Nonpsychotic Major Depression Research Articles

Altered brain function underlying verbal memory encoding and retrieval in psychotic major depression

Psychotic major depression (PMD) is associated with deficits in verbal memory as well as other cognitive impairments. This study investigated brain function in individuals with PMD during a verbal declarative memory task. Participants included 16 subjects with PMD, 15 subjects with non-psychotic major depression (NPMD) and 16 healthy controls (HC). Functional magnetic resonance imaging (fMRI) data were acquired while subjects performed verbal memory encoding and retrieval tasks. During the explicit encoding task, subjects semantically categorized words as either “man-made” or “not man-made.” For the retrieval task, subjects identified whether words had been presented during the encoding task. Functional MRI data were processed using SPM5 and a group by condition ANOVA. Clusters of activation showing either a significant main effect of group or an interaction of group by condition were further examined using t-tests to identify group differences. During the encoding task, the PMD group showed lower hippocampus, insula, and prefrontal activation compared to HC. During the retrieval task, the PMD group showed lower recognition accuracy and higher prefrontal and parietal cortex activation compared to both HC and NPMD groups. Verbal retrieval deficits in PMD may be associated with deficient hippocampus function during encoding. Increased brain activation during retrieval may reflect an attempt to compensate for encoding deficits.

The mineralocorticoid receptor agonist, fludrocortisone, differentially inhibits pituitary–adrenal activity in humans with psychotic major depression

Hypothalamic-pituitary-adrenal (HPA) axis dysregulation has been linked with major depression, particularly psychotic major depression (PMD), with mineralocorticoid receptors (MRs) playing a role in HPA-axis regulation and the pathophysiology of depression. Herein we hypothesize that the MR agonist fludrocortisone differentially inhibits the HPA axis of psychotic major depression subjects (PMDs), non-psychotic major depression subjects (NPMDs), and healthy control subjects (HCs). Fourteen PMDs, 16 NPMDs, and 19 HCs were admitted to the Stanford University Hospital General Clinical Research Center. Serum cortisol levels were sampled at baseline and every hour from 18:00 to 23:00h, when greatest MR activity is expected, on two consecutive nights. On the second afternoon at 16:00h all subjects were given 0.5mg fludrocortisone. Mean cortisol levels pre- and post-fludrocortisone and percent change in cortisol levels were computed. There were no significant group differences for cortisol at baseline: F(2,47)=.19, p=.83. There were significant group differences for post-fludrocortisone cortisol: F(2,47)=5.13, p=.01, which were significantly higher in PMDs compared to HCs (p=.007), but not compared to NPMDs (p=.18). There were no differences between NPMD's and HC's (p=.61). Also, PMDs had a lower percent change from baseline in cortisol levels at 2200h than NPMDs (p=.01) or HCs (p=.009). Individuals with psychotic major depression compared to healthy control subjects have diminished feedback inhibition of the hypothalamic-pituitary-adrenal (HPA) axis in response to the mineralocorticoid receptor agonist fludrocortisone. To our knowledge, this is the first study to examine HPA axis response to MR stimulation in major depression (with and without psychosis), and only the third study to demonstrate that exogenously administered fludrocortisone can down-regulate the HPA axis in humans.

The first 100 patients in the SUN(^_^)D trial (strategic use of new generation antidepressants for depression): examination of feasibility and adherence during the pilot phase

BackgroundInitial glitches and unexpected inconsistencies are unavoidable in the early stage of a large, multi-centre trial. Adaptive modifications of the trial’s protocol and operational procedures to ensure its smooth running are therefore imperative. We started a large pragmatic, multi-centre, assessor-blinded, 25-week trial to investigate the optimal first- and second-line treatments for untreated episodes of nonpsychotic major depression in 2010 [Strategic Use of New generation antidepressants for Depression, abbreviated SUN(^_^)D] and would like to herein report an examination of the trial’s feasibility and adherence among the first 100 participants.MethodsWe examined the participants’ characteristics, the treatments that were allocated and received during each step of the trial, and the quality of the outcome assessments among the first 100 patients enrolled in the SUN(^_^)D trial.ResultsOf the 2,743 first-visit patients who visited the two collaborating centres between December 2010 and July 2011, 382 were judged as potentially eligible, and 100 of these patients provided written informed consent. These patients represented the whole spectrum of mild to very severe depression. Of the 93 patients who had reached Week 3 of the study by the end of July 2011, one withdrew consent for both the treatment and the assessment, and eight withdrew consent for the treatment only. Altogether, the primary outcomes were successfully assessed in 90 (96.8%) of the patients at Week 3. Of the 72 patients who had reached Week 9, three withdrew consent for the treatment, but 70 were successfully interviewed (97.2%). Of the 32 patients who had reached Week 25, 29 (90.5%) were successfully followed up. The inter-rater reliability of the assessments of the primary outcomes was nearly perfect and their successful blinding was confirmed. Minor modifications and clarifications to the protocol were deemed necessary.DiscussionGiven the satisfactory feasibility and adherence to the study protocol and the minor modifications that were necessary, we conclude that the data obtained from the first 100 patients can be safely included in the main study. We now intend to accelerate the study by recruiting more collaborating centres and clinics/hospitals.Trial registrationClinicalTrials.gov identifier: NCT01109693

