Depression in adolescents

A recent report on a large, multisite, industry-sponsored, randomized, controlled trial suggests that nefezadone is more effective than placebo in the treatment of depression in adolescents. Nefazadone was well tolerated. No subject experienced a significant el-... 

Ryan, N., Meyer, V, Dachille, S., Mazzie, D., and Puig-Antich, J. (1988a) Lithium antidepressant augmentation in TCA-refractory depression in adolescents. J Am Acad Child Adolesc Psychiatry 27 371-376. 

Rao U, Ryan ND, Birmaher B, et al. Unipolar depression in adolescents clinical outcome in adulthood. J Am Acad Child Adolesc Psychiatry 1995 34 566-578. 

Apter A, Laufer N, Bar-Sever M, Har-Even D, Ofek H, Weizman A. Serum cholesterol, suicidal tendencies, impulsivity, aggression, and depression in adolescent psychiatric inpatients. Biol Psychiatry 1999 46 532-541. 

Even worse, GSK made sure that Study 329 was eventually published in a whitewashed form in the prestigious Journal of the American Academy of Child and Adolescent Psychiatry (Keller et ah, 2001). The title left no doubt about the scientific nature of the study Efficacy of Paroxetine in the Treatment of Adolescent Major Depression A Randomized, Controlled Trial. The conclusion to the lengthy analysis, a mere one sentence long, left no doubt about what the reader was supposed to learn Paroxetine is generally well tolerated and effective for major depression in adolescents. That one sentence, so prominently displayed as the last line of the abstract, was a drug company public relations triumph, one bound to vastly increase the off-label prescription to children of their ineffective, dangerous drug. 

The UK Committee of Safety of Medicines has previously warned that paroxetine appeared to be no more effective than placebo in the treatment of depression in adolescents and might be associated with a greater risk of self harm (SEDA-28, 16). In a meta-analysis of both published and unpublished placebo-controlled trials of SSRIs in childhood and adolescent depression, only fluoxetine seemed clearly to be associated with a positive benefit-harm balance (26). The evidence of efficacy for sertraline and citalopram was doubtful, while the risk of serious adverse events was significantly increased. Additionally, for both drugs the risk of suicidal behavior was numerically increased. In regard to venlafaxine, the risk of suicidal behavior was significantly greater than placebo. 

There is marginal evidence to support the use of TCAs in the treatment of depression in adolescents but benefits are likely to be moderate at best. 

In the Treatment of SSRl-Resistant Depression in Adolescents (TORDIA) study [7 ], 334 depressed adolescents, who had not responded to a previous trial with an SSRl antidepressant, were randomized to either another SSRl or venlafaxine, with or without cognitive behavioral therapy. There were no significant differences between the groups in the rates of suicidal and non-sui-cidal self-injury, although the significance of this was limited by the lack of a placebo comparison group [8 J. 

Brent DA, Emslie GJ, Clarke GN, Asarnow J, Spirito A, Ritz L. Predictors of spontaneous and systematically assessed suicidal adverse events in the treatment of SSRI-resistant depression in adolescents (TORDIA) study. Am J Psychiatry 2009 166(4) 418-26. 

Data supporting efficacy of antidepressants in children and adolescents are sparse. Fluoxetine is the only antidepressant that is FDA approved for treatment of depression in patients less than 18 years of age. 

Whisman, M. A., Pinto, A. (1997). Hopelessness depression in depressed inpatient adolescents. Cognitive Therapy and Research, 21, 345-358. 

Merry S, McDowell H, Hetrick S, Bir J, Muller N. Psychological and/or educational interventions for the prevention of depression in children and adolescents. Cochrane Database Syst Rev 2004. 

Goenjian AK, Yehuda R, Pynoos RS, Steinberg AM, Tashjian M, Yang RK, Najarian LM, Fairbanks LA (1996) Basal cortisol, dexamethasone suppression of cortisol and MHPG in adolescents after the 1988 earthquake in Armenia. Am J Psychiatry 153 929-934 Gormley GJ, Lowy MT, Reder AT, Hospelhorn VD, Antel JP, Meltzer HY (1985) Glucocorticoid receptors in depression relationship to the dexamethasone suppression test. Am J Psychiatry 142 1278-1284... 

Botteron, K.N., Raichle, M.E., Heath, A.C., and Todd, R.D. (2000) Twin study of brain morphometry in adolescent- or earlier-onset depression. Presented at Depression in the Twenty-first Century. Laguna Beach, CA ... 

Kaufman, J., and Ryan, N. (1999) The neurobiology of child and adolescent depression. In Charney, D., Nestler, E., and Bunny, B., eds. The Neurobiological Foundation of Mental Illness. New York Oxford University Press, pp. 810-821. 

Lewinsohn, P.M., Clarke, G.N., Seeley, J.R., and Rohde, P. (1994) Major depression in community adolescents age at onset, episode duration, and time to recurrence [see comments]. J Am Acad Child Adolesc Psychiatry 33 809-818. 

Puig-Antich, J. and Gittleman, R. (1982) Depression in childhood and adolescence. In Paykel, E. ed. Handbook of Affective Disorders. New York Guilford Press, pp. 379-392. 

Ryan, N., and Dahl, R. (1993) The biology of depression in children and adolescents. In Mann, J. and Kupfer, D., eds. The Biology of Depressive Disorders. New York Plenum Press, pp. 37-58. 

Tutus, A., Kibar, M., Sofuoglu, S., Basturk, M., and Gonul, A.S. (1998) A technetium-99m hexamethylpropylene amine oxime brain single-photon emission tomography study in adolescent patients with major depressive disorder. Eur J Nucl Med 25 601— 606. 

