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The neuroscience of depression in adolescence
Journal of Affective Disorders 61 (2000) S15–S21 www.elsevier.com / locate / jad
The neuroscience of depression in adolescence Ronald J. Steingard* Department of Psychiatry, Harvard Medical School, Cambridge, MA 02139, USA
Abstract The neuroscience of depression in children and adolescents has only recently become a focus of research. Initially, techniques previously used for adult investigations were employed, such as endocrine studies and sleep studies. Endocrine studies have indicated that, as in adult depression, a dysregulation of the serotonin (5-HT) axis is involved in childhood depression. However, both of these techniques are difficult to perform in children and have yielded some inconsistent results. The more recently developed neuroimaging techniques should enable the greatest advances in our understanding of the pathophysiology of depression. These techniques have already implicated the frontal lobes in the pathogenesis of depression in children and adolescents, and further research is ongoing. 2000 Elsevier Science B.V. All rights reserved. Keywords: Depression; Adolescents; Children; Magnetic resonance imaging
1. Introduction Research into the neuroscience of depression in adolescence has only recently gathered momentum. A number of different techniques first developed for the assessment of adults have been used in adolescents, including endocrine studies, sleep studies, and neuroimaging. The most recent techniques include the use of magnetic resonance imaging (MRI), associated magnetic resonance spectroscopy (MRS), and functional MRI (fMRI). This paper reviews the literature and describes the results of current studies using such techniques. To date such studies suggest *Corresponding author. Tel.: 1 1-617-665-1013; fax: 1 1-617665-1390. E-mail address: ronald [email protected] (R.J. Ste] ingard).
that the frontal lobes of the brain are involved in the pathogenesis of depression in adolescents and children.
2. Endocrine studies Research on endocrine markers of depression in adolescents lags behind that done in adults. This is partly because studies with youths were initiated at a later date, and also because these studies are difficult to carry out in children. Indeed, it is common practice among endocrinologists to analyse blood samples collected at 10- or 20-min intervals for up to 3 consecutive days, often with concurrent electroencephalographic (EEG) recordings to determine the waking state of the patient. Even though such studies are difficult to perform in children and
0165-0327 / 00 / $ – see front matter 2000 Elsevier Science B.V. All rights reserved. PII: S0165-0327( 00 )00285-8
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R. J. Steingard / Journal of Affective Disorders 61 (2000) S15 –S21
adolescents, this method has been successfully employed by some researchers (Dahl et al., 1991; Kutcher et al., 1991; De Bellis et al., 1996; Rao et al., 1996) to analyse hypothalamic–pituitary–adrenal (HPA) axis functioning with regard to endocrine markers. However, results have been inconsistent. Using this technique, Kutcher et al. (1991) found that nocturnal growth hormone secretion was significantly higher in depressed adolescents than in control subjects at most time points. This finding, however, was not replicated by a subsequent study (De Bellis et al., 1996). Thyroid stimulating hormone was also significantly higher in the depressed subjects at one time point, but cortisol secretion did not differ significantly between the two groups. Similarly, Rao et al. (1996) failed to show significant differences in cortisol levels between depressed adolescents and normal controls. However, there was a trend towards elevated cortisol levels near sleep onset in subjects with recurrent depression compared with those with no further depressive episodes during follow-up. Dahl et al. (1991) also demonstrated significantly elevated cortisol levels around sleep onset in depressed adolescents. In contrast, De Bellis et al. (1996) found that prepubertal depressed children had lower cortisol secretion during the first 4 h after sleep onset compared with controls. Nocturnal levels of adrenocorticotrophin, prolactin, and growth hormone secretion did not differ between the depressed and control groups. Other studies have analysed the secretion of growth hormone in response to stimulation. A blunted response of growth hormone secretion has been reported in children with prepubertal depression after stimulation with clonidine, a growth hormone releasing hormone, and insulin-induced hypoglycemia compared with non-depressed children (Ryan et al., 1994). Interestingly, in one study (PuigAntich et al., 1984), the insulin-induced hypoglycemic response appeared to persist after recovery. Additionally, children with depression do not demonstrate the blunted response to corticotrophin-releasing hormone and decreased secretion of adrenocorticotrophic hormone that is observed in depressed adults (Birmaher et al., 1996). The dexamethasone suppression test has also been employed to analyse the endocrinology of depression but has yielded variable results (Weller et al., 1986;
Fig. 1. Prolactin response to 5-hydroxy-L-tryptophan infusion in children at high-risk of developing depression, children with major depressive disorder (MDD), and low-risk normal children. *P 5 0.05 compared with high-risk and MDD children; †P 5 0.06 compared with high risk and MDD children. Data from Birmaher et al., 1997.
Bernini et al., 1994). This may be because the test is influenced by many different factors and inter-individual variations, including the metabolism of dexamethasone itself. It has been largely inferred that, as in adults, children with depression have a dysregulation involving the serotonin (5-HT) axis. One study showed that depressed children secreted significantly less cortisol and significantly more prolactin in response to 5-HT infusion compared with non-depressed children (Ryan et al., 1992). There is also an increased prolactin production in depressed female children compared with normal female children and compared with both depressed and normal male children (Ryan et al., 1992). Recently, this observation has been confirmed in children at high risk of developing depression (Birmaher et al., 1997). These children secrete similar levels of prolactin in response to 5-HT infusion compared with children with major depressive disorder (MDD), but significantly more compared with low-risk normal children (P 5 0.05) (Fig. 1).