Neuropsychological performance in a sample of 13–25year olds with a history of non-psychotic major depressive disorder

There is evidence for neuropsychological dysfunction in depression among adult and elderly participants but little research has been conducted on the neuropsychological functioning of youth with depression. The aim of the present study was to investigate the neuropsychological functioning of outpatient young participants with depression. Computerised neuropsychological tests requiring executive functioning, working memory, attention, verbal memory and learning, planning, and visuospatial skills were carried out in a sample of 13-25year-olds with a lifetime history of non-psychotic major depression (n=32) and in healthy age balanced controls (n=65). Psychiatric diagnoses were ascertained using the MINI International Neuropsychiatric Interview. Participants with current or previous major depressive disorder demonstrated impairments in executive function tasks requiring conceptual skills and set-shifting, attention and working memory. However, planning skills were found to be largely intact. Positive affect was associated to better attention, working memory and verbal learning in depressed participants, independently from gender and education. The results may be affected by the small sample size and heterogeneity of the sample. The findings from this study indicate, and are one of the first to identify, that young subjects aged between 13 and 25, with a lifetime history of depression, have impaired executive and working memory functioning.

Lateralized movement-related potential amplitudes differentiate between schizophrenia/schizoaffective disorder and major depression

ObjectiveTo examine whether deficits in focal lateralized motor system activation would differentiate between subjects with schizophrenia/schizoaffective disorder and subjects with a major depressive episode. Reductions of Bereitschaftspotential amplitude have been described for both diagnostic groups. MethodsWe analyzed multi-channel lateralized movement-related potentials (LMRP) during choice reaction movements in 16 schizophrenic/schizoaffective patients in partial remission with predominant negative symptoms, 18 patients with a non-psychotic major depression and two healthy control groups age-matched to the respective patient groups (20/23 subjects). ResultsA significant reduction of lateralized potentials over the (pre-)motor areas immediately preceding and around movement execution was found only in subjects with schizophrenia/schizoaffective disorder but not with a major depressive episode. Reduced LMRP amplitudes correlated with negative symptoms (SANS score). Other movement stages (preceding response-locked ‘contingent negative variation’ during response selection and post-movement evaluation during motor postimperative negative variation) were not affected in the same way. ConclusionsDeficits in focal motor cortex activation during movement execution may reflect rather schizophrenia-specific deficits in fronto-striatal circuits. A general lack of drive and depressed mood did not alter the degree of lateralization of motor activation during movement execution. SignificanceLateralization of movement-related potentials could differentiate psychotic from non-psychotic disorders on the group level.