Kessler, R.C. and Walters, E.E. (1998) Epidemiology of DSM-III-R major depression and minor depression among adolescents and young adults in the National Comorbidity Survey. Depress Anxiety 7 3-14. 

Pine, D.S., Cohen, P., Pine, D.S., Cohen, P., Gurley, D., Brook, J., and Ma, Y. (1998) The risk for early-adulthood anxiety and depressive disorders in adolescents with anxiety and depressive disorders. Arch Gen Psychiatry 55 56—64. 

Mania. Mania and hypomania can also occur in children and adolescents on SSRIs, and, again, it is not known if there is an added developmental risk (Ven-kataraman et al., 1992). In a fluoxetine treatment study for depression, 3 (of 48) patients developed manic symptoms, even after excluding patients with psychotic depression, bipolar symptoms, or a family history of bipolar disorder (Emslie et al., 1997). In a paroxetine treatment study for depression, 5 adolescents (of 93) were removed for emotional lability and 1 for eupho-ria/expansive mood (Keller et al., 2001). 

In a recent pilot study, 16 out of 22 (72%) adolescents with BD treated with additional lamotrigine during their depressed phase responded to treatment by the end of week 4 this suggests that lamotrigine might be useful in adolescent bipolar depression. (Kusumakar and Yathan, 1997). 

There is no empirical evidence available for clinical use in children and adolescents. Yet, Hypericum seems to be used for the treatment of mild to moderate depression in the young (Walter et ah, 2000). St. John s wort should be avoided in young patients with severe depression and bipolar disorder (given the lack of adult data about effectiveness and risk of manic induction, respectively) and in those who have significant suicide risk. Treatments of proven efficacy (e.g., SSRIs, mood stabilisers) should be preferred in these cases. However, St. John s wort may be considered in cases of unipolar depression where conventional treatments have failed and prior to the use of combinations of drugs that have an increased risk of side effects and whose efficacy has not been demonstrated. 

The primary indication for ECT in adolescents is the short-term treatment of mood symptoms, depressive or manic (Walter et al., 1999). Mood symptoms in the course of major depression, psychotic depression, bipolar disorder, organic mood disorders, schizophrenia, and schizoaffective disorder respond well to ECT. Psychotic symptoms in mood disorders also respond well to ECT whereas the effectiveness of ECT in the treatment of psychotic symptoms in schizophrenia is doubtful. There are suggestions that other uncommon clinical conditions in adolescents such as catatonia and neuroleptic malignant syndrome also benefit from ECT. The effectiveness of ECT seems to lessen when there is a comorbid personality disorder or drug and/or alcohol problems. There are very few data about usefulness on prepubertal children. 

Ghaziuddin, N., King, C.A., Naylor, M.W., Ghaziuddin, M., Chaud-hary, N., Giordani, B., Dequardo, J.R., Tandon, R., and Greden, J. (1996) Electroconvulsive treatment in adolescents with pharmacotherapy-refractory depression. / Child Adolesc Psycho-pharmacol 6 259—271. 

In adolescents with MDD, an open study showed significant improvement of refractory depressive symptoms after augmentation of TCA treatment with lithium (Ryan et al., 1988a). Another open-label study did not replicate this finding (Strober et al., 1992). 

Electroconvulsive therapy is one of the most efficacious treatments for adults with nonresistant (70% response) and resistant MDD (50% response) (APA, 2000). Because of the invasiveness of this treatment, however, it remains the treatment of choice only for the most severe, incapacitating forms of resistant depression. No studies have been carried out among adolescents, but anecdotal reports have suggested that adolescents with refractory depression may respond to ECT without significant side effects (Rey and Walter, 1997). Approximately 60% of adult patients treated successfully with ECT tend to relapse after 6 months (APA, 2000). Therefore, they must also receive maintenance treatment with antidepressants and sometimes maintenance ECT. There are no reports of use of maintenance ECT in adolescents. 

Other innovative treatments such as intravenous clomipramine (CMI) and TMS have been used for the treatment of depressed adults who have not responded to standard treatment. In adolescents, intravenous clomipramine has been shown to be efficacious for patients who have failed to respond to other antidepressant treatments (Sallee et al., 1997). 

If at the end of the continuation phase it is decided that the antidepressants should be discontinued, this should be done gradually (e.g., over 6 weeks) to avoid withdrawal effects such as sleep disturbance, irritability, or gastrointestinal symptoms, which may lead the clinician to misinterpret the need for continued medication treatment. Clinical practice has suggested that rapid discontinuation of antidepressants may precipitate a relapse or recurrence of depression. In children and adolescents, it is recommended that treatment be discontinued while they are on extended vacations, rather than during the school year. 

Ambrosini, P.J., Wagner, K.D., Biederman, J., Click, I., Tan, C., Elia, J., Hebeler, J., Rabinovich, H., Lock, J., and Geller, D. (1999) Multicenter open-label sertraline study in adolescent outpatients with major depression. J Am Acad Child Adolesc Psychiatry 38 566-572. 

Birmaher, B., McCafferty, J.P., Bellow, K.M., and Beebe, K.L. (2000b) Comorbid ADHD and disruptive behavior disorders as predictors of response in adolescents treated for major depression. Presented at the American Psychiatric Association Annual Meeting, Chicago, IL. 

Emslie, G.J., Heiligenstein, J.H., Hoog, S.L., Judge, R., Brown E.B., and Nilsson, M. (2000) Fluoxetine for acute treatment of depression in children and adolescents a placebo controlled randomized clinical trial. Presented at the 39th Annual Meeting of the American College of Neuropsychopharmacology, San Juan, Puerto Rico. 

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