Steven J. Garlow

Defining Critical White Matter Pathways Mediating Successful Subcallosal Cingulate Deep Brain Stimulation for Treatment-Resistant Depression

BACKGROUND Subcallosal cingulate white matter (SCC) deep brain stimulation (DBS) is an evolving investigational treatment for depression. Mechanisms of action are hypothesized to involve modulation of activity within a structurally defined network of brain regions involved in mood regulation. Diffusion tensor imaging was used to model white matter connections within this network to identify those critical for successful antidepressant response. METHODS Preoperative high-resolution magnetic resonance imaging data, including diffusion tensor imaging, were acquired in 16 patients with treatment-resistant depression, who then received SCC DBS. Computerized tomography was used postoperatively to locate DBS contacts. The activation volume around the contacts used for chronic stimulation was modeled for each patient retrospectively. Probabilistic tractography was used to delineate the white matter tracts traveling through each activation volume. Patient-specific tract maps were calculated using whole-brain analysis. Clinical evaluations of therapeutic outcome from SCC DBS were defined at 6 months and 2 years. RESULTS Whole-brain activation volume tractography demonstrated that all DBS responders at 6 months (n = 6) and 2 years (n = 12) shared bilateral pathways from their activation volumes to 1) medial frontal cortex via forceps minor and uncinate fasciculus; 2) rostral and dorsal cingulate cortex via the cingulum bundle; and 3) subcortical nuclei. Nonresponders did not consistently show these connections. Specific anatomical coordinates of the active contacts did not discriminate responders from nonresponders. CONCLUSIONS Patient-specific activation volume tractography modeling may identify critical tracts that mediate SCC DBS antidepressant response. This suggests a novel method for patient-specific target and stimulation parameter selection.

An Interactive Web-Based Method of Outreach to College Students at Risk for Suicide

Objective and Participants: From 2002 to 2005, the authors tested an interactive, Web-based method to encourage college students at risk for suicide to seek treatment. Methods: The authors invited students at 2 universities to complete an online questionnaire that screened for depression and other suicide risk factors. Respondents received a personalized assessment and were able to communicate anonymously with a clinical counselor online. At-risk students were urged to attend in-person evaluation and treatment. Results: A total of 1,162 students (8% of those invited) completed the screening questionnaire; 981 (84.4%) were designated as at high or moderate risk. Among this group, 190 (19.4%) attended an inperson evaluation session with the counselor, and 132 (13.5%) entered treatment. Students who engaged in online dialogues with the counselor were 3 times more likely than were those who did not to come for evaluation and enter treatment. Conclusions: The method has considerable promise for encouraging previously untreated, at-risk college students to get help.

A randomized, placebo-controlled trial of risperidone augmentation for patients with difficult-to-treat unipolar, non-psychotic major depression.

OBJECTIVE Patients (30-50%) with non-psychotic major depression will not respond despite an adequate trial of antidepressant medication. This study evaluated risperidone as an augmenting agent for patients who failed or only partially responded to an adequate trial of an antidepressant medication. METHOD Ninety-seven patients with unipolar non-psychotic major depression who were not responsive to antidepressant monotherapy were randomized to risperidone (0.5-3mg/day) or placebo augmentation in a four-week, double-blind, placebo controlled treatment trial. The primary outcome measure was remission defined by a score of < or =10 on the Montgomery-Asberg Depression Rating Scale (MADRS). Secondary outcomes measures were the Hamilton Rating Scale for Depression, the Clinician Global Impression of Severity scale and the overall satisfaction item of the Quality of Life and Enjoyment Questionnaire. RESULTS Subjects in both treatment groups improved significantly over time. The odds of remitting were significantly better for patients in the risperidone vs. placebo arm (OR=3.33, p=.011). At the end of 4 weeks of treatment 52% of the risperidone augmentation group remitted (MADRS< or =10) compared to 24% of the placebo augmentation group (CMH(1)=6.48, p=.011), but the two groups were converging. Patients in the risperidone group also reported significantly more improvement in quality-of-life than patients in the placebo group. There were no between-group differences in the number of adverse events reported, however, weight gain was significantly higher in the group receiving risperidone. CONCLUSION Augmentation of an antidepressant with risperidone for patients with difficult-to-treat depression leads to more rapid response and a higher remission rate and better quality-of-life.

Cocaine use disorders and suicidal ideation

The goal of this study was to determine the contribution of substance abuse to the expression of suicidal ideation in a sample of patients referred for evaluation of chemical dependency in a large urban Psychiatric Emergency Service (PES). Records from 777 consecutive patients referred to the chemical dependency service of the PES were analyzed. Of this sample, 43.7% of the patients with only a cocaine use disorder expressed suicidal ideation compared to 38% of those with both cocaine and alcohol use disorders, 24.3% with only an alcohol use disorder and 17% with other drug use disorders (chi(2)=24.768; df=3; P<0.0001). More than half of the patients (55.26%) with a substance-induced mood or psychotic disorder expressed suicidal ideation (chi(2)=23.174, df=1, P<0.0001), and the majority (85%) of these patients had a cocaine use disorder (chi(2)=12.309, df=1, P<0.0005). In this sample of patients served by an urban PES, cocaine use is associated with suicidal ideation, more so than other substances of abuse.

Pharmaco-genetically guided treatment of recurrent rage outbursts in an adult male with 15q13.3 deletion syndrome.