3. Sleep studies Sleep studies have also yielded inconsistent results in the study of childhood and adolescent depression. A number of studies have demonstrated a reduced rapid eye movement (REM) latency (Kutcher et al., 1992; Emslie et al., 1994; Riemann et al., 1995; Williamson et al., 1995; Dahl et al., 1996) and
R. J. Steingard / Journal of Affective Disorders 61 (2000) S15 –S21
prolonged sleep latency (Kutcher et al., 1992; Dahl et al., 1996) in depressed adolescents compared with normal controls. Although another study did not find sleep differences between depressed and normal adolescents initially, it found that normal controls who would later develop depression had significantly higher density of REM and a trend for reduced REM latency compared to controls with no psychiatric disorder at follow-up (Rao et al., 1996). It should be noted, however, that stressful life events also significantly reduce REM latency and increase total REM time in adolescents and this should therefore be taken into account in such studies (Williamson et al., 1995). A number of sleep studies have also been performed in younger children but only one of them has clearly demonstrated a decrease in REM latency and prolonged sleep onset latency (Emslie et al., 1990). There has been one study in children to assess whether sleep changes return to normal after recovery (Puig-Antich et al., 1983). A shorter REM period latency and increased number of REM periods were observed in depressed children after recovery compared with when they were depressed.
4. Neuroimaging Neuroimaging studies have allowed the greatest steps forward in terms of improving our understanding of the underlying pathophysiology of depression. Such studies may also enable the identification of markers to distinguish subjects at risk of developing depression and also to predict response to treatment. Potential markers may be identified by probing either a specific function, such as the neurotransmitter circuit involved in affect recognition, or a specific brain region, such as the frontal lobe (Fig. 2). By comparing results obtained in normal adult subjects, a normal adolescent population, and a depressed adolescent population, markers of adolescent depression may be identified. There are now a number of different imaging modalities available: computerized axial tomography (CAT), single photon emission computerized tomography (SPECT), positron emission tomography (PET), magnetic resonance imaging (MRI), and magnetic resonance spectroscopy (MRS). CAT,
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SPECT, and PET all have their disadvantages. The most obvious of which is that scanning involves radionucleotide exposure which limits their use in this population, particularly for studies requiring repeat scans. However, the use of MRI circumvents this problem.
4.1. Magnetic resonance imaging MRI does not involve the use of a radionucleotide and therefore is potentially safer than SPECT or PET, enabling repeat scans to be performed. It also gives high anatomic resolution and the ability to assess not only volume but shape in a way which cannot be achieved with the other imaging modalities. In addition, MRS and functional MRI (fMRI) allow the assessment of structure and function. An early disadvantage of MRI was the time it took for older machines to capture an anatomic scan (about 1 h), a considerable time for children / adolescents to stay still. Recent technology has, however, reduced this time to between 10 and 20 min. The scanner is noisy and claustrophobic, which may also be problematic when trying to scan children and adolescents. Such problems can be minimized by preparing the child for the scan and familiarizing them with the machine. They may also be comforted with music while undergoing the scan, and parents and study personnel are able to stay in the same room while the child is imaged. MRI has been used to implicate the frontal lobes of the brain in the pathogenesis of depression in children and adolescents (Steingard et al., 1996). This retrospective study of over 1000 children and adolescents hospitalized for psychiatric illness over a 4-year period, identified 65 (30 male and 35 female) who reliably met criteria for depressive disorder (mean age6S.D. 5 13.462.3 years). Using routine MRI scans, the whole cerebral volume (CV), temporal lobe volume, frontal lobe volume (FLV), and ventricular volume (VV) of these patients were compared with those of 18 control subjects (13 male and 5 female; mean age6S.D. 5 10.862.9 years) (Table 1). To correct for differences in absolute CV associated with different body and head sizes, the ratios of FLV/ CV and VV/ CV were compared between the groups. In the depressed population, the
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Fig. 2. Location of Voxel used in MRS.
Table 1 Volumetric MRI in children and adolescents with depressive disorders
Cerebral volume (CV, cm 3 ) Frontal lobe volume (FLV, cm 3 ) Ventricular volume (VV, cm 3 ) FLV/ CV VV/ CV
Depressed (S.D.)
Control (S.D.)
1070.240(120.38)* 212.760(54.86)** 13.770(10.57) 0.200(0.04)*** 0.013(0.009)****
1148.140(110.50) 273.910(10.57) 8.530(3.77) 0.220(0.03) 0.007(0.003)
*P 5 0.035, **P 5 0.004, ***P 5 0.035, ****P 5 0.040 for depressed population compared with controls.
FLV/ CV ratio was significantly lower (P | 0.035) and the VV/ CV ratio was significantly higher (P 5 0.040) compared with the normal population. These
data agree with previous reports in depressed adults (Coffey et al., 1993). A concern of children and adolescent studies is
R. J. Steingard / Journal of Affective Disorders 61 (2000) S15 –S21
that the effects of age are being observed. The neurophysiology of subjects naturally changes with age and may therefore vary during the course of a study. This must be taken into account when analysing imaging data. For example, in the study described above there was a significant age effect on the size of the frontal lobe (P 5 0.0006); however, there did appear to be an independent diagnostic effect as well (Table 2). Such effects necessitate that imaging data are rigorously analysed and indicate that neurophysiological measures in depressed children and adolescents must be compared with normal subjects of the same age. This effect applies not only to neuroimaging studies but also to neuroendocrine and sleep studies.
