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Regional Effects. Studies of regional metabolism and blood flow with recovery from a major depressive episode consistently report normalization of many regional abnormalities identified in the pretreatment state. Changes in cortical (prefrontal, parietal), limbic-paralimbic (cingulate, amygdala, insula), and subcortical (caudate/pallidum, thalamus, brainstem) areas have been described following various treatments including medication, psychotherapy, sleep deprivation, electroconvulsive therapy (ECT), repetitive transcranial magnetic stimulation (rTMS), and ablative surgery (Bench et al., 1995; Buchsbaum et al., 1997, Brody et al., 2001b; Nobler et al., 2001; Tenenback et al., 1999). Normalization of frontal hypometabolism is the best replicated finding, seen with all classes of medication, although normalization of frontal hypermetabolism is also reported. Changes in limbic-paralimbic and subcortical regions are also seen, often involving changes in previously "normal" functioning regions (Fig. 7.4a and b). Requisite changes mediating clinical recovery have not been determined, nor have clear distinctions been made between different modes of treatment.

Receptor Changes with Treatment. Treatment studies using SSRIs or tri-cyclic antidepressants report down-regulation of 5-HT2A receptors consistent with pharmacological studies in animals (Yatham et al., 1999; Meyer et al., 2001). Like the abnormalities identified in the pretreated depressed state, the reported changes are generally global rather than focal. 5-HT1A receptors show no change with treatment, suggesting the pretreatment abnormalities may be a compensatory rather than a primary etiological finding (Sargent et al., 2000), as postulated in recent postmortem studies of these markers. While there are no direct comparisons of SSRI and NRI action on serotonin binding, the areas with the greatest magnitude change with desipramine treatment are medial frontal regions—overlapping sites of the most robust metabolic decreases with more selective SSRIs such as fluoxetine and areas of highest concentration of the serotonin transporter. While striatal D2-dopamine changes have been reported, extrastriatal binding is unreliable with currently available tracers.

Time Course of Brain Changes. Examination of the time course of changes and differences between responders and nonresponders to a given treatment provides additional localizing clues (Mayberg et al., 2000). Responders and nonresponders to 6 weeks of fluoxetine, for example, show similar regional metabolic changes after 1 week of treatment (brainstem, hippocampus increases; posterior cingulate, striatal, tha-lamic decreases), which is concordant with absence of clinical change in both groups. In contrast, the 6-week metabolic change pattern discriminates them, with clinical improvement uniquely associated with limbic-paralimbic and striatal decreases (sub-genual cingulate, hippocampus, pallidum, insula) and brainstem and dorsal cortical increases (prefrontal, anterior cingulate, posterior cingulate, parietal). Failed response to fluoxetine was associated with a persistent 1-week pattern (hippocampal increases; striatal, posterior cingulate decreases) and absence of either subgenual cingulate or prefrontal changes.

Figure 7.4. Common changes in subgenual cingulate (Cg25) with different treatments. Decreases in subgenual cingulate, relative to patient baseline pretreatment scans are seen with clinical response to both 6 weeks of fluoxetine in unipolar depressed (A) and Parkinson's depressed patients (C). A similar pattern is seen with response to 6 weeks of paroxetine (B) and placebo (D). Persistence of this pattern is seen in a separate group of patients in full remission on maintenance medication (E). Limbic leucotomy (F), a surgical procedure that combines subcaudate tractotomy (lower arrow) and cingulotomy (upper arrow), disrupts both afferent and efferent subgenual cingulate pathways as well as intercingulate connections, demonstrating additional anatomical concordance. Abbreviations: fluox, fluoxetine; SSRI, selective serotonin reuptake inhibitor. (Data fromCosgrove and Rauch, 1995; Kennedy et al., 2001; Liotti etal., 2002; Mayberg et al., 2000, 2002; Stefurak et al., 2001b). See ftp site for color image.

