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FEATURE: Andrew Cotgrove Should young people be given antidepressants? Yes BMJ 2007; 335: 750 [Full text]

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Young people and antidepressants: we need a balanced debate

Anne L. Appleton   (15 October 2007)

Neurotransmitter Precursors first before SSRI's

Frederick W. Nelson M.S., M.A.   (18 October 2007)

Benefits and risks of SSRI: a case for shared decision making

Sarah E Hetrick   (19 October 2007)

Usual care with SSRI treatment

Erin Rogers   (20 October 2007)

Young people and antidepressants: we need a balanced debate 15 October 2007
Anne L. Appleton, Breast Physician Weybridge Breast Clinic, Weybridge, Surrey. KT13 8AL Send response to journal: Re: Young people and antidepressants: we need a balanced debate	I read the debate by Drs Cotgrove and Timimi (1) on whether young people should be given antidepressants with interest but some dismay. How are non-specialists (that is, the vast majority of us when dealing with specialty outside of our own) to glean a practical take-home message on this important subject when the specialist authors themselves present such polarised views? A more helpful article for generalists (this is after all the BMJ, not a specialist psychiatry journal) would have explained why the views expressed by the authors were contradictory on several keys points (for example the methodology and significance of the ADAPT trial) and would have summarised the evidence for and against in a more balanced fashion. After all, the vast majority of us are also parents, as well as doctors, and we need a balanced view on this topical subject, just as much as non-medical parents will seek our guidance and opinion on this topical and controversial subject. (1) Should young people be given antidepressants? Cotgrove A., Timimi S. BMJ 13 Oct 2007 (vol 335); 750 - 751 Competing interests: None declared
Neurotransmitter Precursors first before SSRI's 18 October 2007
Frederick W. Nelson M.S., M.A., Mindbody Therapist private practice Nelson Counseling & Therapy 444 NE Ravenna Blvd. Seattle WA USA 98115 Send response to journal: Re: Neurotransmitter Precursors first before SSRI's	My work with adolescents has shown that they respond rapidly to amino acid precursors of neurotransmitters. The amino acids such as L-phenylalanine, 5-HTP, and GABA derived from glutamine are quickly incorporated into depressed adolescent and adolescents with ADD ADHD as well as adolescents with anxiety issues. It seems wise to me to give brain neurochemistry systems a chance to be self- correcting before adding in chemicals / drugs that are NOT manufactured biologically by humans. There are no nutritional deficits of the SSRI's and other antidepressants. But, it has been shown that depression is related to deficits of neurotransmitters. MY clinical experience has been that neuerotransmitter precursors act with in 1-2 hrs for immediate issues such as concentration and focus, anxiety, irritability, and within a day for depression and obsessional thinking associated with depression. The brain has an active transport system which pumps over neurotransmitter precursors and if one elevates the precrsors in the blood sans meals one gets active incorporation into the desired neurotransmitters of serotonin, PEA, dopamine, norepinephrine and GABA. I presented a poster session at the ISSTS conference in New Orleans in 2004 on this material. See fwnelson.com These interventions work with adolescents and children and should be used before introducing drugs that are designed not to be easily metabolized and consequently can over stimulate various neurological receptors and cause potential developmental shifts out of a normal pattern. Serotonin enhancement using 5-HTP overcomes genetic impairment of the hydroxylation of tryptophan in adolescents with ADD and ADHD which is the rate-limiting step for serotonin production. L-Phenylalanine makes PEA in the brain which is the natural stimulant neurotransmitter which releases dopamine, serotonin, and norepinephrine. L-phenylalanine in converted in the liver to tyrosine which is the precursor to dopamine and there by norepinephrine. L-phenylalanine taken at night using 250 -500 mg. for children and adolescents suppresses traumatic nightmares associated with PTSD the night they take it. See fwnelson.com I believe we have missed the boat on treatment for children with depression by not utilizing neurotransmitter precursor direct nutritional intervention. The brain has thousands of checks and balances for handling nutrition and shunting the nutrients into biochemical pathways to achieve neurotransmitter balance. Let us use the natural stimulant PEA before putting our adolescents on speed (stimulants like