Reelin, a Marker of Stress Resilience in Depression and Psychosis

Reelin protein is an extracellular matrix protease responsible for normal lamination of the brain during embryogenesis, and is involved in cell signaling and synaptic plasticity in adult life. The Reelin gene (RELN) is localized to chromosome 7 in humans and chromosome 5 in mice, and produces a protein product with relative molecular mass of 388 kDa. Reelin protein is localized to a number of brain sites, specifically Cajal–Retzius cells located in layer 1 of neocortex, GABAergic interneurons, and cerebellar granule cells. Activation of the Reelin signaling pathway leads to various, important functions such as enhancement of long-term potentiation, cell proliferation, cell migration, and more importantly dendritic spine morphogenesis. Spontaneous mutation of the RELN gene in the reeler homozygous mutant mouse leads to the development of ataxia and a reeling gait and reversal of the normal layering of the brain (Goffinet, 1979). The reeler cerebellum is hypoplastic and the Purkinje cell number is diminished potentially explaining the ataxic gait. Historically, comparative studies of the homozygous and heterozygous reeler mutant mice and the similarities in their cognitive, anatomic, and biochemical abnormalities to mental diseases caused an upsurge in generation of new information about Reelin's involvement in various neuropsychiatric disorders. Multiple postmortem studies have implicated a pathologic involvement of RELN gene in several neuropsychiatric disorders, namely, schizophrenia, bipolar disorder, autism, major depression, lissencephaly, and Alzheimer's disease. Erminio Costa and coworkers reported on deficits in brain levels of Reelin mRNA and the protein in patients suffering from schizophrenia and psychotic bipolar disorder (Impagnatiello et al, 1998). Later reports by Fatemi (2005) confirmed and extended these findings to patients with non-psychotic bipolar disorder, major depression, and autism. Additional reports by other investigators showed that Reelin deficits are common phenomena subserving cognitive deficits in multiple disorders including lissencephaly, Alzheimer's disease, and temporal lobe epilepsy. The causative factors may include a mutation in the RELN gene (lissencephaly) to variable expression of the molecule due to hypermethylation of the promoter region of the RELN gene or other unknown mechanisms. Moreover, several non-CNS disorders have been associated with changes in expression of Reelin including several forms of cancers and otosclerosis. In the current issue, Teixeira and colleagues evaluated the effects of overexpression of Reelin in a transgenic mouse model as compared with wild-type mice and to heterozygous reeler mutant mice using a battery of behavioral tests (Texeira et al, 2011). These investigators tested the hypothesis that if downregulation of Reelin production could lead to various behavioral abnormalities, upregulation of this molecule could lead to reversal of these deficits. The effects of Reelin overexpression on (1) anxiety (open field, novelty-suppressed feeding, black and white box), (2) depression (forced-swim test in presence or absence of the stress-associated hormone corticosterone), (3) mania and positive symptoms of schizophrenia (cocaine sensitization and cocaine self-administration), and (4) gating abnormalities in schizophrenia (prepulse inhibition) were assessed at 8 weeks of age in presence or absence of the NMDA antagonist MK-801. Additionally, all animals were subjected to electrophysiological recordings to evaluate for functionality of the NMDA-NR2B glutamatergic transmission. The results demonstrated that although heterozygousreeler mice did not show any behavioral abnormalities, mice overexpressing Reelin exhibited several salient and novel findings ie, (1) increased brain levels of Reelin protected the transgenic mice from developing depression-like behavior in the forced-swim test, (2) stress induced NMDA NR2B—mediated synaptic transmission (a marker of depression) was reduced in transgenic mice, and lastly (3) evidence for positive symptoms of schizophrenia ie, behavioral sensitization to cocaine and gating deficits (PPI abnormalities) were reduced in transgenic mice. These findings are both positive and potentially important as they point to Reelin as a therapeutic agent to treat some aspects of depression, psychosis, and autistic behavior. Previous findings of Reelin production induced by various psychotropic medications including citalopram support these results (Jaako et al, 2011). Additionally, in a previous work by the same laboratory, it was demonstrated that Reelin overexpression in the hippocampus of the transgenic mice resulted in potentiation of synaptic strength and hypertrophy of dendritic spine morphology, albeit with no change in dendritic spine density (Pujadas et al, 2010). These changes in the hippocampus reflect Reelin's ability to act as an antidepressant by both increasing neurogenesis and improving learning and memory. As Reelin abnormalities are pervasive and span a range of neuropsychiatric disorders, future studies should focus on and expand the scope of genetic, biochemical, and clinical studies to better define the etiopathologic and therapeutic roles of this important and evolutionary conserved molecule.