Figure 7.4. Common changes in subgenual cingulate (Cg25) with different treatments. Decreases in subgenual cingulate, relative to patient baseline pretreatment scans are seen with clinical response to both 6 weeks of fluoxetine in unipolar depressed (A) and Parkinson's depressed patients (C). A similar pattern is seen with response to 6 weeks of paroxetine (B) and placebo (D). Persistence of this pattern is seen in a separate group of patients in full remission on maintenance medication (E). Limbic leucotomy (F), a surgical procedure that combines subcaudate tractotomy (lower arrow) and cingulotomy (upper arrow), disrupts both afferent and efferent subgenual cingulate pathways as well as intercingulate connections, demonstrating additional anatomical concordance. Abbreviations: fluox, fluoxetine; SSRI, selective serotonin reuptake inhibitor. (Data fromCosgrove and Rauch, 1995; Kennedy et al., 2001; Liotti etal., 2002; Mayberg et al., 2000, 2002; Stefurak et al., 2001b). See ftp site for color image.

This same combination of reciprocal dorsal cortical and ventral limbic changes has also been demonstrated with response to paroxetine (Kennedy et al., 2001), in Parkinson's depression treated with fluoxetine (Stefurak et al., 2001b), as well as with placebo responders treated as such as part of the fluoxetine study just described (Mayberg et al.,

2002) (Fig. 1.4b-d). It is, however, the unique subcortical changes with active medication (brainstem, hippocampal, caudate), which are not seen with placebo-treated responders, that provides the best initial support for the hypothesis that both treatment-specific and response-specific effects can be identified.

Since improvement in depressive symptoms best correlates with increases in the activity of prefrontal cortex (F9/46) and decreases in subgenual cingulate (Cg25), it is additionally postulated that these changes may be most critical for illness remission. This hypothesis is further refined by preliminary evidence of persistent Cg25 hypometabolism and posterior cingulate hypermetabolism in a new group of fully recovered patients on maintenance SSRI treatment (Liotti et al., 2002) (Fig. 1.4e). These findings might suggest that persistent limbic changes in remitted patients are the adaptive homeostatic response necessary to maintain a recovered state. In this context, it is interesting to note that the limbic leukotomy procedure performed to treat severe refractory depression disrupts afferent and efferent subgenual cingulate pathways (subcaudate tractotomy component, Fig. 1.4 f, bottom arrow), as well as intercingu-late connections (cingulotomy component, top arrow) (Haber et al., 2000; Vogt and Pandya, 1981).

Despite this convergence of findings, a further demonstration of comparable changes with a formal nonpharmacological therapy is needed. At issue is whether remission mediated by cognitive or psychotherapies involve similar or unique brain changes as compared to those seen with medication. The few published studies thus far show no common patterns. A new preliminary analysis comparing remission achieved through cognitive behavioral therapy (CBT) on the one hand and through paroxetine on the other, studied in two separate outpatient cohorts revealing some interesting differences (Goldapple et al., 2002; Kennedy et al., 2001). Remission with paroxetine treatment, as seen with fluoxetine, was associated with metabolic increases in prefrontal cortex and decreases in subgenual cingulate and hippocampus. In contrast, CBT response was associated with a completely different set of changes: lateral prefrontal decreases, similar to those seen with interpersonal psychotherapy (Brody et al., 2001b), as well as medial frontal decreases and hippocampal and rostral cingulate increases, not previously described. These CBT-specific changes are particularly interesting given current cognitive models (Beck et al., 1919; Segal et al., 1999) and the known roles of rostral cingulate and hippocampus in emotional monitoring and memory and lateral and medial frontal cortices in perception, action, and self-reference (reviewed in Grady, 1999).

The differences in change effects between the two interventions thus provide new support for treatment-specific effects rather than a common response-effect pattern, as posited by previous studies. However, the similarity in change pattern seen with fluox-etine and paroxetine despite differences in baseline frontal activity further suggests a more complex interaction between pretreatment abnormalities, attempted compensatory responses, and actual treatment effects. Testing of this hypothesis likely requires the use of a multivariate statistical approach, where relationships between independent and dependent variables can be simultaneously observed (Mcintosh, 1999).

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