4.2. Magnetic resonance spectroscopy MRS is commonly used to detect the spin of two compounds, N-acetyl-L-aspartate (NAA) and choline. NAA is thought to be a neuronal marker, and reductions in NAA have been found in a number of pathological conditions (Fujimoto et al., 1996; Schuff et al., 1997). Choline is considered to be a marker of membrane synthesis and cellularity, and increases in pathological conditions (Charles et al., 1994; Fujimoto et al., 1996; Kato et al., 1996). Renshaw et al. (1997) demonstrated that depressed adults have a significantly lower ratio of choline to creatinine (Cho / Cr) in the basal ganglia than comparative subjects and this reduction was more pronounced in treatment responders than in non-responders. It should be noted that levels of NAA and choline are affected by age so these observations require confirmation in younger patients. MRI and proton MRS were performed on 26 healthy adolescents and 14 depressed adolescents (Steingard et al., 1998). Proton MRS was acquired from an area of the left anterior medial frontal lobe. Cho / Cr ratio (P 5 0.0498) and gray matter content Table 2 Regression summary of frontal lobe volume / cerebral volume ratio Independent variable
T (df 5 79)
P-value
Age (years) Sex Diagnosis
2 3.582 0.487 2.148
0.0006 0.6276 0.0348
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(P 5 0.0473) were significantly increased in the left anterior medial frontal lobe of depressed subjects. These findings appear to be independent of age and gender effects. There was no significant difference in age, gender, or NAA / Cr ratio between the two groups. These findings suggest the presence of structural and functional abnormalities in the frontal lobes of adolescents who are predisposed to developing depression.
4.3. Functional magnetic resonance imaging Using the recently developed scanning techniques, the different magnetic properties of oxygenated and deoxygenated blood can be used to analyse the perfusion of different areas of the brain. This method has been used to analyse the brains of schizophrenic and bipolar adults during the presentation of cortical challenge paradigms including finger tapping, word production, and the recognition of facial affect (Yurgelun-Todd et al., 1996; Yurgelun-Todd and Renshaw, 1999). A recent study in bipolar subjects examined cortical changes in response to an affect recognition test and found a reduction of blood flow in the orbital frontal cortex of bipolar patients compared with normal subjects (Yurgelun-Todd et al., 1998). However, if these patients were treated with loxapine they recovered with regard to symptoms and phenomenology, and their ability to process this information in the orbital frontal cortex changed. Such FMRI techniques are currently being used to study affect recognition as a paradigm looking at functioning in the orbital frontal cortex and the amygdala in adolescents. The field of MRI is rapidly developing. Using the present technology we are now able to look for markers of depression in adolescents and to study whether these markers correlate with the presence of symptoms. These functional studies may also educate us about the process of recovery and enable us to predict recovery in individuals.
5. Conclusion Endocrine and sleep studies have yielded inconsistent results about the neuroscience of depression in
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children and adolescents. Neuroimaging using MR techniques appears to represent the most promising area for future studies. MRI studies have already demonstrated a decrease in frontal lobe volume in depressed children and adolescents compared with normal subjects, suggesting that the frontal lobes of the brain are involved in the pathogenesis of depression in children and adolescents. Additionally, MRS has identified a significant increase in the Cho / Cr ratio in the anterior medial frontal lobe of depressed adolescents compared with normal controls. Involvement of the frontal lobes in adolescent depression is currently being further investigated using MRI techniques. Future research in this rapidly developing field should improve our understanding of the pathophysiology of depression, and may identify markers which identify subjects at risk of developing depression and predict patient response to treatment.
References Bernini, G.P., Argenio, G.F., Cern, F., Franchi, F., 1994. Comparison between the suppressive effects of dexamethasone and loperamide on cortisol and ACTH secretion in some pathological conditions. J. Endocrinol. Invest. 17, 799–804. Birmaher, B., Dahl, R.E., Perel, J., Williamson, D.E., Nelson, B., Stull, S., Kaufman, J., Waterman, G.S., Rao, U., Nguyen, N., Puig-Antich, J., Ryan, N.D., 1996. Corticotrophin-releasing hormone challenge in prepubertal major depression. Biol. Psychiatry 39, 267–277. Birmaher, B., Kaufman, J., Brent, D.A., Dahl, R.E., Perel, J.M., al-Shabbout, M., Nelson, B., Stull, S., Rao, U., Waterman, G.S., Williamson, D.E., Ryan, N.D., 1997. Neuroendocrine response to 5-hydroxy-L-tryptophan in prepubertal children at high risk of major depressive disorder. Arch. Gen. Psychiatry 54, 1113–1119. Charles, H.C., Lazeyras, F., Krishnan, K.R., Boyko, O.B., Payne, M., Moore, D., 1994. Brain choline in depression: in vivo detection of potential pharmacodynamic effects of antidepressant therapy using hydrogen localized spectroscopy. Prog. Neuropsychopharmacol. Biol. Psychiatry 18, 1121–1127. Coffey, C.E., Wilkinson, W.E., Weiner, D.R., Parashos, I.A., Djang, W.T., Webb, M.C., Figiel, G.S., Spritzer, C.E., 1993. Quantitative cerebral anatomy in depression. A controlled magnetic resonance imaging study. Arch. Gen. Psychiatry 50, 7–16. Dahl, R.E., Ryan, N.D., Puig-Antich, J., Nguyen, N.A., al-Shabbout, M., Meyer, V.A., Perel, J., 1991. Twenty-four hour cortisol measures in adolescents with major depression: a controlled study. Biol. Psychiatry 30, 25–36.
