The genetics of severe depression.

Genome-wide association studies (GWASs) of major depressive disorder (MDD) have recently achieved extremely large sample sizes and yielded substantial numbers of genome-wide significant loci. Because of the approach to ascertainment and assessment in many of these studies, some of these loci appear to be associated with dysphoria rather than with MDD, potentially decreasing the clinical relevance of the findings. An alternative approach to MDD GWAS is to focus on the most severe forms of MDD, with the hope that this will enrich for loci of larger effect, rendering their identification plausible, and providing potentially more clinically actionable findings. Here we review the genetics of severe depression by using clinical markers of severity including: age of onset, recurrence, degree of impairment, and treatment with ECT. There is evidence for increased family-based and Single Nucleotide Polymorphism (SNP)-based estimates of heritability in recurrent and early-onset illness as well as severe functional impariment. GWAS have been performed looking at severe forms of MDD and a few genome-wide loci have been identified. Several whole exome sequencing studies have also been performed, identifying associated rare variants. Although these findings have not yet been rigorously replicated, the elevated heritability seen in severe MDD phenotypes suggests the value of pursuing additional genome-wide interrogation of samples from this population. The challenge now is generating a cohort of adequate size with consistent phenotyping that will allow for careful and robust classifications and distinctions to be made. We are currently pursuing such a strategy in our 50-site worldwide Gen-ECT-ics consortium.

Effects of lithium on serum Brain-Derived Neurotrophic Factor in Alzheimer's patients with agitation.

BACKGROUND: There is ample evidence in animal models that lithium increases Brain-Derived Neurotrophic Factor (BDNF) with supporting evidence in human studies. Little is known, however, about the effects of lithium on BDNF in Alzheimer's Dementia (AD). In one study of patients with Mild Cognitive Impairment, serum BDNF increased after treatment with lithium. These patients also showed mild improvement in cognitive function. OBJECTIVES: To evaluate low-dose lithium treatment of agitation in Alzheimer's disease (AD). METHOD: We measured levels of BDNF in patients treated with lithium prior to and after a 12-week randomized placebo-controlled trial. RESULTS: BDNF levels did not change significantly and were not associated with improvement in overall neuropsychiatric symptoms or in cognitive function. CONCLUSIONS: More research is needed to understand the potential effects of lithium on BDNF in AD including whether its use might be dependent on the stage of cognitive decline and dementia.

Prevalence of Suicidal Behaviors in Residents of Long-Term Care Facilities: A Systematic Review and Meta-Analysis.

BACKGROUND: Long-term care facilities (LTC) plays a pivotal role in caring for geriatric population. However, the risk of suicide in long-term care institutions among older individuals is little understood (e.g., nursing homes, assisted living facilities). OBJECTIVE: The purpose of this systematic review is to pool and meta-analyze the data on prevalence of suicidal behaviors in geriatric population residing in long-term care facilities. METHODS: We have conducted the systematic review in accordance with the PRISMA guidelines. The utilized databases are Pubmed, Medline, Google scholar and Scopus. The Meta-analysis was done using OpenMeta [analyst] software. Subgroup analysis was also performed. RESULTS: After running an analysis on pooled data from twenty cross-sectional studies with 3,023,224 participants, the prevalence of suicidal behavior is 6.4% (95% CI = 5.7-7) in LTC. CONCLUSION: This meta-analysis shows pooled prevalence of suicidal behavior among geriatric residents of LTC was found to be moderately high all over the world.

Low Dose Lithium Treatment of Behavioral Complications in Alzheimer's Disease: Lit-AD Randomized Clinical Trial.