Depression symptom dimensions as predictors of antidepressant treatment outcome: replicable evidence for interest-activity symptoms

Symptom dimensions have not yet been comprehensively tested as predictors of the substantial heterogeneity in outcomes of antidepressant treatment in major depressive disorder. We tested nine symptom dimensions derived from a previously published factor analysis of depression rating scales as predictors of outcome in 811 adults with moderate to severe depression treated with flexibly dosed escitalopram or nortriptyline in Genome-based Therapeutic Drugs for Depression (GENDEP). The effects of symptom dimensions were tested in mixed-effect regression models that controlled for overall initial depression severity, age, sex and recruitment centre. Significant results were tested for replicability in 3637 adult out-patients with non-psychotic major depression treated with citalopram in level I of Sequenced Treatment Alternatives to Relieve Depression (STAR*D). The interest-activity symptom dimension (reflecting low interest, reduced activity, indecisiveness and lack of enjoyment) at baseline strongly predicted poor treatment outcome in GENDEP, irrespective of overall depression severity, antidepressant type and outcome measure used. The prediction of poor treatment outcome by the interest-activity dimension was robustly replicated in STAR*D, independent of a comprehensive list of baseline covariates. Loss of interest, diminished activity and inability to make decisions predict poor outcome of antidepressant treatment even after adjustment for overall depression severity and other clinical covariates. The prominence of such symptoms may require additional treatment strategies and should be accounted for in future investigations of antidepressant response.

FMRI Correlates of White Matter Hyperintensities in Late-Life Depression

This study tests whether or not the structural white matter lesions that are characteristic of late-life depression are associated with alterations in the functional affective circuits of late-life depression. This study used an emotional faces paradigm that has been shown to engage the affective limbic brain regions. Thirty-three elderly depressed patients and 27 nondepressed comparison subjects participated in this study. The patients were recruited through the NIMH-sponsored Advanced Center for Interventions and Services Research for the Study of Late-Life Mood Disorders at the University of Pittsburgh Center for Bioethics and Health Law. Structural and functional MRI was used to assess white matter hyperintensity (WMH) burden and functional magnetic resonance imaging (fMRI) blood-oxygen-level-dependent (BOLD) response on a facial expression affective-reactivity task in both elderly participants with nonpsychotic and nonbipolar major depression (unmedicated) and nondepressed elderly comparison subjects. As expected, greater subgenual cingulate activity was observed in the depressed patients relative to the nondepressed comparison subjects. This same region showed greater task-related activity associated with a greater burden of cerebrovascular white matter change in the depressed group. Moreover, the depressed group showed a significantly greater interaction of WMH by fMRI activity effect than the nondepressed group. The observation that high WMH burden in late-life depression is associated with greater BOLD response on the affective-reactivity task supports the model that white matter ischemia in elderly depressed patients disrupts brain mechanisms of affective regulation and leads to limbic hyperactivation.

Factor structure and dimensionality of the two depression scales in STAR*D using level 1 datasets

The factor structure and dimensionality of the HAM-D(17) and the IDS-C(30) are as yet uncertain, because psychometric analyses of these scales have been performed without a clear separation between factor structure profile and dimensionality (total scores being a sufficient statistic). The first treatment step (Level 1) in the STAR*D study provided a dataset of 4041 outpatients with DSM-IV nonpsychotic major depression. The HAM-D(17) and IDS-C(30) were evaluated by principal component analysis (PCA) without rotation. Mokken analysis tested the unidimensionality of the IDS-C(6), which corresponds to the unidimensional HAM-D(6.) For both the HAM-D(17) and IDS-C(30), PCA identified a bi-directional factor contrasting the depressive symptoms versus the neurovegetative symptoms. The HAM-D(6) and the corresponding IDS-C(6) symptoms all emerged in the depression factor. Both the HAM-D(6) and IDS-C(6) were found to be unidimensional scales, i.e., their total scores are each a sufficient statistic for the measurement of depressive states. STAR*D used only one medication in Level 1. The unidimensional HAM-D(6) and IDS-C(6) should be used when evaluating the pure clinical effect of antidepressive treatment, whereas the multidimensional HAM-D(17) and IDS-C(30) should be considered when selecting antidepressant treatment.

Treatment-emergent suicidal ideation during 4 months of acute management of unipolar major depression with SSRI pharmacotherapy or interpersonal psychotherapy in a randomized clinical trial