Dahl, R.E., Ryan, N.D., Matty, M.K., Birmaher, B., al-Shabbout, M., Williamson, D.E., Kupfer, D.J., 1996. Sleep onset abnormalities in depressed adolescents. Biol. Psychiatry 39, 400– 410. De Bellis, M.D., Dahl, R.E., Perel, J.M., Birmaher, B., al-Shabbout, M., Williamson, D.E., Nelson, B., Ryan, N.D., 1996. Nocturnal ACTH, cortisol, growth hormone, and prolactin secretion in prepubertal depression. J. Am. Acad. Child. Adolesc. Psychiatry 35, 1130–1138. Emslie, G.J., Rush, A.J., Weinberg, W.A., Rintelmann, J.W., Roffwarg, H.P., 1990. Children with major depression show reduced rapid eye movement latencies. Arch. Gen. Psychiatry 47, 119–124. Emslie, G.J., Rush, A.J., Weinberg, W.A., Rintelmann, J.W., Roffwarg, H.P., 1994. Sleep EEG features of adolescents with major depression. Biol. Psychiatry 36, 573–581. Fujimoto, T., Nakano, T., Takano, T., Takeuchi, K., Yamada, K., Fukuzako, T., Akimoto, H., 1996. Proton magnetic resonance spectroscopy of basal ganglia in chronic schizophrenia. Biol. Psychiatry 40, 14–18. Kato, T., Hamakawa, H., Shioiri, T., 1996. Choline-containing compounds detected by proton magnetic resonance spectroscopy in the basal ganglia in bipolar disorder. J. Psychiatry Neurosci. 21, 248–254. Kutcher, S., Malkin, D., Silverberg, J., Marton, P., Williamson, P., Malkin, A., Szalai, J., Katic, M., 1991. Nocturnal cortisol, thyroid stimulating hormone, and growth hormone secretory profiles in depressed adolescents. J. Am. Acad. Child. Adolesc. Psychiatry 30, 407–414. Kutcher, S., Williamson, P., Marton, P., Szalai, J., 1992. REM latency in endogenously depressed adolescents. Br. J. Psychiatry 161, 399–402. Puig-Antich, J., Goetz, R., Hanlon, C., Tabrizi, M.A., Davies, M., Weitzman, E.D., 1983. Sleep architecture and REM sleep measures in prepubertal major depressives. Studies during recovery from the depressive episode in a drug-free state. Arch. Gen. Psychiatry 40, 187–192. Puig-Antich, J., Novacenko, H., Davies, M., Tabrizi, M.A., Ambrosini, P., Goetz, R., Bianca, J., Goetz, D., Sachar, E.J., 1984. Growth hormone secretion in prepubertal children with major depression. III. Response to insulin-induced hypoglycemia after recovery from a depressive episode in a drugfree state. Arch. Gen. Psychiatry 41, 471–475. Rao, U., Dahl, R.E., Ryan, N.D., Birmaher, B., Williamson, D.E., Giles, D.E., Rao, R., Kaufman, J., Nelson, B., 1996. The relationship between longitudinal clinical course and sleep cortisol changes in adolescent depression. Biol. Psychiatry 40, 474–484. Renshaw, P.F., Lafer, B., Babb, S.M., Fava, M., Stoll, A.L., Christensen, J.D., Moore, C.M., Yurgelun-Todd, D.A., Bonello, C.M., Pillay, S.S., Rothschild, A.J., Nierenberg, A.A., Rosenblaum, J.F., Cohen, B.M., 1997. Basal ganglia choline levels in depression and response to fluoxetine treatment: an in vivo proton magnetic resonance spectroscopy study. Biol. Psychiatry 41, 837–843. Riemann, D., Kammerer, J., Low, H., Schmidt, M.H., 1995. Sleep in adolescents with primary major depression and schizophrenia: a pilot study. J. Child. Psychol. Psychiatry 36, 313–326.
R. J. Steingard / Journal of Affective Disorders 61 (2000) S15 –S21 Ryan, N.D., Birmaher, B., Perel, J.M., Dahl, R.E., Meyer, V., al-Shabbout, M., Iyengar, S., Puig-Antich, J., 1992. Neuroendocrine response to L-5-hydroxytryptophan challenge in prepubertal major depression. Depressed vs. normal children. Arch. Gen. Psychiatry 49, 843–851. Ryan, N.D., Dahl, R.E., Birmaher, B., Williamson, D.E., Iyengar, S., Nelson, B., PuigAntich, J., Perel, J.M., 1994. Stimulatory tests of growth hormone secretion in prepubertal major depression: depressed versus normal children. J. Am. Acad. Child. Adolesc. Psychiatry 33, 824–833. Schuff, N., Amend, D., Ezekiel, F., Steinman, S.K., Tanabe, J., Norman, D., Jagust, W., Kramer, J.H., Mastrianni, J.A., Fein, G., Weiner, M.W., 1997. Changes of hippocampal N-acetyl aspartate and volume in Alzheimer’s disease. A proton MR spectroscopic imaging and MRI study. Neurology 49, 1513– 1521. Steingard, R.J., Renshaw, P.F., Yurgelun-Todd, D., Appelmans, K.E., Lyoo, I.K., Shorrock, K.L., Bucci, J.P., Cesena, M., Abebe, D., Zurakowski, D., Poussaint, T.Y., Barnes, P., 1996. Structural abnormalities in brain magnetic resonance images of depressed children. J. Am. Acad. Child. Adolesc. Psychiatry 35, 307–331. Steingard, R.J., Renshaw, P.F., Yurgelun-Todd, D.A., 1998. Proton
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MRS and structural MRI of the orbitofrontal cortex of depressed adolescents. In: 37th Annual Meeting of the American College Neuropsychopharmacology, Las Croabas, Puerto Rico, Abstract. Weller, E.B., Weller, R.A., Fristad, M.A., 1986. Dexamethasone suppression test and clinical outcome in prepubertal depressed children. Am. J. Psychiatry 143, 1469–1470. Williamson, D.E., Dahl, R.E., Birmaher, B., Goetz, R.R., Nelson, B., Ryan, N.D., 1995. Stressful life events and EEG sleep in depressed and normal control adolescents. Biol. Psychiatry 37, 859–865. Yurgelun-Todd, D.A., Waternaux, C.M., Cohen, B.M., Gruber, S.A., English, C.D., Renshaw, P.F., 1996. Functional magnetic resonance imaging of schizophrenics and controls during word production. Am. J. Psychiatry 153, 200–205. Yurgelun-Todd, D.A., Renshaw, P.F., in press. Applications of fMRI to research in psychiatry. Neuroimaging Clinics of North America. W.B. Saunders Company, Philadelphia, PA. Yurgelun-Todd, D.A., Gruber, S.A., Baird, A.A., Renshaw, P.F., Cohen, B.C., 1998. fMRI Cortical Changes in Bipolar Disorder: BOLD and DSCMRI Studies. Am. Coll. Neuropsychopharm. Ann. Mtg, Puerto Rico, December.