BACKGROUND: A case series suggested efficacy for lithium to treat agitation in dementia, but no placebo-controlled trials have been conducted. OBJECTIVES: To evaluate low-dose lithium treatment of agitation in Alzheimer's disease (AD). METHOD: In a four-site trial, patients with AD and agitation/aggression score ≥4 on the Neuropsychiatric Inventory (NPI) were randomized, double-blind, to lithium carbonate 150-600 mg daily or placebo for 12 weeks. Primary efficacy outcome was change in NPI agitation/aggression; secondary efficacy outcome was treatment response (30% reduction in NPI score for agitation/aggression plus psychosis and a Clinical Global Impression (CGI) score of much or very much improved). Safety profile of lithium was assessed. RESULTS: Fifty-eight of 77 patients (75.3%) completed the trial. In linear mixed effects model analyses, lithium was not significantly superior to placebo for agitation/aggression. Proportion of responders was 31.6% on lithium and 17.9% on placebo (χ2=1.26, p = 0.26). Moderate or marked improvement (CGI) was greater on lithium (10/38=36.8%) than placebo (0/39=0%, Fisher's exact test p <0.001). In exploratory analyses, improvement on lithium was greater than placebo on NPI delusions and irritability/lability (p's<0.05). Lithium showed greater reduction than placebo in patients with high Young Mania Rating Scale scores (ß=5.06; 95%CI,1.18 to 8.94, p = 0.01). Oral dose and serum levels demonstrated similar associations with efficacy outcomes. Lithium did not differ significantly from placebo on safety outcomes. CONCLUSIONS: Low-dose lithium was not efficacious in treating agitation but was associated with global clinical improvement and excellent safety. A larger trial may be warranted of likely lithium-responsive behavioral symptoms that overlap with mania.

Longitudinal Neurocognitive Effects of Combined Electroconvulsive Therapy (ECT) and Pharmacotherapy in Major Depressive Disorder in Older Adults: Phase 2 of the PRIDE Study.

OBJECTIVE: There is limited information regarding neurocognitive outcomes of right unilateral ultrabrief pulse width electroconvulsive therapy (RUL-UB ECT) combined with pharmacotherapy in older adults with major depressive disorder. We report longitudinal neurocognitive outcomes from Phase 2 of the Prolonging Remission in Depressed Elderly (PRIDE) study. METHOD: After achieving remission with RUL-UB ECT and venlafaxine, older adults (≥60 years old) were randomized to receive symptom-titrated, algorithm-based longitudinal ECT (STABLE) plus pharmacotherapy (venlafaxine and lithium) or pharmacotherapy-only. A comprehensive neuropsychological battery was administered at baseline and throughout the 6-month treatment period. Statistical significance was defined as a p-value of less than 0.05 (two-sided test). RESULTS: With the exception of processing speed, there was statistically significant improvement across most neurocognitive measures from baseline to 6-month follow-up. There were no significant differences between the two treatment groups at 6 months on measures of psychomotor processing speed, autobiographical memory consistency, short-term and long-term verbal memory, phonemic fluency, inhibition, and complex visual scanning and cognitive flexibility. CONCLUSION: To our knowledge, this is the first report of neurocognitive outcomes over a 6-month period of an acute course of RUL-UB ECT followed by one of 2 strategies to prolong remission in older adults with major depression. Neurocognitive outcome did not differ between STABLE plus pharmacotherapy versus pharmacotherapy alone over the 6-month continuation treatment phase. These findings support the safety of RUL-UB ECT in combination with pharmacotherapy in the prolonging of remission in late-life depression.

Neurocognitive Effects of Combined Electroconvulsive Therapy (ECT) and Venlafaxine in Geriatric Depression: Phase 1 of the PRIDE Study.

OBJECTIVE: There is limited information regarding the tolerability of electroconvulsive therapy (ECT) combined with pharmacotherapy in elderly adults with major depressive disorder (MDD). Addressing this gap, we report acute neurocognitive outcomes from Phase 1 of the Prolonging Remission in Depressed Elderly (PRIDE) study. METHODS: Elderly adults (age ≥60) with MDD received an acute course of 6 times seizure threshold right unilateral ultrabrief pulse (RUL-UB) ECT. Venlafaxine was initiated during the first treatment week and continued throughout the study. A comprehensive neurocognitive battery was administered at baseline and 72 hours following the last ECT session. Statistical significance was defined as a two-sided p-value of less than 0.05. RESULTS: A total of 240 elderly adults were enrolled. Neurocognitive performance acutely declined post ECT on measures of psychomotor and verbal processing speed, autobiographical memory consistency, short-term verbal recall and recognition of learned words, phonemic fluency, and complex visual scanning/cognitive flexibility. The magnitude of change from baseline to end for most neurocognitive measures was modest. CONCLUSION: This is the first study to characterize the neurocognitive effects of combined RUL-UB ECT and venlafaxine in elderly adults with MDD and provides new evidence for the tolerability of RUL-UB ECT in an elderly sample. Of the cognitive domains assessed, only phonemic fluency, complex visual scanning, and cognitive flexibility qualitatively declined from low average to mildly impaired. While some acute changes in neurocognitive performance were statistically significant, the majority of the indices as based on the effect sizes remained relatively stable.

