Prognostic Markers

Response Predictors. In light of the described differences between responders and nonresponders with treatment, an obvious related question is whether baseline findings predict eventual treatment outcomes. Several studies have found that pretreatment metabolic activity in the rostral (pregenual) cingulate uniquely distinguishes medication responders from nonresponders (Mayberg et al., 1997), a pattern replicated in Parkinson's disease and other unipolar depressed cohorts (Kennedy et al., 2001; Stefu-rak et al., 2001b). A similar finding also predicts good response to one night of sleep deprivation (Wu et al., 1999). While additional studies are needed, these data suggest physiological differences among patient subgroups that may be critical to understanding brain plasticity and adaptation to illness, including propensity to respond to treatment. Additional evidence of persistent hypermetabolism in patients in full remission on maintenance SSRI treatment for more than a year further suggests a critical compensatory or adaptive role for rostral cingulate in facilitating and maintaining long-term clinical responses (Liotti et al., 2002).

Relapse Risk and Illness Vulnerability. A further goal concerns identification of patients at risk for illness relapse as well as those vulnerable to illness onset. Challenge or stress tests might be seen as a possible avenue toward this goal. As such, mood induction experiments initially conducted in healthy subjects to define brain regions mediating modulation of acute changes in mood state relevant to depressive dysphoria have been similarly performed in acutely depressed and remitted depressed subjects, and have identified disease-specific modifications of these pathways (Liotti et al., 2002). Specifically, with acute sad mood induction in healthy volunteers, ventral and subgenual cingulate blood flow increases are consistently described (Damasio et al., 2000; Mayberg et al., 1999). These cingulate increases are not found in depressed patients comparably provoked, where unique dorsal cingulate increases and medial and orbital frontal decreases are instead seen. Similar findings in both euthymic-remitted and acutely depressed patients suggest that these differences may be depression trait markers. In addition, the pattern seen with memory-provoked sadness shows striking similarities to resting state studies of refractory unipolar and neurologically depressed patients (Mayberg, 1994), as well as the changes seen following acute tryptophan depletion during the early phase of SSRI treatment (Bremner et al., 1997). This brain change pattern has also been described using fMRI in a recent case of iatrogenic mood symptoms induced by high-frequency deep-brain stimulation of the right subthalamic nucleus for treatment of intractable Parkinson's disease in a patient with a remote history of major depression (Stefurak et al., 2001a; see also Bejjani et al., 1999). Consistent with recent clinical studies demonstrating increased relapse risk in those remitted depressed patients with persistent hypersensitivity to negative emotional stimuli (Segal et al., 1999), the converging imaging evidence suggests strategies for future studies of potential neural mechanisms of relapse vulnerability.

Challenge experiments of this type may additionally identify presyndromal subjects with high illness risk as suggested by preliminary studies demonstrating differential rest and stress-induced patterns of change in healthy control subjects selected for high and low neurotic temperaments (Keightley et al., 2002; Zald et al., 2002). Partial but not complete overlap between the change patterns with sad-stress seen in high neurotic never depressed subjects and in remitted depressed patients suggests a potential marker of illness vulnerability, unmasked only with emotional stress. Further development of these types of paradigms may have future potential for preclinical testing of unaffected family members of genetically defined cohorts. Directly testing this hypothesis is the demonstration that sensitivity to the tryptophan depletion challenge among healthy volunteers with and without a family history of depression is most critically linked to the presence of the s/s homozygous form of the 5HTTLPR gene (Neumeister et al., 2002). This question revisits the interesting but complex interactions between neuroticism, mood stress sensitivity, gene polymorphisms, and depression vulnerability.

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