The study addressed whether melancholic features in adolescent MDD comprise a distinct clinical syndrome. To our knowledge, this is the first attempt to examine possible specific abnormalities in the neurobiology of adolescent M-MDD.
As expected, adolescents with M-MDD exhibited more severe depressive ratings compared to their NonM-MDD counterparts and displayed different neurobiological profiles. Major findings are of significantly decreased plasma TRP levels and increased KYN/TRP (estimating IDO activity) in adolescents with M-MDD compared to both NonMMDD and control adolescents. Importantly, findings remained significant when controlled for CDRS-R scores, suggesting that they are not related to increased symptom severity observed in the M-MDD group. The NonM-MDD group did not differ from healthy controls with respect to any KP measure. We also found associations between KP measures (e.g., KYN and 3-HAA/KYN) and severity of MDD episode (measured by CDRS-R) in the adolescent M-MDD, exclusively. However, we did not detect differences in other KP measures (i.e., KYN, 3-HAA, and 3-HAA/KYN). On balance, findings support the notion that the neurobiology of adolescent M-MDD may be distinct from other clinical subtypes of adolescent MDD.
To date, biological research and/or treatment studies in adolescent M-MDD have been scarce. An earlier study by Robbins et al. found that melancholic features are associated with failure to respond to psychosocial treatment (Robbins, Alessi, & Colfer, 1989
). The recent Treatment for Adolescents with Depression Study also found that melancholic features were predictive of relatively less favorable response to selective serotonin reuptake inhibitors (Curry et al., 2006
). These treatment findings support the concept of a distinct neurobiology in adolescent M-MDD.
Our findings of decreased TRP and increased KYN/TRP in the M-MDD group compared to both the NonM-MDD and control groups are consistent with reports in adults citing lower plasma TRP and TRP/competing amino acids levels in adults with M-MDD compared to controls as well as NonM-MDD subjects (Maes et al., 1994
; Anderson, Parry-Billings, News-holme, Poortmans, & Cowen, 1990
; Maes et al., 1996
; Cowen, Parry-Billings, & Newsholme, 1989
; Maes, De Ruyter, Hobin, & Suy, 1987
). In an early study Curzon and Bridges found that women with ‘endogenous’ depression (i.e., M-MDD) exhibited increased urinary excretion of KYN and 3-HK compared to controls after an oral load of TRP (Curzon & Bridges, 1970
). More recently, in adult cancer patients undergoing treatment with IFN-α or IL-2, a positive correlation was reported between the development of neurovegetative symptoms – which are prominent in M-MDD – and reduction of plasma TRP (Capuron et al., 2002
). Also supporting a possible role of IDO in M-MDD are findings of highest plasma levels of neopterin, a pteridine released from macrophages/monocytes in parallel to IDO activity, in adults with M-MDD (Maes et al., 1994
As dietary intake may affect plasma TRP concentrations, we required all blood samples to be collected in the morning following an overnight fast in order to minimize confounding effects of diet on TRP levels (Badawy, 2009
While the increased KYN/TRP ratios found in the M-MDD group suggest increased IDO activation, this finding may be attributed to the decreased TRP as KYN levels did not differ across the groups. However, the significant negative relationship observed between MDD severity and KYN in the M-MDD group indicates increased KYN metabolism in this clinical group. This hypothesis is further supported by the significant positive correlation also found between 3-HAA/KYN and MDD severity only in the M-MDD group. Taken together, these findings suggest that KYN is preferentially metabolized toward the neurotoxic branch, and that production of neurotoxins may be a factor in M-MDD (see ).
Several studies reinforce our hypothesis that KYN metabolism is shifted toward the neurotoxic branch, including our recent findings of positive correlations between plasma KYN and 3-HAA and striatal tCho (cell membrane turnover biomarker) exclusively in M-MDD adolescents (Gabbay et al., 2010
). Relatedly, in an adult immunotherapy study Wichers et al. reported positive correlations between KYN/KA (reflecting neurotoxic metabolite load) and symptoms that are prominent in M-MDD (e.g., observed sadness, tension/irritability, decreased appetite, sleep problems, and social withdrawal) (Wichers et al., 2005
). This investigation also failed to find changes in KYN plasma levels (Wichers et al., 2005
The concept that neuroplasticity impairment may play a specific role in M-MDD is also supported by studies reporting more pronounced reductions of γ
-aminobutyric acid (GABA) concentrations in the plasma (Petty, Kramer, Gullion, & Rush, 1992
), cerebrospinal fluid (Roy, Dejong, & Ferraro, 1991
) and the occipital lobe (Sanacora et al., 2004
), as well as increased brain glutamate concentrations (Sanacora et al., 2004
), in adults with M-MDD compared to controls.
The study has a number of limitations. We have not assessed other relevant metabolites such as KA (NMDA receptor antagonist) as well as 3-HK and QUIN (neurotoxins) (illustrated in ). Additionally, the availability of TRP uptake to the brain is proportionally affected by plasma concentrations of several other amino acids (tyrosine, valine, phenylalanine, leucine, isoleucine), collectively termed competing amino acids (CAA). As we did not measure CAA concentrations we cannot conclude that TRP availability to the brain was decreased in the adolescents with M-MDD. Further, a substantial proportion of MDD adolescents (34%) were on psychotropic medications, which have anti-inflammatory effects and, as such, may have limited the identification of other differences in KP measures (e.g., KYN levels). Additionally, the groups were not matched with respect to their ethnic distribution having higher proportions of African Americans (AA) in the M-MDD group and higher proportions of Hispanics in the NonM-MDD group. A recent study reported no ethnic differences in TRP, 3-HK, and KA, while 3-HAA was decreased in AA compared to Caucasians and Hispanics and KYN decreased in AA and Hispanics compared to Caucasians (Badawy et al., 2007
). These data suggest decreased activation of the KP and of the neurotoxic pathway in AA. Since our findings suggest opposite directions (i.e., activation of the KP and increased neurotoxicity) in M-MDD, our findings are likely not the result of having increased proportions of AA in the melancholic group but instead suggest that we may have detected a greater effect if the groups were better matched. Last, we did not assess menstrual cycle, which may affect KP activity (Hrboticky, Leiter, & Anderson, 1989
In summary, our findings suggest a possible specific role of the KP in adolescent M-MDD. The identification of homogenous and valid clinical subtypes is important to inform the nosology and guide clinical care through better understanding of the disorder’s biological underpinnings.
Findings should be replicated, optimally with medication-free adolescents with MDD while examining other KP metabolites, such as 3-HK and KA, to elucidate the role of the KP in M-MDD. Additionally, future studies should examine whether specific symptoms associated with melancholia (e.g., sleep, eating disturbances) account for KP abnormalities.
Failure of much of the research to identify biological correlates of adolescent MDD may be related to the heterogeneity of the syndrome. Study findings point to the potential importance of distinguishing between adolescents with and without M-MDD, whether addressing family history, biology, treatment, or course.