Neurocognitive effects of transcranial direct current stimulation (tDCS) in unipolar and bipolar depression: Findings from an international randomized controlled trial.

OBJECTIVE: Transcranial direct current stimulation (tDCS) has been found to have antidepressant effects and may have beneficial neurocognitive effects. However, prior research has produced an unclear understanding of the neurocognitive effects of repeated exposure to tDCS. The study's aim was to determine the neurocognitive effects following tDCS treatment in participants with unipolar or bipolar depression. METHOD: The study was a triple-masked, randomized, controlled clinical trial across six international academic medical centers. Participants were randomized to high dose (2.5 mA for 30 min) or low dose (0.034 mA, for 30 min) tDCS for 20 sessions over 4 weeks, followed by an optional 4 weeks of open-label high dose treatment. The tDCS anode was centered over the left dorsolateral prefrontal cortex at F3 (10/20 EEG system) and the cathode over F8. Participants completed clinical and neurocognitive assessments before and after tDCS. Genotype (BDNF Val66Met and catechol-o-methyltransferase [COMT] Val158Met polymorphisms) were explored as potential moderators of neurocognitive effects. RESULTS: The study randomized 130 participants. Across the participants, tDCS treatment (high and low dose) resulted in improvements in verbal learning and recall, selective attention, information processing speed, and working memory, which were independent of mood effects. Similar improvements were observed in the subsample of participants with bipolar disorder. There was no observed significant effect of tDCS dose. However, BDNF Val66Met and COMT Val158Met polymorphisms interacted with tDCS dose and affected verbal memory and verbal fluency outcomes, respectively. CONCLUSIONS: These findings suggest that tDCS could have positive neurocognitive effects in unipolar and bipolar depression. Thus, tDCS stimulation parameters may interact with interindividual differences in BDNF and COMT polymorphisms to affect neurocognitive outcomes, which warrants further investigation.

Transcranial Photobiomodulation (tPBM) With 1,064-nm Laser to Improve Cerebral Metabolism of the Human Brain In Vivo.

BACKGROUND AND OBJECTIVES: In our previous proof-of-principle study, transcranial photobiomodulation (tPBM) with 1,064-nm laser was reported to significantly increase concentration changes of oxygenated hemoglobin (∆[HbO]) and oxidized-state cytochrome c oxidase (∆[oxi-CCO]) in the human brain. This paper further investigated (i) its validity in two different subsets of young human subjects at two study sites over a period of 3 years and (ii) age-related effects of tPBM by comparing sham-controlled increases of ∆[HbO] and ∆[oxi-CCO] between young and older adults. STUDY DESIGN/MATERIALS AND METHODS: We measured sham-controlled ∆[HbO] and ∆[oxi-CCO] using broadband near-infrared spectroscopy (bb-NIRS) in 15 young (26.7 ± 2.7 years of age) and 5 older (68.2 ± 4.8 years of age) healthy normal subjects before, during, and after right-forehead tPBM/sham stimulation with 1,064-nm laser. Student t tests were used to test statistical differences in tPBM-induced ∆[HbO] and ∆[oxi-CCO] (i) between the 15 young subjects and those of 11 reported previously and (ii) between the two age groups measured in this study. RESULTS: Statistical analysis showed that no significant difference existed in ∆[HbO] and ∆[oxi-CCO] during and post tPBM between the two subsets of young subjects at two study sites over a period of 3 years. Furthermore, the two age groups showed statistically identical net increases in sham-controlled ∆[HbO] and ∆[oxi-CCO]. CONCLUSIONS: This study provided strong evidence to validate/confirm our previous findings that tPBM with 1,064-nm laser enables to increase cerebral ∆[HbO] and ∆[oxi-CCO] in the human brain, as measured by bb-NIRS. Overall, it demonstrated the robust reproducibility of tPBM being able to improve cerebral hemodynamics and metabolism of the human brain in vivo in both young and older adults. Lasers Surg. Med. © 2020 The Authors. Lasers in Surgery and Medicine published by Wiley Periodicals, Inc.