The neuroscience of depression in adolescence Ronald J. Steingard* Department of Psychiatry, Harvard Medical School, Cambridge, MA 02139, USA
Abstract The neuroscience of depression in children and adolescents has only recently become a focus of research. Initially, techniques previously used for adult investigations were employed, such as endocrine studies and sleep studies. Endocrine studies have indicated that, as in adult depression, a dysregulation of the serotonin (5-HT) axis is involved in childhood depression. However, both of these techniques are difficult to perform in children and have yielded some inconsistent results. The more recently developed neuroimaging techniques should enable the greatest advances in our understanding of the pathophysiology of depression. These techniques have already implicated the frontal lobes in the pathogenesis of depression in children and adolescents, and further research is ongoing. 2000 Elsevier Science B.V. All rights reserved. Keywords: Depression; Adolescents; Children; Magnetic resonance imaging
1. Introduction Research into the neuroscience of depression in adolescence has only recently gathered momentum. A number of different techniques first developed for the assessment of adults have been used in adolescents, including endocrine studies, sleep studies, and neuroimaging. The most recent techniques include the use of magnetic resonance imaging (MRI), associated magnetic resonance spectroscopy (MRS), and functional MRI (fMRI). This paper reviews the literature and describes the results of current studies using such techniques. To date such studies suggest *Corresponding author. Tel.: 1 1-617-665-1013; fax: 1 1-617665-1390. E-mail address: ronald [email protected] (R.J. Ste] ingard).
that the frontal lobes of the brain are involved in the pathogenesis of depression in adolescents and children.
2. Endocrine studies Research on endocrine markers of depression in adolescents lags behind that done in adults. This is partly because studies with youths were initiated at a later date, and also because these studies are difficult to carry out in children. Indeed, it is common practice among endocrinologists to analyse blood samples collected at 10- or 20-min intervals for up to 3 consecutive days, often with concurrent electroencephalographic (EEG) recordings to determine the waking state of the patient. Even though such studies are difficult to perform in children and
0165-0327 / 00 / $ – see front matter 2000 Elsevier Science B.V. All rights reserved. PII: S0165-0327( 00 )00285-8
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R. J. Steingard / Journal of Affective Disorders 61 (2000) S15 –S21
adolescents, this method has been successfully employed by some researchers (Dahl et al., 1991; Kutcher et al., 1991; De Bellis et al., 1996; Rao et al., 1996) to analyse hypothalamic–pituitary–adrenal (HPA) axis functioning with regard to endocrine markers. However, results have been inconsistent. Using this technique, Kutcher et al. (1991) found that nocturnal growth hormone secretion was significantly higher in depressed adolescents than in control subjects at most time points. This finding, however, was not replicated by a subsequent study (De Bellis et al., 1996). Thyroid stimulating hormone was also significantly higher in the depressed subjects at one time point, but cortisol secretion did not differ significantly between the two groups. Similarly, Rao et al. (1996) failed to show significant differences in cortisol levels between depressed adolescents and normal controls. However, there was a trend towards elevated cortisol levels near sleep onset in subjects with recurrent depression compared with those with no further depressive episodes during follow-up. Dahl et al. (1991) also demonstrated significantly elevated cortisol levels around sleep onset in depressed adolescents. In contrast, De Bellis et al. (1996) found that prepubertal depressed children had lower cortisol secretion during the first 4 h after sleep onset compared with controls. Nocturnal levels of adrenocorticotrophin, prolactin, and growth hormone secretion did not differ between the depressed and control groups. Other studies have analysed the secretion of growth hormone in response to stimulation. A blunted response of growth hormone secretion has been reported in children with prepubertal depression after stimulation with clonidine, a growth hormone releasing hormone, and insulin-induced hypoglycemia compared with non-depressed children (Ryan et al., 1994). Interestingly, in one study (PuigAntich et al., 1984), the insulin-induced hypoglycemic response appeared to persist after recovery. Additionally, children with depression do not demonstrate the blunted response to corticotrophin-releasing hormone and decreased secretion of adrenocorticotrophic hormone that is observed in depressed adults (Birmaher et al., 1996). The dexamethasone suppression test has also been employed to analyse the endocrinology of depression but has yielded variable results (Weller et al., 1986;
Fig. 1. Prolactin response to 5-hydroxy-L-tryptophan infusion in children at high-risk of developing depression, children with major depressive disorder (MDD), and low-risk normal children. *P 5 0.05 compared with high-risk and MDD children; †P 5 0.06 compared with high risk and MDD children. Data from Birmaher et al., 1997.
Bernini et al., 1994). This may be because the test is influenced by many different factors and inter-individual variations, including the metabolism of dexamethasone itself. It has been largely inferred that, as in adults, children with depression have a dysregulation involving the serotonin (5-HT) axis. One study showed that depressed children secreted significantly less cortisol and significantly more prolactin in response to 5-HT infusion compared with non-depressed children (Ryan et al., 1992). There is also an increased prolactin production in depressed female children compared with normal female children and compared with both depressed and normal male children (Ryan et al., 1992). Recently, this observation has been confirmed in children at high risk of developing depression (Birmaher et al., 1997). These children secrete similar levels of prolactin in response to 5-HT infusion compared with children with major depressive disorder (MDD), but significantly more compared with low-risk normal children (P 5 0.05) (Fig. 1).
