Real world efficacy and safety of various accelerated deep TMS protocols for major depression.

There is growing interest in accelerated rTMS dosing regimens, wherein multiple sessions of rTMS are applied per day. This Phase IV study evaluated the safety, efficacy, and durability of various accelerated Deep TMS protocols used in clinical practice. Data were aggregated from 111 patients with major depressive disorder (MDD) at 4 sites. Patients received one of several accelerated Deep TMS protocols (2x/day, 3x/day, 5x/day, 10x/day). Self-assessment questionnaires (PHQ-9, BDI-II) and clinician-based rating scales (HDRS-21, MADRS) were collected. On average, accelerated TMS led to an 80.2% response and 50.5% remission rate in the first month based on the most rated scale for each patient. There was no significant difference between protocols (Response: 2x/day:89.6%; 3x/day:75%; 5x/day:81%; 10x/day:67.6%). Response occurred after 10 (3x/day), 20 (5x/day), and 31 sessions (10x/day) on average- all of which occur on day 3-4 of treatment. Of patients with longer term follow up, durability was found in 86.7% (n = 30; 60 days) and 92.9% (n = 14; 180 days). The protocols were well-tolerated with no reported serious adverse events. Accelerated Deep TMS protocols are found to be safe, effective therapeutic options for MDD. They offer treatment resistant patients a treatment option with a rapid onset of action and with long durability.

Decreased brainstem and putamen SERT binding potential in depressed suicide attempters using [11C]-zient PET imaging.

BACKGROUND: Deficits in serotonergic neurotransmission have been implicated in the pathogenesis of depression and suicidality. The present study utilized a novel positron-emission tomography (PET) ligand to quantitate and compare brain regional serotonin transporter (SERT) binding potential in depressed patients with a past history of suicide attempts to that of healthy comparison subjects. METHOD: We used [(11) C]-ZIENT PET to label SERT in the serotonergic cell body rich brainstem, and forebrain projection fields. Quantitative PET emission data from 21 adults (10 healthy controls and 11 drug-free patients with major depression) was used for group comparison. SERT binding potential (BPND ) in eight MRI-based brain regions of interest (ROI) were compared in high-resolution PET images. RESULTS: SERT binding potential was significantly decreased in the midbrain/pons (P = .029) and putamen (P = .04) of depressed patients with a past suicide attempt relative to comparison subjects. Forebrain SERT binding was also reduced in the patient sample, though these region effects did not survive a multiple comparison correction. CONCLUSION: These results suggest that decreased availability of the brainstem and basal ganglia SERT represents a biomarker of depression and thus confirm and extend the role of dysregulation of brain serotonergic neurotransmission in the pathophysiology of depression and suicide.

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 ($51,232 vs. $35,893); African American suicide victims did not ($17,384 vs. $18,179). Elderly suicide victims (>or= 65 years) were more likely to live in the lowest per capita income areas compared with other age groups (OR 1.80, 95% C.I. 1.14, 2.84). Cox proportional hazards models showed increasing income increased the instantaneous risk of suicide among adolescents (HR 2.76; 95% C.I. 2.15, 3.53), particularly African American adolescents (HR 4.22; 95% C.I. 2.19, 8.11), and decreased risk among the elderly (HR 0.58; 95% C.I. 0.50, 0.68). Socioeconomic status had differential associations among age- and race-defined groups of suicide victims.

Compartmental modeling of 11C-HOMADAM binding to the serotonin transporter in the healthy human brain.