Adderall, Ritalin and Desoxyn). PEA lasts 20 minutes when released by the brain not like stimulants that continually stimulate release of neurotransmitters that results in depletion. First try using the evolutionary system evolved to make neurotransmitters before using an artificial reuptake inhibitor with its structure designed to resist metabolic breakdown. We should have learned from the tranquilizers specifically the benzodiazepines that if you inhibit a receptor you get more receptors being produced or degraded. In neurological development receptors come and go but with SSRI's et. cetra continual stimulation leads to development imbalances. Let us begin to enhance brain nutrition and neurotransmitter balance before inhibiting and pushing the balance toward a specific therapeutic objective while ignoring developmental growing brain processes. Frederick W. Nelson M.S., M.A. Nelson Counseling & Therapy, Suite 200-C, 444 NE Ravenna Blvd. Seattle WA 98115-6467 fwnelson@verizon.net fwnelson.com For the readers convenience I have included below a brief bibliography about amino acid and brain metabolism. AMINO ACIDS IN THERAPY A Guide to the Therapeutic Application of Protein Constituents, Leon Chaitlow, N.D. D.O. M.D.O.A., Thorsons Publishers Ltd, 1986. NATURAL ALTERNATIVES TO PROZAC, Michael T. Murray, N.D., William Morrow & Co. Inc, NYNY, 1996. 5-HTP The Natural Way to Overcome Depression , Obesity, and Insomnia, Murray, M., ND, Bantam Books, NY, 1998. Fernstrom J. D. "Dietary Amino Acids and Brain function, Perspective in Practice, J. American Dietetic Association. 1994, 94(1), pp.71-77. Kravitz, H.M. and Sabelli, H.C. ,"Dietary Supplements of Phenylalanine and Other Amino Acids Precursors of Brain Neuroamines in the Treatment of Depression." J. American Osteopathy Assoc. Sept. 1984, Vol. (Supple1) pp. 119-123. Mouret, J. et. al. "L-Tyrosine Cures Immediate and Long-Term Dependent Depressions/" Comptes Rendus De L'Academie Des Sciences. 1988, Vol. 306, pp. 93-98. Birdsall, T. C. "5-Hydroxytryptophan: A Clinically-Effective Serotonin Precursor." Alternative medicine Reiew. November 4, 1998, vol. 3, pp. 271-280. Sabelli, H.C. and Javaid J.I. " Phenylethylamine Modulation Effects: Therapeutic and Diagnostic Implicatins." J. of Neuopsychiatry Clinical Neuroscience, Winter, 1995, vol. 7(1) pp. 6-14. Sabelli, H. C. Fink, P., Fawcett, J., thom, C., " Sustained Antidepressant Effect of PEA Replacement." J. Neuropsychiaatry Clinical Neuroscience. Spring , 1996. Vol. 8(2), pp. 158-171. Competing interests: None declared
Benefits and risks of SSRI: a case for shared decision making 19 October 2007
Sarah E Hetrick, Research Fellow ORYGEN Research Centre, Department of Psychiatry, University of Melbourne, Melbourne, Australia Send response to journal: Re: Benefits and risks of SSRI: a case for shared decision making	As Andrew Cotgrove concluded, what is required is a clear and balanced view of the data on SSRIs [1], that ultimately enables young people and their families supported to make an informed collaborative decision with their treatment provider. Perhaps neither of the pieces from Cotgrove and Timini achieved this [1]. Our systematic review attempted to present data about the benefits and risks of SSRIs in a balanced way without going beyond the results of the trials [2]. While Cotgrove correctly reported a “significant benefit” over placebo for some SSRIs, it is more accurate to state that this is a statistically significant benefit, with effect sizes modest at best. For example, for fluoxetine, the only SSRI with consistent evidence of its effectiveness in reducing depression symptoms in both children and adolescents, the treatment effect is -5.63 (95% CI -7.38 to -3.88) on the CDRS-R, a scale with a total range of range of 17-113. The response rates in the fluoxetine trial groups varied between 41% and 61% and in the placebo groups between 20% and 35% [2]. However, the exclusion of ‘placebo -responders’ in the lead-in time to these fluoxetine trials no doubt has an impact on response rate data. It is also certainly the case that in a real-world setting, particularly primary care, a percentage of those presenting for treatment represent this 'placebo-reponse' group who recover, even in the presence of a non-active intervention. Only two of the trials of fluoxetine reported on functioning [3,4], with neither showing any difference between the group on fluoxetine and the group on placebo. The data about suicidality should equally be presented in a balanced way. There were no reports of completed suicide in a total sample of 2,240 young people, however, suicide is a rare event and much larger sample sizes with longer follow-up are needed to assess the risk fully. The trials on SSRIs show a consistent but small increased