3. Sleep studies Sleep studies have also yielded inconsistent results in the study of childhood and adolescent depression. A number of studies have demonstrated a reduced rapid eye movement (REM) latency (Kutcher et al., 1992; Emslie et al., 1994; Riemann et al., 1995; Williamson et al., 1995; Dahl et al., 1996) and
R. J. Steingard / Journal of Affective Disorders 61 (2000) S15 –S21
prolonged sleep latency (Kutcher et al., 1992; Dahl et al., 1996) in depressed adolescents compared with normal controls. Although another study did not find sleep differences between depressed and normal adolescents initially, it found that normal controls who would later develop depression had significantly higher density of REM and a trend for reduced REM latency compared to controls with no psychiatric disorder at follow-up (Rao et al., 1996). It should be noted, however, that stressful life events also significantly reduce REM latency and increase total REM time in adolescents and this should therefore be taken into account in such studies (Williamson et al., 1995). A number of sleep studies have also been performed in younger children but only one of them has clearly demonstrated a decrease in REM latency and prolonged sleep onset latency (Emslie et al., 1990). There has been one study in children to assess whether sleep changes return to normal after recovery (Puig-Antich et al., 1983). A shorter REM period latency and increased number of REM periods were observed in depressed children after recovery compared with when they were depressed.
4. Neuroimaging Neuroimaging studies have allowed the greatest steps forward in terms of improving our understanding of the underlying pathophysiology of depression. Such studies may also enable the identification of markers to distinguish subjects at risk of developing depression and also to predict response to treatment. Potential markers may be identified by probing either a specific function, such as the neurotransmitter circuit involved in affect recognition, or a specific brain region, such as the frontal lobe (Fig. 2). By comparing results obtained in normal adult subjects, a normal adolescent population, and a depressed adolescent population, markers of adolescent depression may be identified. There are now a number of different imaging modalities available: computerized axial tomography (CAT), single photon emission computerized tomography (SPECT), positron emission tomography (PET), magnetic resonance imaging (MRI), and magnetic resonance spectroscopy (MRS). CAT,
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SPECT, and PET all have their disadvantages. The most obvious of which is that scanning involves radionucleotide exposure which limits their use in this population, particularly for studies requiring repeat scans. However, the use of MRI circumvents this problem.
4.1. Magnetic resonance imaging MRI does not involve the use of a radionucleotide and therefore is potentially safer than SPECT or PET, enabling repeat scans to be performed. It also gives high anatomic resolution and the ability to assess not only volume but shape in a way which cannot be achieved with the other imaging modalities. In addition, MRS and functional MRI (fMRI) allow the assessment of structure and function. An early disadvantage of MRI was the time it took for older machines to capture an anatomic scan (about 1 h), a considerable time for children / adolescents to stay still. Recent technology has, however, reduced this time to between 10 and 20 min. The scanner is noisy and claustrophobic, which may also be problematic when trying to scan children and adolescents. Such problems can be minimized by preparing the child for the scan and familiarizing them with the machine. They may also be comforted with music while undergoing the scan, and parents and study personnel are able to stay in the same room while the child is imaged. MRI has been used to implicate the frontal lobes of the brain in the pathogenesis of depression in children and adolescents (Steingard et al., 1996). This retrospective study of over 1000 children and adolescents hospitalized for psychiatric illness over a 4-year period, identified 65 (30 male and 35 female) who reliably met criteria for depressive disorder (mean age6S.D. 5 13.462.3 years). Using routine MRI scans, the whole cerebral volume (CV), temporal lobe volume, frontal lobe volume (FLV), and ventricular volume (VV) of these patients were compared with those of 18 control subjects (13 male and 5 female; mean age6S.D. 5 10.862.9 years) (Table 1). To correct for differences in absolute CV associated with different body and head sizes, the ratios of FLV/ CV and VV/ CV were compared between the groups. In the depressed population, the
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Fig. 2. Location of Voxel used in MRS.
Table 1 Volumetric MRI in children and adolescents with depressive disorders
Cerebral volume (CV, cm 3 ) Frontal lobe volume (FLV, cm 3 ) Ventricular volume (VV, cm 3 ) FLV/ CV VV/ CV
Depressed (S.D.)
Control (S.D.)
1070.240(120.38)* 212.760(54.86)** 13.770(10.57) 0.200(0.04)*** 0.013(0.009)****
1148.140(110.50) 273.910(10.57) 8.530(3.77) 0.220(0.03) 0.007(0.003)
*P 5 0.035, **P 5 0.004, ***P 5 0.035, ****P 5 0.040 for depressed population compared with controls.
FLV/ CV ratio was significantly lower (P | 0.035) and the VV/ CV ratio was significantly higher (P 5 0.040) compared with the normal population. These
data agree with previous reports in depressed adults (Coffey et al., 1993). A concern of children and adolescent studies is
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that the effects of age are being observed. The neurophysiology of subjects naturally changes with age and may therefore vary during the course of a study. This must be taken into account when analysing imaging data. For example, in the study described above there was a significant age effect on the size of the frontal lobe (P 5 0.0006); however, there did appear to be an independent diagnostic effect as well (Table 2). Such effects necessitate that imaging data are rigorously analysed and indicate that neurophysiological measures in depressed children and adolescents must be compared with normal subjects of the same age. This effect applies not only to neuroimaging studies but also to neuroendocrine and sleep studies.
4.2. Magnetic resonance spectroscopy MRS is commonly used to detect the spin of two compounds, N-acetyl-L-aspartate (NAA) and choline. NAA is thought to be a neuronal marker, and reductions in NAA have been found in a number of pathological conditions (Fujimoto et al., 1996; Schuff et al., 1997). Choline is considered to be a marker of membrane synthesis and cellularity, and increases in pathological conditions (Charles et al., 1994; Fujimoto et al., 1996; Kato et al., 1996). Renshaw et al. (1997) demonstrated that depressed adults have a significantly lower ratio of choline to creatinine (Cho / Cr) in the basal ganglia than comparative subjects and this reduction was more pronounced in treatment responders than in non-responders. It should be noted that levels of NAA and choline are affected by age so these observations require confirmation in younger patients. MRI and proton MRS were performed on 26 healthy adolescents and 14 depressed adolescents (Steingard et al., 1998). Proton MRS was acquired from an area of the left anterior medial frontal lobe. Cho / Cr ratio (P 5 0.0498) and gray matter content Table 2 Regression summary of frontal lobe volume / cerebral volume ratio Independent variable
T (df 5 79)
P-value
Age (years) Sex Diagnosis
2 3.582 0.487 2.148
0.0006 0.6276 0.0348
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(P 5 0.0473) were significantly increased in the left anterior medial frontal lobe of depressed subjects. These findings appear to be independent of age and gender effects. There was no significant difference in age, gender, or NAA / Cr ratio between the two groups. These findings suggest the presence of structural and functional abnormalities in the frontal lobes of adolescents who are predisposed to developing depression.