To date, few randomized controlled trials (RCTs) of major depression have examined suicidal ideation as an outcome measure. Our aim is to determine the incidence of treatment-emergent suicidal ideation (ESI) and behaviors during the acute phase of treatment with an SSRI antidepressant or interpersonal psychotherapy (IPT) in patients with unipolar major depression. In a two-site RCT, 291 adult outpatients with nonpsychotic major depression and a Hamilton Depression Rating Scale (HDRS) score ≥15 were randomly allocated to IPT or SSRI. Participants who did not remit with monotherapy received augmentation with the other treatment. ESI was defined as a post-baseline HDRS suicidality item score ≥2 or a post-baseline Quick Inventory of Depressive Symptomatology (QIDS) score ≥2 in patients with a baseline score ≤1. Of the 231 participants who had no suicidal ideation at baseline, 32 (13.8%) subsequently exhibited ESI on at least one post-baseline visit. Time to suicidal ideation was significantly longer in patients allocated to SSRI compared to those allocated to IPT (HR = 2.21, 95% CI 1.04-4.66, P = .038), even after controlling for treatment augmentation, benzodiazepine use, and comorbidity with anxiety disorders. Worsening of suicidal ideation occurred in 7/60 patients who had suicidal ideation at baseline. In the large majority of cases, suicidal ideation was successfully managed with the study protocol. In the context of careful monitoring and frequent contact, selective serotonin reuptake inhibitor (SSRI) was associated with a lower risk of ESI than IPT and both SSRI and IPT appeared to be safe treatments for patients with past suicide attempts, none of whom exhibited ESI during the study.

Aberrant Brain Activation During a Working Memory Task in Psychotic Major Depression

The authors sought to better understand the neural circuitry associated with working memory deficits in psychotic major depression by examining brain function during an N-back task. Study subjects were 16 patients with psychotic major depression, 15 patients with nonpsychotic major depression, and 19 healthy comparison subjects. Functional MRI data were collected while participants responded to letter stimuli that were repeated from the previous trial (1-back) or the one before that (2-back). Relative to the healthy comparison group, both the psychotic and nonpsychotic major depression groups had significantly greater activation in the right parahippocampal gyrus during the 2-back task, and the psychotic major depression group showed this overactivation during the 1-back task as well. The nonpsychotic major depression group showed significantly lower activation than other groups in the right dorsolateral prefrontal cortex and greater activation than the healthy comparison group in the superior occipital cortex. The psychotic major depression group was unique in showing greater activation than both other groups in the right temporoparietal junction, a cluster that also demonstrated connectivity with activation in the left prefrontal cortex. The psychotic major depression group showed aberrant parahippocampal activation at a lower demand level than observed in nonpsychotic major depression. While the nonpsychotic major depression group showed abnormalities in frontal executive regions, the psychotic major depression group showed abnormalities in temporoparietal regions associated with orienting to unexpected stimuli. Considering the functional connectivity of this cluster with left dorsolateral prefrontal cortex regions, these findings may reflect neural compensation for sensory gating deficits in psychotic major depression.

MRI signal hyperintensities and treatment remission of geriatric depression

Background White matter abnormalities may interfere with limbic–cortical balance and contribute to chronic depressive syndromes in the elderly. This study sought to clarify the relationship of SH to treatment response. We hypothesized that patients who failed to remit during a 12-week controlled treatment trial of escitalopram would exhibit greater SH burden than patients who remitted. Methods The participants were 42 non-demented individuals with non-psychotic major depression and 25 elderly comparison subjects. After a 2-week single blind placebo period, subjects who still had a Hamilton Depression Rating Scale (HDRS) of 18 or greater received escitalopram 10 mg daily for 12 weeks. Remission was defined as a HDRS score of 7 or below for 2 consecutive weeks. FLAIR sequences were acquired on a 1.5 T scanner and total SH were quantified using a semi-automated thresholding method. Results The patient sample consisted of 22 depressed patients who achieved remission during the study and 20 depressed patients who remained symptomatic. ANCOVA, with age and gender as covariates, revealed that depressed subjects had greater total SH burden relative to non-depressed controls. Furthermore, patients who failed to remit following escitalopram treatment had significantly greater SH burden than both patients who remitted and elderly comparison subjects, whereas SH burden did not differ between depressed patients who remitted and elderly comparison subjects. Limitations Patients were treated with a fixed dose of antidepressants and the index of SH is an overall measure that does not permit examination of the relationship of regional SH to treatment remission. Discussion SH may contribute to a “disconnection state” both conferring vulnerability to and perpetuating late-life depression.