Racial Disparities in the Administration of ECT in Texas, 1998-2013.

OBJECTIVE: Electroconvulsive therapy (ECT) is a treatment of choice for severe depression but has been underutilized among black patients. This study investigates racial disparities in the administration of ECT in the state of Texas between 1998 and 2013 using population data. DESIGN: Data from the Texas Department of State Health Services were obtained corresponding to the use for all ECT conducted in nonfederal settings during the period from January 2, 1998, to August 30, 2013. The data set comprised quarterly reports generated for each patient, totaling 27,931 patient quarters. Using year-by-year intercensal population estimates for the state of Texas, ECT treatments per capita were compared among black, white, Latina/Latino, and other individuals during this time period. RESULTS: Significantly more white patients were treated each quarter than minority patients (P < 0.001), with Latina/Latino patients recording fewer treatment quarters than any other racial group (P < 0.005). Large discrepancies in diagnosis by race were observed. Black patients were less likely than white and Latina/Latino patients to be diagnosed with depression and 4 times as likely as white patients to carry a diagnosis of schizophrenia. CONCLUSIONS: Concordant with previous data, large racial disparities in the administration of ECT were found in this Texas data set. Despite the limited nature of this data set, these results suggest that continued investigation is required to determine factors responsible for these disparities.

Electroconvulsive Therapy and All-Cause Mortality in Texas, 1998-2013.

INTRODUCTION: Electroconvulsive therapy (ECT) remains an effective treatment for major depressive disorder. Since 1995, Texas has maintained an ECT database including patient diagnoses and outcomes, and reporting any deaths within 14 days of receiving an ECT treatment, encompassing a total of 166,711 ECT treatments administered in Texas over the previously unreported period of 1998 to 2013. METHODS: Descriptive analysis summarized information on deaths reported during the 16-year period-cause of death, type of treatment (index or maintenance) and patient demographics. Multiple logistic regression of death incidence by treatment session was performed to determine whether patient age, sex, race, diagnosis, or year of treatment was associated with death after ECT. RESULTS: Of those deaths occurring within 1 day of an ECT treatment, the death rate was 2.4 per 100,000 treatments. Looking at all deaths within 14 days of an ECT treatment, the death rate increased to 18 per 100,000 treatments but included all deaths regardless of likelihood of causal association with ECT, for example, accidents and suicides, the latter a leading cause of death among individuals with severe major depression or other disorders for which ECT is indicated. Death rate increased significantly with increasing patient age (P = 0.001) and male sex (P = 0.009), and there was a nonsignificant trend toward increased death amongst patients with bipolar disorder or schizophrenia (P = 0.058) versus depression. CONCLUSIONS: Our data indicate that ECT is in general a safe procedure with respect to the likelihood of immediate death. Suicide remains a significant risk in ECT patients, despite evidence that ECT reduces suicidal ideation.

Defining treatment-resistant depression: a comprehensive review of the literature.

BACKGROUND: Despite the common occurrence and debilitating nature of treatment-resistant depression (TRD), currently there is no universally accepted definition for TRD. This review summarizes the different methods used to define TRD, and provides an overview of the TRD literature. METHODS: PsycInfo, Medline, and Ovid were searched to identify relevant articles published in peer-reviewed journals. A combination and/or variation of the following keywords were searched: treatment resistant, treatment refractory, depression, defining, staging, and modeling. Identified articles provided a description of the methods utilized for defining and/or measuring TRD, prevalence and impact of TRD, risk factors for TRD, and/or factors that contribute to the misclassification of non-TRD patients. RESULTS: Multiple methods for defining/measuring TRD have been proposed; however, variability in these methods has limited the comparability between TRD studies. Although various risk factors for TRD have been suggested, few have been consistently supported. The misclassification of non-TRD patients as having TRD is related to various clinical and treatment-related factors. CONCLUSIONS: Adopting a universal standard definition for TRD is necessary to reduce the variability in how TRD is defined, and the misclassification of non-TRD patients. A universal definition would benefit clinical and research settings by allowing data to be easily compared across these settings.