15q13.3 deletion syndrome (15q13.3DS) is a common recurrent genomic disorder associated with epilepsy, intellectual impairment, aggressive behavior, schizophrenia, and autism. A 39‐year‐old male presented with 15q13.3DS, epilepsy, intellectual impairment, psychosis, and recurrent episodes of aggressive rage. We hypothesized that the patients aggressive behavior reflected deficits in α7 nicotinic cholinergic receptor (NChR)‐mediated neurotransmission, arising from haploinsufficiency of the structural gene CHRNA7 due to the deletion. Treatment with the NChR allosteric modulator and acetylcholinesterase (AChE) inhibitor, galantamine, led to a dramatic decline in the frequency and intensity of rage outbursts, suggesting that enhancement of α7 NChR function can ameliorate 15q13.3DS‐associated rage outbursts.

Coadministration of modafinil and a selective serotonin reuptake inhibitor from the initiation of treatment of major depressive disorder with fatigue and sleepiness: a double-blind, placebo-controlled study.

Background Previous studies suggest that adjunctive modafinil treatment provides benefit for patients with depression with significant sleepiness and fatigue. Methods We conducted a multisite, double-blind, placebo-controlled study of the treatment of major depression characterized by excessive sleepiness and fatigue, adding adjunctive modafinil or placebo to a selective serotonin reuptake inhibitor from the beginning of treatment. Seventy-three of 90 consenting patients met all screening criteria to begin treatment with open-label selective serotonin reuptake inhibitor therapy and double-blind addition of either modafinil (100 mg/d for 1 week then 200 mg/d) or matching placebo for 6 weeks. Results Mixed-model analysis of the change in the Epworth Sleepiness Scale, the primary outcome measure, showed no difference between modafinil- and placebo-treated patients. However, the hypersomnia items on the 31-item Hamilton Depression Scale were significantly more improved with modafinil than placebo. The total 31-item Hamilton Depression Scale score was significantly better with modafinil than placebo at Weeks 4 and 5, but not at the final study visit. There was no difference in dropout rates caused by adverse events, but 2 patients in the modafinil-treated group developed new onset or worsening of suicidal ideation, leading to the trial being discontinued prematurely. Conclusions Power to detect differences between modafinil and placebo was limited because of the premature discontinuation of the trial. Although modafinil did not show evidence of benefit over placebo on the Epworth Sleepiness Scale, secondary measures suggested modafinil may have provided benefit for symptoms of excessive sleepiness in patients with depression.

A connectomic approach for subcallosal cingulate deep brain stimulation surgery: prospective targeting in treatment-resistant depression

Target identification and contact selection are known contributors to variability in efficacy across different clinical indications of deep brain stimulation surgery. A retrospective analysis of responders to subcallosal cingulate deep brain stimulation (SCC DBS) for depression demonstrated the common impact of the electrical stimulation on a stereotypic connectome of converging white matter bundles (forceps minor, uncinate fasciculus, cingulum and fronto-striatal fibers). To test the utility of a prospective connectomic approach for SCC DBS surgery, this pilot study used the four-bundle tractography ‘connectome blueprint’ to plan surgical targeting in 11 participants with treatment-resistant depression. Before surgery, targets were selected individually using deterministic tractography. Selection of contacts for chronic stimulation was made by matching the post-operative probabilistic tractography map to the pre-surgical deterministic tractography map for each subject. Intraoperative behavioral responses were used as a secondary verification of location. A probabilistic tract map of all participants demonstrated inclusion of the four bundles as intended, matching the connectome blueprint previously defined. Eight of 11 patients (72.7%) were responders and 5 were remitters after 6 months of open-label stimulation. At one year, 9 of 11 patients (81.8%) were responders, with 6 of them in remission. These results support the utility of a group probabilistic tractography map as a connectome blueprint for individualized, patient-specific, deterministic tractography targeting, confirming retrospective findings previously published. This new method represents a connectomic approach to guide future SCC DBS studies.

Practical Considerations in the Development and Refinement of Subcallosal Cingulate White Matter Deep Brain Stimulation for Treatment-Resistant Depression

BACKGROUND Deep brain stimulation has been investigated in the past decade as a viable intervention for treatment-resistant depression. METHODS Several anatomic targets have been tested, with the most extensive published experience found for the subcallosal cingulate (SCC) white matter. RESULTS This article reviews the current state of clinical research of SCC deep brain stimulation for treatment-resistant depression, including an overview of the rationale for targeting SCC, practical considerations for subject recruitment and evaluation, surgical planning, and stimulation parameters. CONCLUSION Clinical management of patients in the initial and long-term naturalistic phases of treatment, including the potential role for psychotherapeutic rehabilitation, is discussed.

Differential association of socioeconomic status in ethnic and age-defined suicides.

Suicide rates vary among racel- and age-defined groups, yet little is known about how suicide risk factors differentially impact individual groups. This study assessed differential associations of socioeconomic status among age- and race-defined groups of suicide victims. A database containing demographic information on declared suicides in Fulton County, GA, from 1 January 1988 through 31 December 2003 was combined with annual per capita income by zip code in Atlanta, GA. Analyses were performed to evaluate differential associations of socioeconomic status among age- and race-defined groups of suicide victims. Compared with the respective ethnic populations of Fulton County, white suicide victims lived in areas with lower per capita income (

Peak window of suicides occurs within the first month of diagnosis: implications for clinical oncology

51,232 vs.