Drs. Nelson and Papakostas Reply

Drs. Nelson and Papakostas Reply

Does rTMS Work

Research into the efficacy of repetitive transcranial magnetic stimulation (rTMS) in depression has produced variable results and prompted questions about the adequacy of the sham control. In this NIH-sponsored study, researchers randomized 190 antidepressant-free patients with unipolar nonpsychotic major depression to sham or active, moderately fast, left prefrontal rTMS (10 Hz). Patients had failed an average of 1.5 antidepressant …

Response suppression deficits in treatment-naïve first-episode patients with schizophrenia, psychotic bipolar disorder and psychotic major depression

Recent evidence indicates common genetic, neurobiological, and psychopharmacological aspects of schizophrenia and psychotic affective disorders. Some similarities in neurocognitive deficits associated with these disorders have also been reported. We investigated performance on antisaccade and visually-guided saccade tasks in treatment-naïve first-episode psychosis patients (schizophrenia n = 59, major depression n = 15, bipolar disorder n = 9), matched non-psychotic major depression patients ( n = 40), and matched healthy individuals ( n = 106). All psychosis groups displayed elevated antisaccade error rates relative to healthy individuals. Antisaccade latencies were elevated in schizophrenia, but no significant error rate or latency differences were observed among psychosis groups. For schizophrenia only, shorter visually guided saccade latencies were associated with higher antisaccade error rates. Schizophrenia was also the only group without a significant relationship between visually guided and antisaccade latencies. Reflexive saccades were unimpaired except in psychotic unipolar depression, where saccades were hypometric. As in schizophrenia, antisaccade abnormalities are present in affective psychoses, even early in the course of illness and prior to treatment. Disturbances in frontostriatal systems are believed to occur in both affective psychoses and schizophrenia, potentially causing some similar cognitive abnormalities across psychotic disorders. However, the distinct pattern of dysfunction in schizophrenia across oculomotor paradigms suggests possible unique causes of their observed oculomotor performance deficits.

Pharmacogenetics Studies in STAR*D: Strengths, Limitations, and Results

Pharmacogenetics Studies in STAR*D: Strengths, Limitations, and Results

Anterior cingulate cortical volumes and treatment remission of geriatric depression

Structural abnormalities of the anterior cingulate cortex (ACC) may interfere with the interaction of cortical and limbic networks involved in emotional regulation and contribute to chronic depressive syndromes in the elderly. This study examined the relationship of regional anterior cingulate cortical volumes with treatment remission of elderly depressed patients. We hypothesized that patients who failed to remit during a 12-week controlled treatment trial of escitalopram would exhibit smaller anterior cingulate gray matter volumes than patients who remitted. The participants were 41 non-demented individuals with non-psychotic major depression. After a 2-week single-blind placebo period, subjects who still had a Hamilton Depression Rating Scale (HDRS) of 18 or greater received escitalopram 10 mg daily for 12 weeks. Remission was defined as a HDRS score of 7 or below for at least 2 consecutive weeks. The patient sample consisted of 22 depressed patients who achieved remission during the study and 19 depressed patients who remained symptomatic. High-resolution magnetization-prepared rapidly acquired gradient echo (MPRAGE) sequences were acquired on a 1.5 T scanner and regional ACC volumes were manually outlined (dorsal, rostral, anterior subgenual, and posterior subgenual). Repeated measure analyses revealed that patients who failed to remit following escitalopram treatment had smaller dorsal and rostral anterior cingulate gray matter volumes than patients who remitted, whereas subgenual cortical volumes did not differ between the groups. Structural abnormalities of the dorsal and rostral anterior cingulate may perpetuate late-life depression.

Does the Dexamethasone Suppression Test Reliably Discriminate Between Psychotic and Nonpsychotic Major Depression?

Previous research has shown that psychotic major depression (PMD) is often associated with higher rates of nonsuppression on the dexamethasone suppression test (DST) compared with nonpsychotic major depression (NMD), suggesting the potential importance of cortisol hypersecretion in the psychotic subtype of the disorder. However, these patient groups also are known to differ from one another on a variety of other clinical variables, and there are numerous factors independent of diagnostic status known to affect the DST. Thus, we investigated possible confounds that could help account for the apparent DST abnormalities in PMD sometimes reported in past research. Hospitalized patients with PMD (n = 11) and NMD (n = 58) were compared on the DST and other clinical variables. As expected, PMD patients showed significantly higher rates of DST nonsuppression (55% vs. 24%; p = 0.04). However, PMD patients also had significantly higher levels of anxiety severity (p = 0.01). The higher rates of nonsuppression in the PMD group were attenuated when these patients were compared with a subsample of NMD patients matched on anxiety severity (55% vs. 55%). Implications for future research on biological markers of PMD are discussed.