Clinical Outcomes of Magnetic Seizure Therapy vs Electroconvulsive Therapy for Major Depressive Episode: A Randomized Clinical Trial.

Importance: Electroconvulsive therapy (ECT) is highly effective and rapid in treating depression, but it carries a risk of significant cognitive adverse effects. Magnetic seizure therapy (MST), an investigational antidepressant treatment, may maintain the robust antidepressant efficacy of ECT while substantially reducing adverse effects due to its enhanced focality and weaker stimulation strength; however, previous clinical trials of MST were limited by small sample sizes. Objective: To compare the antidepressant efficacy of MST vs ultrabrief pulse right unilateral (RUL) ECT. Design, Setting, and Participants: A between-participants, double-blinded, randomized clinical trial was conducted at 3 academic hospitals from June 2007 to August 2012. Adults aged 18 to 90 years who were referred for treatment with ECT, had a major depressive episode in the context of major depressive disorder or bipolar disorder, and had a baseline 24-item Hamilton Depression Rating Scale (HDRS-24) total score of 18 or higher were included. Participants were randomly assigned 1:1 to treatment with MST or ultrabrief pulse RUL ECT. After the treatment course, patients were naturalistically followed up for up to 6 months to examine the durability of clinical effects. Interventions: Treatment with MST, applied at 100 Hz at 100% of the maximum device power for 10 seconds, or ultrabrief pulse RUL ECT, applied at 6 times seizure threshold. Main Outcomes and Measures: The primary outcome was change from baseline in HDRS-24 total score, with patients followed up for up to 6 months. A reduction of at least 50% in the HDRS-24 score indicated response, and at least a 60% decrease in the HDRS-24 score and a total score of 8 or less indicated remission. Results: Of the 73 participants (41 [56.2%] female; mean [SD] age, 48 [14.1] years), 35 were randomized to MST and 38 to ECT. Among them, 53 (72.6%) were classified as completers (29 in the MST group and 24 in the ECT group). Both MST and ECT demonstrated clinically meaningful antidepressant effects. In the intent-to-treat sample, 18 participants (51.4%) in the MST group and 16 (42.1%) in the ECT group met response criteria; 13 (37.1%) in the MST group and 10 (26.3%) in the ECT group met remission criteria. Among completers, 17 of 29 (58.6%) in the MST group and 15 of 24 (62.5%) in the ECT group met response criteria; 13 of 29 (44.8%) in the MST group and 10 of 24 (41.7%) in the ECT group met remission criteria. There was no significant difference between MST and ECT for either response or remission rates. However, the mean (SD) number of treatments needed to achieve remission was 9.0 (3.1) with MST and 6.7 (3.3) with ECT, a difference of 2.3 treatments (t71.0 = 3.1; P = .003). Both MST and ECT showed a sustained benefit over a 6-month follow-up period, again with no significant difference between them. Compared with MST, ECT had significantly longer time to orientation after treatment (threshold level: F1,56 = 10.0; P = .003) and greater severity of subjective adverse effects, particularly in the physical and cognitive domains. Conclusions and Relevance: This randomized clinical trial found that the efficacy of MST was indistinguishable from that of ultrabrief pulse RUL ECT, the safest form of ECT currently available. These results support the continued development of MST and provide evidence for advantages relative to state-of-the-art ECT. Trial Registration: ClinicalTrials.gov Identifier: NCT00488748.

Disruption of component processes of spatial working memory by electroconvulsive shock but not magnetic seizure therapy.