4.3. Functional magnetic resonance imaging Using the recently developed scanning techniques, the different magnetic properties of oxygenated and deoxygenated blood can be used to analyse the perfusion of different areas of the brain. This method has been used to analyse the brains of schizophrenic and bipolar adults during the presentation of cortical challenge paradigms including finger tapping, word production, and the recognition of facial affect (Yurgelun-Todd et al., 1996; Yurgelun-Todd and Renshaw, 1999). A recent study in bipolar subjects examined cortical changes in response to an affect recognition test and found a reduction of blood flow in the orbital frontal cortex of bipolar patients compared with normal subjects (Yurgelun-Todd et al., 1998). However, if these patients were treated with loxapine they recovered with regard to symptoms and phenomenology, and their ability to process this information in the orbital frontal cortex changed. Such FMRI techniques are currently being used to study affect recognition as a paradigm looking at functioning in the orbital frontal cortex and the amygdala in adolescents. The field of MRI is rapidly developing. Using the present technology we are now able to look for markers of depression in adolescents and to study whether these markers correlate with the presence of symptoms. These functional studies may also educate us about the process of recovery and enable us to predict recovery in individuals.
5. Conclusion Endocrine and sleep studies have yielded inconsistent results about the neuroscience of depression in
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children and adolescents. Neuroimaging using MR techniques appears to represent the most promising area for future studies. MRI studies have already demonstrated a decrease in frontal lobe volume in depressed children and adolescents compared with normal subjects, suggesting that the frontal lobes of the brain are involved in the pathogenesis of depression in children and adolescents. Additionally, MRS has identified a significant increase in the Cho / Cr ratio in the anterior medial frontal lobe of depressed adolescents compared with normal controls. Involvement of the frontal lobes in adolescent depression is currently being further investigated using MRI techniques. Future research in this rapidly developing field should improve our understanding of the pathophysiology of depression, and may identify markers which identify subjects at risk of developing depression and predict patient response to treatment.
References Bernini, G.P., Argenio, G.F., Cern, F., Franchi, F., 1994. Comparison between the suppressive effects of dexamethasone and loperamide on cortisol and ACTH secretion in some pathological conditions. J. Endocrinol. Invest. 17, 799–804. Birmaher, B., Dahl, R.E., Perel, J., Williamson, D.E., Nelson, B., Stull, S., Kaufman, J., Waterman, G.S., Rao, U., Nguyen, N., Puig-Antich, J., Ryan, N.D., 1996. Corticotrophin-releasing hormone challenge in prepubertal major depression. Biol. Psychiatry 39, 267–277. Birmaher, B., Kaufman, J., Brent, D.A., Dahl, R.E., Perel, J.M., al-Shabbout, M., Nelson, B., Stull, S., Rao, U., Waterman, G.S., Williamson, D.E., Ryan, N.D., 1997. Neuroendocrine response to 5-hydroxy-L-tryptophan in prepubertal children at high risk of major depressive disorder. Arch. Gen. Psychiatry 54, 1113–1119. Charles, H.C., Lazeyras, F., Krishnan, K.R., Boyko, O.B., Payne, M., Moore, D., 1994. Brain choline in depression: in vivo detection of potential pharmacodynamic effects of antidepressant therapy using hydrogen localized spectroscopy. Prog. Neuropsychopharmacol. Biol. Psychiatry 18, 1121–1127. Coffey, C.E., Wilkinson, W.E., Weiner, D.R., Parashos, I.A., Djang, W.T., Webb, M.C., Figiel, G.S., Spritzer, C.E., 1993. Quantitative cerebral anatomy in depression. A controlled magnetic resonance imaging study. Arch. Gen. Psychiatry 50, 7–16. Dahl, R.E., Ryan, N.D., Puig-Antich, J., Nguyen, N.A., al-Shabbout, M., Meyer, V.A., Perel, J., 1991. Twenty-four hour cortisol measures in adolescents with major depression: a controlled study. Biol. Psychiatry 30, 25–36.
