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The common pattern of cortical glucose metabolism increases and limbic-paralimbic metabolism decreases in placebo and fluoxetine responders suggests that facilitation of these changes may be necessary for depression remission, regardless of treatment modality. Clinical improvement in the group receiving placebo as part of an inpatient study is consistent with the well-recognized effect that altering the therapeutic environment may significantly contribute to reducing clinical symptoms. The additional subcortical and limbic metabolism decreases seen uniquely in fluoxetine responders may convey additional advantage in maintaining long-term clinical response and in relapse prevention.

The relationship between pretreatment regional cerebral glucose metabolism and eventual antidepressant drug response was measured using positron emission tomography (PET) in hospitalized patients with unipolar depression. Rostral anterior cingulate metabolism uniquely differentiated eventual treatment responders from non-responders. Hypometabolism characterized non-responders when compared with controls, in contrast to responders who were hypermetabolic. Metabolism in no other region discriminated the two groups, nor did associated demographic, clinical or behavioral measures, including motor speed, cognitive performance, depression severity or illness chronicity. Cingulate hypermetabolism may represent an important adaptive response to depression and failure of this response may underlie poor outcome. A critical role for rostral cingulate area 24a/b in the limbic-cortical network involved in abnormal mood states is proposed.

This study was aimed at resolving the time course of clinical action of antidepressants (ADs) and the type of early behavioral changes that precede recovery in treatment-responsive depressed patients. The first goal was to identify, during the first 2 weeks of treatment, the onset of clinical actions of the selective serotonin reuptake inhibitor (SSRI), paroxetine, and the selective noradrenergic reuptake inhibitor, desipramine (DMI). The second aim was to test the hypothesis that the two pharmacologic subtypes would induce different early behavioral changes in treatment-responsive patients. The design was a randomized, parallel group, placebo-controlled, double-blind study for 6 weeks of treatment following a 1-week washout period. The study utilized measures of the major behavioral components of the depressive disorder as well as overall severity. The results indicated that the onset of clinical actions of DMI ranged from 3 to 13 days, averaged 13 days for paroxetine, and was 16-42 days for placebo. Furthermore, as hypothesized, the different types of ADs initially impacted different behavioral aspects of the disorder. After 1 week of treatment, DMI produced greater reductions in motor retardation and depressed mood than did paroxetine and placebo, and this difference persisted at the second week of treatment. Early improvement in depressed mood-motor retardation differentiated patients who responded to DMI after 6 weeks of treatment from those that did not. Paroxetine initially reduced anxiety more in responders than in nonresponders, and by the second week, significantly improved depressed mood and distressed expression in responders to a greater extent. Depressed patients who responded to placebo showed no consistent early pattern of behavior improvement. Early drug-specific behavioral changes were highly predictive of ultimate clinical response to the different ADs, results that could eventually be applied directly to clinical practice.

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Drugs thought to be selective inhibitors of either the uptake of serotonin (5-HT) or norepinephrine (NE) are known to be effective antidepressants. In general, a relative selectivity for NE vs. 5-HT uptake inhibition greater than 50-fold in vitro is thought to be sufficient to maintain such selectivity in vivo. To explore this issue, we carried out a study in which depressed patients were treated with either the selective serotonin reuptake inhibitor (SSRI) paroxetine or the selective norepinephrine reuptake inhibitor (SNRI) desipramine. Patients were treated with either drug or placebo for 6 wk. Drug levels in plasma and platelet 5-HT content were measured 12 times during the treatment period using HPLC procedures. Both drug treatments caused a significant reduction of platelet 5-HT content. Paroxetine reduced platelet 5-HT content to approx. 1% of pretreatment levels (n = 3). The inhibition of 5-HT uptake by paroxetine appeared to be immediate and complete. Desipramine reduced platelet 5-HT content to 38.7+/-6.2 % of pretreatment levels (n = 5) at a mean plasma level of 195 ng/ml. The percent reduction of platelet 5-HT content after 6 wk of drug treatment was proportional to the steady state plasma level of desipramine. The IC50 value of desipramine to reduce platelet 5-HT was 135 ng/ml. These results demonstrate that therapeutic concentrations of the SNRI desipramine as well as the SSRI paroxetine inhibited serotonin uptake in platelets of depressed patients. If such effects occur in the brain, desipramine might have some component of its therapeutic effects due to actions on the uptake of 5-HT.

Previous studies indicate that high frequency power (>20Hz) in the electroencephalogram (EEG) are associated with feature binding and attention. It has been hypothesized that hallucinations and perceptual abnormalities might be linked to irregularities in fast frequency activity. This study examines the power and distribution of high frequency activity (HFA) during sleep in healthy control subjects and unmedicated patients with schizophrenia and depression. This is a post-hoc analysis of an archival database collected under identical conditions. Groups were compared using multivariate analyses of covariance (MANCOVA) using group frequency by stage analysis. A multiple regression analyzed the association between HFA power and clinical symptoms. Schizophrenic (SZ) and major depressive disorder (MDD) patients showed significantly greater high frequency (HF) power than healthy controls (HC) in all sleep stages (p<0.0001). SZs also exhibited significantly greater HF power than MDD patients in all sleep stages except wakefulness (W) (p<0.05). In all groups, gamma (35-45Hz) power was greater in W, decreased during slow wave sleep (SWS) and decreased further during rapid eye movement (REM). Beta 2 (20-35 Hz) power was greater in W and REM than in SWS. Only positive symptoms exhibited an association with HF power. Elevated HFA during sleep in unmedicated patients with SZ and MDD is associated with positive symptoms of illness. It is not clear how HFA would change in relation to clinical improvement, and further study is needed to clarify the association of HFA to the state/trait characteristics of SZ and MDD.