Self-ordered spatial working memory measures provide important information regarding underlying cognitive strategies, such as stereotypy. This strategy is based on repetitive sequential selection of a spatial pattern once a correct sequence has been identified. We previously reported that electroconvulsive shock (ECS) but not magnetic seizure therapy (MST) impaired performance on a spatial working memory task in a preclinical model. Here we tested the hypothesis that ECS disrupted stereotyped patterns in the selection of spatial stimuli. In a within-subject study design, we assessed the effects of ECS, MST, and sham on stereotypy and reaction time in a preclinical model. Stereotypy was assessed by the correlation of actual and predicted response patterns of spatial stimuli. Predicted patterns were based on performance during baseline sessions. ECS resulted in lower correlations between predicted and actual responses to spatial stimuli in two of the three subjects, and it also disrupted stereotypy. For one subject, there was change in the predictability of the spatial locus of responses between experimental conditions. For all three subjects, reaction time was significantly longer in ECS, relative to MST and sham. This is the first study to examine the effect of ECS, and to contrast the effects of ECS and MST, on spatial working memory component processes. Our preliminary findings show that ECS, but not MST decreased stereotypy and increased reaction time. This line of investigation may have significant implications in our understanding cognitive component processes of memory function and impairment.

Advances in brain stimulation for depression.

BACKGROUND: Major depressive disorder is a common and debilitating psychiatric disorder that negatively impacts a large portion of the population. Although a range of antidepressant treatments have been developed, many patients are unable to obtain an adequate therapeutic response despite completing several antidepressant medication trials. As a result, neurostimulation treatment modalities have been developed as potential alternatives. This article provides an overview of advances in neurostimulation for treating depression. METHODS: We conducted a comprehensive review of the neurostimulation literature to identify recent findings involving the description and rationale, efficacy, and side effects of vagus nerve stimulation (VNS), transcranial magnetic stimulation (TMS), magnetic seizure therapy (MST), and deep brain stimulation (DBS). RESULTS: VNS and TMS are the newest neurostimulation modalities that have been approved by the FDA for treating depression. VNS is approved for patients with treatment-resistant depression (TRD), while TMS has demonstrated efficacy only for milder forms of TRD. Despite demonstrated efficacy, further research is needed to address certain limitations and/or determine how best to utilize these forms of neurostimulation. Investigational forms of neurostimulation include MST and DBS. Although MST and DBS have demonstrated promise as a depression treatment, research is still being conducted to determine and/or enhance their antidepressant properties. CONCLUSIONS: Although electroconvulsive therapy remains the primary and most effective treatment option for patients with severe TRD, there have been considerable gains in the field of neurostimulation. Many of the neurostimulation techniques described in this review represent promising treatment alternatives for patients with TRD.

Severity of depressive and motor symptoms impacts quality of life in Parkinson's disease patients at an academic movement clinic: A cross-sectional study.

Introduction: Parkinson's disease (PD) is a neurodegenerative disease with motor and non-motor manifestations that have been previously reported to affect patient quality of life (QoL). Our objective is to investigate the factors that contribute to QoL in a cohort of PD patients receiving care at a major academic institution. Methods: In this cross-sectional study of 124 participants (71.77% male, mean age 65.20, mean UPDRS-III score 11.25), we analyzed if certain clinical features such as UPDRS-III, QIDS-C, and total disease duration contributed to QoL as measured by two different metrics (PDQ-39 and EQ-5D) in PD patients at a university Movement Disorders Clinic. Results: Motor symptoms of PD, with the exception of tremor, as well as depression and specific depressive symptoms were significantly and positively correlated with lower QoL metrics for patients with Parkinson's, with total depressive symptom severity (QIDS-C16 Total score) contributing most to QoL scores. Of the specific depressive and motor symptoms, anhedonia and rigidity contributed the most to QoL. Disease duration was significantly correlated with lower QoL for participants with Parkinson's according to the QoL metric PDQ-39 but not ED-5D. Parkinson's patients with access to high-quality healthcare are at risk for having diminished QoL due to both depressive and motor symptoms. Conclusion: While severity of motor symptoms certainly impacted QoL in our cohort, our findings suggest that depressive symptoms contribute more to impaired QoL than severe motor symptoms do. This phenomenon suggests that concomitant depression in PD as well as one's psychological adjustment to disability may have a greater impact on QoL than severe motor symptoms.

Neural correlates of successful response inhibition in unmedicated patients with late-life depression.