Dahl, R.E., Ryan, N.D., Matty, M.K., Birmaher, B., al-Shabbout, M., Williamson, D.E., Kupfer, D.J., 1996. Sleep onset abnormalities in depressed adolescents. Biol. Psychiatry 39, 400– 410. De Bellis, M.D., Dahl, R.E., Perel, J.M., Birmaher, B., al-Shabbout, M., Williamson, D.E., Nelson, B., Ryan, N.D., 1996. Nocturnal ACTH, cortisol, growth hormone, and prolactin secretion in prepubertal depression. J. Am. Acad. Child. Adolesc. Psychiatry 35, 1130–1138. Emslie, G.J., Rush, A.J., Weinberg, W.A., Rintelmann, J.W., Roffwarg, H.P., 1990. Children with major depression show reduced rapid eye movement latencies. Arch. Gen. Psychiatry 47, 119–124. Emslie, G.J., Rush, A.J., Weinberg, W.A., Rintelmann, J.W., Roffwarg, H.P., 1994. Sleep EEG features of adolescents with major depression. Biol. Psychiatry 36, 573–581. Fujimoto, T., Nakano, T., Takano, T., Takeuchi, K., Yamada, K., Fukuzako, T., Akimoto, H., 1996. Proton magnetic resonance spectroscopy of basal ganglia in chronic schizophrenia. Biol. Psychiatry 40, 14–18. Kato, T., Hamakawa, H., Shioiri, T., 1996. Choline-containing compounds detected by proton magnetic resonance spectroscopy in the basal ganglia in bipolar disorder. J. Psychiatry Neurosci. 21, 248–254. Kutcher, S., Malkin, D., Silverberg, J., Marton, P., Williamson, P., Malkin, A., Szalai, J., Katic, M., 1991. Nocturnal cortisol, thyroid stimulating hormone, and growth hormone secretory profiles in depressed adolescents. J. Am. Acad. Child. Adolesc. Psychiatry 30, 407–414. Kutcher, S., Williamson, P., Marton, P., Szalai, J., 1992. REM latency in endogenously depressed adolescents. Br. J. Psychiatry 161, 399–402. Puig-Antich, J., Goetz, R., Hanlon, C., Tabrizi, M.A., Davies, M., Weitzman, E.D., 1983. Sleep architecture and REM sleep measures in prepubertal major depressives. Studies during recovery from the depressive episode in a drug-free state. Arch. Gen. Psychiatry 40, 187–192. Puig-Antich, J., Novacenko, H., Davies, M., Tabrizi, M.A., Ambrosini, P., Goetz, R., Bianca, J., Goetz, D., Sachar, E.J., 1984. Growth hormone secretion in prepubertal children with major depression. III. Response to insulin-induced hypoglycemia after recovery from a depressive episode in a drugfree state. Arch. Gen. Psychiatry 41, 471–475. Rao, U., Dahl, R.E., Ryan, N.D., Birmaher, B., Williamson, D.E., Giles, D.E., Rao, R., Kaufman, J., Nelson, B., 1996. The relationship between longitudinal clinical course and sleep cortisol changes in adolescent depression. Biol. Psychiatry 40, 474–484. Renshaw, P.F., Lafer, B., Babb, S.M., Fava, M., Stoll, A.L., Christensen, J.D., Moore, C.M., Yurgelun-Todd, D.A., Bonello, C.M., Pillay, S.S., Rothschild, A.J., Nierenberg, A.A., Rosenblaum, J.F., Cohen, B.M., 1997. Basal ganglia choline levels in depression and response to fluoxetine treatment: an in vivo proton magnetic resonance spectroscopy study. Biol. Psychiatry 41, 837–843. Riemann, D., Kammerer, J., Low, H., Schmidt, M.H., 1995. Sleep in adolescents with primary major depression and schizophrenia: a pilot study. J. Child. Psychol. Psychiatry 36, 313–326.
R. J. Steingard / Journal of Affective Disorders 61 (2000) S15 –S21 Ryan, N.D., Birmaher, B., Perel, J.M., Dahl, R.E., Meyer, V., al-Shabbout, M., Iyengar, S., Puig-Antich, J., 1992. Neuroendocrine response to L-5-hydroxytryptophan challenge in prepubertal major depression. Depressed vs. normal children. Arch. Gen. Psychiatry 49, 843–851. Ryan, N.D., Dahl, R.E., Birmaher, B., Williamson, D.E., Iyengar, S., Nelson, B., PuigAntich, J., Perel, J.M., 1994. Stimulatory tests of growth hormone secretion in prepubertal major depression: depressed versus normal children. J. Am. Acad. Child. Adolesc. Psychiatry 33, 824–833. Schuff, N., Amend, D., Ezekiel, F., Steinman, S.K., Tanabe, J., Norman, D., Jagust, W., Kramer, J.H., Mastrianni, J.A., Fein, G., Weiner, M.W., 1997. Changes of hippocampal N-acetyl aspartate and volume in Alzheimer’s disease. A proton MR spectroscopic imaging and MRI study. Neurology 49, 1513– 1521. Steingard, R.J., Renshaw, P.F., Yurgelun-Todd, D., Appelmans, K.E., Lyoo, I.K., Shorrock, K.L., Bucci, J.P., Cesena, M., Abebe, D., Zurakowski, D., Poussaint, T.Y., Barnes, P., 1996. Structural abnormalities in brain magnetic resonance images of depressed children. J. Am. Acad. Child. Adolesc. Psychiatry 35, 307–331. Steingard, R.J., Renshaw, P.F., Yurgelun-Todd, D.A., 1998. Proton
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MRS and structural MRI of the orbitofrontal cortex of depressed adolescents. In: 37th Annual Meeting of the American College Neuropsychopharmacology, Las Croabas, Puerto Rico, Abstract. Weller, E.B., Weller, R.A., Fristad, M.A., 1986. Dexamethasone suppression test and clinical outcome in prepubertal depressed children. Am. J. Psychiatry 143, 1469–1470. Williamson, D.E., Dahl, R.E., Birmaher, B., Goetz, R.R., Nelson, B., Ryan, N.D., 1995. Stressful life events and EEG sleep in depressed and normal control adolescents. Biol. Psychiatry 37, 859–865. Yurgelun-Todd, D.A., Waternaux, C.M., Cohen, B.M., Gruber, S.A., English, C.D., Renshaw, P.F., 1996. Functional magnetic resonance imaging of schizophrenics and controls during word production. Am. J. Psychiatry 153, 200–205. Yurgelun-Todd, D.A., Renshaw, P.F., in press. Applications of fMRI to research in psychiatry. Neuroimaging Clinics of North America. W.B. Saunders Company, Philadelphia, PA. Yurgelun-Todd, D.A., Gruber, S.A., Baird, A.A., Renshaw, P.F., Cohen, B.C., 1998. fMRI Cortical Changes in Bipolar Disorder: BOLD and DSCMRI Studies. Am. Coll. Neuropsychopharm. Ann. Mtg, Puerto Rico, December.