GABAB Receptors, Schizophrenia and Sleep Dysfunction

The STAR*D (Sequenced Treatment Alternatives to Relieve Depression) study used a series of sequenced, randomized treatment trials following a first and, if needed, subsequent treatment steps to define the tolerability and effectiveness of various options in both acute and longer term treatment. Adult outpatients (n=4041) with nonpsychotic major depressive disorder, substantial chronic and recurrent depression, and co-morbid psychiatric and general medical conditions were enrolled in 41 representative primary and specialty care settings. About one-third of participants remitted in first step treatment with citalopram, 50% of these within 6 weeks. Poorer outcomes were associated with minority status, socioeconomic disadvantage, more axis I and III co-morbid disorders, lower function and quality of life, and anxious and melancholic features. In step 2 medication switch, there were no significant differences in remission among within-class, out-of-class or dual-action agents: sertraline (27%), bupropion-sustained release (26%) and venlafaxine-extended release (25%). In step 2 medication augmentation of citalopram, there was no significant difference in remission between bupropion-sustained release (39%) and buspirone (33%), although participants using bupropion-sustained release had greater symptom reduction and better tolerability. There were no significant differences in remission in step 2 between cognitive therapy and medication treatment in either the switch (31% vs 27%) or augmentation (31% vs 33%) strategies, although participants in cognitive therapy augmentation had a longer time to remission than those in medication augmentation (55 vs 40 days). In step 3, there were no differences in remission between a switch to mirtazapine (8%) or nortriptyline (12%), or between augmentation with lithium (13%) or T(3) (triiodothyronine, liothyronine) [25%], although more participants discontinued lithium due to adverse effects than discontinued T(3). In the fourth step, there was no difference in remission between tranylcypromine (14%) or venlafaxine-extended release plus mirtazapine (16%), although the combination treatment had fewer adverse effects and had the advantages of not requiring a washout period or diet restrictions. Participants requiring more than two well delivered treatments may be characterized as treatment resistant given the substantially lower remission rates after that point. Treatment resistance was associated with more concurrent axis I or III co-morbid conditions, socioeconomic disadvantage, chronicity and melancholic or anxious features. However, if participants remained in treatment for up to four steps, about 67% reached remission. Times to remission were not substantially longer for later treatment steps. The importance of reaching remission is highlighted by the lower relapse rates in naturalistic follow-up for participants entering in remission compared with those entering with response but not remission (step 1: 34% vs 59%; step 2: 47% vs 68%; step 3: 42% vs 76%; step 4: 50% vs 83%). Clinical decision making based on the itemized measurement of symptoms and adverse effects at each treatment visit was feasible in STAR*D's real world settings and resulted in adequate dosages and durations of treatment that generally exceeded those typically found in practice settings. Although switch and augmentation strategies could not be directly compared due to the equipoise stratified randomized design, the higher remission rates at step 2 with medication augmentation are intriguing and merit further study.

Serotonin transporter polymorphisms, microstructural white matter abnormalities and remission of geriatric depression

This study compared microstructural abnormalities in depressed elders and controls and studied the association of the serotonin transporter gene status to white matter abnormalities and to remission of depression. The subjects were Caucasians with non-psychotic major depression and normal elders. Depressed subjects received escitalopram 10 mg daily for 12 weeks. Remission was defined as a HDRS score of 7 or below for 2 consecutive weeks. Diffusion tensor imaging was performed and voxel-based analysis of fractional anisotropy (FA) was conducted using age and mean diffusivity as covariates. Depressed elders (N=27) had lower FA than controls (N=27) in several frontolimbic areas. Depressed elderly S-allele carriers also had lower FA than L homozygotes in frontolimbic brain areas, including the dorsal and rostral anterior cingulate, posterior cingulate, dorsolateral prefrontal and medial prefrontal regions, thalamus, and in other regions. S-allele carriers had a lower remission rate than L homozygotes. Small number of subjects, lack of random sampling, fixed antidepressant dose, short follow-up. Lower FA was observed in several frontolimbic and other regions in depressed elders compared to controls. Depressed S-allele carriers had both microstructural white matter abnormalities in frontolimbic networks and a low remission rate. It remains unclear whether the risk for chronicity of geriatric depression in S-allele carriers is mediated by frontolimbic compromise. However, these observations set the stage for studies aiming to identify the relationship of S allele to impairment in specific frontolimbic functions interfering with response of geriatric depression to antidepressants.