/cgi/eletters/327/7420/933-b#38400 9. Messori A et al. Questionable cost-effectiveness of statins for primary prevention of cardiovascular events. http://bmj.com/cgi/eletters/326/7404/1407#34612 10. Vacca F et al. Cost effectiveness of statins in men vs women. http://bmj.com/cgi/eletters/327/7420/933-b#39209 11. Messori A et al. Absolute and relative rankings in cost- effectiveness comparisons. http://bmj.com/cgi/eletters/327/7426/1237#42094 12. Autori Vari. L’uso dei farmaci in Italia. Rapporto nazionale 2002. Osservatorio Nazionale sull’impiego dei farmaci. 13. Revicki DA, Brown RE, Keller MB, Gonzales J, Culpepper L, Hales RE. Cost-effectiveness of newer antidepressants compared with tricyclic antidepressants in managed care settings. J Clin Psychiatry. 1997 Feb;58(2):47-58. Competing interests: None declared |
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