OBJECTIVE: Accumulating evidence implicates a strong association between abnormal frontostriatal-limbic brain circuits, executive dysfunction, and late-life depression (LLD). The stop signal task (SST) was designed by Rubia et al. for use with functional magnetic resonance imaging (fMRI) to identify the neural correlates of motor response inhibition, a well-characterized executive function. In this study, we compared brain activation between a group of unmedicated participants with LLD and an unmedicated healthy cohort during SST performance. METHODS: Participants 55-85 years of age were screened, clinically evaluated, and entered into either the LLD (n = 15) or healthy comparison group (n = 13). Both groups underwent neuroimaging while performing the SST under similar conditions. The brain circuitry of successful motor inhibition was evaluated by contrasting the condition of correctly inhibiting responses with the condition of correctly responding to Go signals. Differential areas of brain activation between the LLD and comparison groups were determined with FMRIB Software Library. RESULTS: Despite comparable SST performance measures, LLD participants demonstrated greater blood oxygen level dependent activation relative to the comparison group in predominantly left-lateralized frontostriatal-limbic circuitry that included the bilateral superior frontal cortices and left-hemispheric orbitofrontal gyri, insular cortex, cingulate cortex, caudate, and putamen. Conversely, the healthy comparison group did not exhibit any areas of greater activation than the LLD group. CONCLUSION: Unmedicated participants with LLD activate additional areas within frontostriatal-limbic brain circuitry when performing the SST at a level comparable to a healthy cohort.

Motor symptoms at onset of Parkinson disease and risk for cognitive impairment and depression.

OBJECTIVE: To determine whether side and type of initial motor symptoms in Parkinson disease (PD) predict risk for later development of cognitive impairment or depressive symptoms. METHODS: We recruited 124 non-demented patients with PD to participate in a cohort study of cognitive function and depressive symptoms that used validated neuropsychological tests and a depressive symptom inventory. We first reviewed the patients' charts to determine their initial motor symptom and side of onset, and then classified the patients into 4 groups: right-sided onset tremor, right-sided onset bradykinesia/rigidity, left-sided onset tremor, and left-sided onset bradykinesia/rigidity. We excluded patients with bilateral symptom onset. We used analysis of variance on neuropsychological test performance and depressive symptoms to determine whether group classification affected risk of cognitive impairment or depressive symptoms. We controlled our analyses for disease duration and motor severity as measured by the Unified Parkinson Disease Rating Scale Part III motor score. RESULTS: There were no differences in any cognitive measure by side and type of initial motor symptoms. The right-sided onset tremor group had the lowest depressive symptom scores, and no patient in any group reported severe depressive symptoms. CONCLUSIONS: Our findings suggest that patterns of nigral cell loss correlating to the initial side and type of motor symptoms in PD are not related to the risk of later cognitive impairment. By contrast, patients with right-sided onset of tremor seem to have a lower risk of depressive symptoms than patients with other presentations.

Residual symptoms in depressed outpatients who respond by 50% but do not remit to antidepressant medication.

Little is known about the quantity or quality of residual depressive symptoms in patients with major depressive disorder (MDD) who have responded but not remitted with antidepressant treatment. This report describes the residual symptom domains and individual depressive symptoms in a large representative sample of outpatients with nonpsychotic MDD who responded without remitting after up to 12 weeks of citalopram treatment in the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study. Response was defined as 50% or greater reduction in baseline 16-item Quick Inventory of Depressive Symptomatology--Self-Report (QIDS-SR16) by treatment exit, and remission as a final QIDS-SR16 of less than 6. Residual symptom domains and individual symptoms were based on the QIDS-SR16 and classified as either persisting from baseline or emerging during treatment. Most responders who did not remit endorsed approximately 5 residual symptom domains and 6 to 7 residual depressive symptoms. The most common domains were insomnia (94.6%), sad mood (70.8%), and decreased concentration (69.6%). The most common individual symptoms were midnocturnal insomnia (79.0%), sad mood (70.8%), and decreased concentration/decision making (69.6%). The most common treatment-emergent symptoms were midnocturnal insomnia (51.4%) and decreased general interest (40.0%). The most common persistent symptoms were midnocturnal insomnia (81.6%), sad mood (70.8%), and decreased concentration/decision making (70.6%). Suicidal ideation was the least common treatment-emergent symptom (0.7%) and the least common persistent residual symptom (17.1%). These findings suggest that depressed outpatients who respond by 50% without remitting to citalopram treatment have a broad range of residual symptoms. Individualized treatments are warranted to specifically address each patient's residual depressive symptoms.