risk of suicidal ideation and definitive suicidal behaviour (using the Columbia Classification [5]) with a risk of between 1 and 13% (a total of 63 events in 1,167 patients) in the SSRI group and between 0 and 7% (a total of 32 events in 1,073 patients) in the placebo group in our meta-analysis [2]. Most of these trials excluded those with co-morbid conditions, which increases the risk of suicidal ideation and suicidal behaviours [6-9] and excluded those at risk of suicide. Hence it is unclear what the effect of treatment with an SSRI would be on suicide related outcomes in a population of depressed children and adolescents at risk of suicide and with co-morbid conditions. This issue of exclusion of young people at risk of suicide and who have co-morbid conditions also renders it impossible to assess the effectiveness of SSRI medication in a more severely unwell group of young people. As there are no trials of SSRIs compared to placebo in this group, any assertions regarding efficacy or risk are premature. What is clear is that young people with depressive disorder are at risk, not only of suicide, but of developing other psychiatric and substance use disorders, impairments in social and occupational functioning, and probable negative effects on brain regions such as the hippocampus [10-18]. While observational studies are touted as providing evidence that reduced prescribing of SSRIs has resulted in an increase in suicide [19,20], Libby’s recent article highlights one of many other possibilities that may account for an increase in suicide, that is, a lack of diagnosis and treatment more generally of young people with depressive disorders [21]. Treatment is necessary, but so to is the explicit and balanced presentation of what the data does and does not show in a process of shared decision making with young people and their families about how to manage depression. 1. Cotgrove, A., Timimi, S. (2007). Should young people be given antidepressants? BMJ, 335, 750-751 2. Hetrick S, Merry S, McKenzie J, Sindahl P, Proctor M. Selective serotonin reuptake inhibitors (SSRIs) for depressive disorders in children and adolescents. Cochrane Database of Systematic Reviews 2007, Issue 3. Art. No.: CD004851. DOI: 10.1002/14651858.CD004851pub2. In: The Cochrane Library. Chichester, UK: John Wiley & Sons, Ltd 3. Emslie, G. J., Rush, R., Weinberg, W. A., Kowatch, W. A., Hughes, C. W., Carmody, T., et al. (1997). A double blind, randomized, placebo- controlled trial of fluoxetine in children and adolescents with depression. Archives of General Psychiatry, 54, 1031-1037. 4. Emslie, G. J., Heiligenstein, J. H., Wagner, K. D., Hoog, S. I., Ernest, D. E., Brown, E., et al. (2002). Fluoxetine for acute treatment of depression in children and adolescents: A placebo-controlled randomized clinical trial. Journal of the American Academy of Child and Adolescent Psychiatry, 41, 1205-2015. 5. Posner, K., Oquendo, M., Gould, M., Stanley, B., & Davies, M. (2007). Columbia classification algorithm of suicidal assessment (C- CASA): Classification of suicidal events in the FDA's pediatric suicidal risk analysis of antidepressants. American Journal of Psychiatry, 164(7), 1035-1043. 6. Andrews, J. A., & Lewinsohn, P. M. (1992). Suicide attempts among older adolescents: prevalence and co-occurance with psychiatric disorder. Journal of the American Academy of Child and Adolescent Psychiatry, 31(4), 655-662. 7. Brent, D. A., Kalas, R., Edelbrock, C., Costello, A., J, Dulcan, M. K., & Conover, N. (1986). Psychopathology and its relationship to suicidal ideation in childhood and adolescence. Journal of the American Academy of Child and Adolescent Psychiatry, 25(5), 666-673. 8. Esposito, C. L., & Clum, G. A. (2002). Psychiatric symptoms and their relationship to suicidal ideation in a high-risk adolescent community sample. Journal of the American Academy of Child and Adolescent Psychiatry, 41(1), 44-51. 9. Shaffer, D., Gould, M. S., Fisher, P., Trautman, P., Moreau, D., Kleinman, M. M. A., et al. (1996). Psychiatric diagnosis in child and adolescent suicide. Archives of General Psychiatry, 53(4), 339-348. 10. Harrington R, Fudge H, Rutter M, Pickles A, Hill J: Adult outcomes of childhood and adolescent depression. I. Psychiatric status. Arch Gen Psychiatry 1990;47: 465-473. 11. Birmaher B, Ryan ND, Williamson DE, Brent DA, Kaufman J, Dahl RE, Perel J, Nelson B: Childhood and adolescent depression: A review of the past 10 years. Part 1. J Am Acad Child Adolesc Psychiatry 1996;35: 1427- 1435. 12. Judd LL, Paulus MP, Wells KB, Rapaport MH: Socioeconomic burden of subsyndromal depressive symptoms and major depression in a sample of the general population. Am J Psychiatry 1996;153: 1411-1417 13. Kovacs M, Feinberg TL, Crouse-Novak MA, Paulauskas SL, Finkelstein R: Depressive disorders in childhood: I. A longitudinal prospective study of characteristics and recovery. Arch Gen Psychiatry 1984;41: 229-237. 14. Campbell S, Marriott M, Nahmias C, MacQueen GM: Lower hippocampal volume in patients suffering from depression: a meta-analysis. Am J Psychiatry 2004;161: 598–607 15. Videbech P, Ravnkilde B: Hippocampal volume and depression: a meta-analysis of MRI studies. Am J Psychiatry 2004;161: 1957–66. 16. Blumenthal SJ: Youth suicide: Risk factors, assessment, and treatment of adolescent and young adult suicidal patients. Psychiatr Clin North Am 1990;13(3):511-557 17. Rao U, Weissman MM, Martin JA, Hammond RW: Childhood depression and risk of suicide: A preliminary report of a longitudinal study. J Am Acad Child Adolesc Psychiatry 1993;32: 21-27. 18. Weissman MM, Wolk S, Goldstein RB, Moreau D, Adams P, Greenwald S, Klier CM, Ryan ND, Dahl RE, Wickramaratne P: Depressed adolescents grown up. JAMA 1999;281: 1707-1713 19. Gibbons, R. D., Brown, C. H., Hur, K., Marcus, S. M., Bhaumik, D. K., & Mann, J. J. (2007). Relationship Between Antidepressants and Suicide Attempts: An Analysis of the Veterens Health Administration Data American Journal of Psychiatry, 164(7), 1044-1038. 20. Simon, G. E., & Savarino, J. (2007). Suicide Attempts Among Patients Starting Depression Treatment With Medication or Psychotherapy. American Journal of Human Genetics, 164(7), 1029-1034. 21. Libby, A. M., Brent, D. A., Morrato, E. H., Orton, H. D., Allen, R., & Valuck, R. J. (2007). Decline in Treatment of Pediatric Depression After FDA Advisory on Risk of Suicidality With SSRIs. . American Journal of Human Genetics, 164(6), 884-891. Competing interests: None declared
Usual care with SSRI treatment 20 October 2007
Erin Rogers, health science specialist VA NYHHCS, New York, NY 10010 Send response to journal: Re: Usual care with SSRI treatment	I think it is important to be specific about the level of usual care given in what is described as “fluoxetine alone” treatment of choice for severe depression [1]. In the ADAPT study, for example, their SSRI-only group still received usual care, which was an offer of nine or more sessions with a specialist going over such things as depression education, family or peer conflicts, and co-morbidities, as well as connecting with schools and “other agencies” [2]. It is also worth noting that 21% of persons screened for the trial were excluded from randomization because they responded to a brief initial intervention of this usual care. Clarke et al.’s study utilized HMO usual care, which included an average of 5 mental health outpatient visits by the SSRI-treatment-as-usual participants, and authors suggested this level of treatment may have been so effective that their study was underpowered to detect added effectiveness from CBT in this setting [3]. These types of care are very different from literal fluoxetine-alone treatment, where a prescription is given with medication follow-up but no psychotherapeutic support, which is seen in some U.S. care environments [4,5]. Also, longer-term data were recently published for the TADS study, showing that CBT-alone, fluoxetine-alone, and combined treatment responses converge by week 30 of treatment [6]. TADS authors suggested in this article that while fluoxetine-alone and combined treatment both accelerate depression improvement, they recommend combined treatment because it reduces persistent suicidal ideation and events. 1. Cotgrove, A., Timimi, S. (2007). Should young people be given antidepressants? BMJ, 335, 750-751. 2. Goodyer I, Dubicka B, Wilkinson P, Kelvin R, Roberts C, Byford S, et al. Selective serotonin reuptake inhibitors and routine specialist care with and without cognitive behaviour therapy in adolescents with major depression: randomised controlled trial. BMJ 2007;335:142. 3. Clark G, Debar L, Lynch F, Powell J, Gale J, O'Connor E, et al. A randomized effectiveness trial of brief cognitive-behavioral therapy for depressed adolescents receiving antidepressant medication. J Am Acad Child Adolesc Psychiatry 2005;44:888-98. 4. Jun Ma, M.D., R.D., Ph.D., Ky-Van Lee, Ph.D., Randall S. Stafford, M.D., Ph.D. Depression treatment during outpatient visits by U.S. children and adolescents, J Adol Health. 2005;37:434-442. 5. Mark Olfson, MD, MPH; Marc J. Gameroff, PhD; Steven C. Marcus, PhD; Bruce D. Waslick, MD. Outpatient Treatment of Child and Adolescent Depression in the United States. Arch Gen Psychiatry. 2003;60:1236-1242. 6. March JS, Silva S, Petrycki S, Curry J, Wells K, Fairbank J, Burns B, Domino M, McNulty S, Vitiello B, Severe J. The Treatment for Adolescents With Depression Study (TADS): long-term effectiveness and safety outcomes. Arch Gen Psychiatry. 2007 Oct;64(10):1132-43. Competing interests: None declared