UNLABELLED: The novel PET radioligand (11)C-N,N-dimethyl-2-(2'-amino-4'-hydroxymethylphenylthio)benzylamine ((11)C-HOMADAM) binds with high affinity and selectively to the serotonin transporter (SERT). The purpose of this study was to develop a reliable kinetic model to describe the uptake of (11)C-HOMADAM in the healthy human brain. METHODS: Eight volunteers participated in the study; 5 of them were fitted with arterial catheters for blood sampling and all were scanned on a high-resolution research tomograph after the injection of (11)C-HOMADAM. Regional distribution volumes and binding potentials were calculated with 2- and 4-parameter arterial-input compartment models, a 3-parameter reference tissue compartment model, and the Logan graphic approach. RESULTS: The 2-parameter arterial-input compartment model was statistically superior to the 4-parameter model and described all brain regions. Calculated binding potentials agreed well between the arterial-input model and the reference tissue model when the cerebellum was used as the reference tissue. The Logan graphic approach was not able to estimate the higher concentration of SERT in the dorsal raphe than in the midbrain. CONCLUSION: (11)C-HOMADAM is a highly promising radioligand with high ratios of specific binding to nonspecific binding in known SERT-rich structures, such as the raphe nuclei. The 3-parameter reference tissue model approach permits a simplified quantitatively accurate method for estimating SERT binding potentials.

The dexamethasone/corticotropin-releasing factor test in men with major depression: role of childhood trauma.

BACKGROUND: The dexamethasone/corticotropin-releasing factor (CRF) test is considered to be the most sensitive measure of hypothalamic-pituitary-adrenal (HPA) axis hyperactivity and has been demonstrated to be altered in patients with major depression (MDD). Although childhood trauma is a demonstrated risk factor for MDD and patients with a history of childhood abuse and MDD demonstrate HPA axis hyperactivity, the dexamethasone/CRF test remains unstudied in this population. We determined the impact of childhood trauma on dexamethasone/CRF test results in patients with MDD. METHODS: Forty-nine healthy men, ages 18-60 years, without mania or psychosis, active substance abuse, or eating disorder and medication-free were recruited into four study groups, including: 1) normal subjects with no childhood abuse history or psychiatric disorder (n = 14); 2) men with childhood abuse histories without current MDD (n = 14); 3) men with childhood abuse histories with current MDD (n = 15); and 4) men with current MDD and no childhood abuse history (n = 6). Plasma adrenocorticotropin (ACTH) and cortisol concentrations were measured in response to dexamethasone/CRF administration. RESULTS: Men with childhood trauma histories exhibited increases in ACTH and cortisol responses to dexamethasone/CRF compared with non-abused men. In particular, abused men with current MDD showed increased responsiveness compared with control subjects and depressed men without childhood abuse experience. Increased response was associated with the severity, duration, and earlier onset of the abuse. The effects were not explained by concurrent posttraumatic stress disorder. CONCLUSIONS: Childhood trauma increases HPA axis activity as measured with the dexamethasone/CRF test in adult men with MDD, potentially reflecting environmental risk for developing depression.

Cocaine and alcohol use preceding suicide in African American and white adolescents.

The goal of this investigation was to determine whether cocaine and ethanol use was a differentiating factor between African American and white teenage suicide victims. This is a retrospective analysis of medical examiner's records of all completed suicides in Fulton County, GA from 01/1989 to 12/2003, and included 1296 cases. There were 79 suicide victims aged 19 and younger during the study interval, and of this group, 49 (62%) were African American, 26 (33%) were white, and 4 (5%) other race, compared to adults (20 years) where 28.5% were African American, 68.6% white and 2.9% other race (chi(2)=42.678, d.f.=2, p<0.0001). Of the black teenaged victims, 82.2% had no cocaine or alcohol detected at autopsy, while 41.7% of the white victims were positive for one or both substance (chi(2)=4.633, d.f.=1, p=0.04). Only 8.9% of the black teenage suicide victims had used cocaine prior to death compared to 28% of the whites (chi(2)=4.432; d.f.=1; p<0.04). The suicide rate (suicide/100,000/year) for black teens was 5.48 compared to 4.16 for whites, but the rate of cocaine positive teen suicides was 1.12 for whites and 0.45 for blacks. The pattern of cocaine use changes dramatically in the adult group, with 27% of African American suicide victims compared to 7.7% of whites being positive (chi(2)=73.272; d.f.=1; p<0.001). Use of intoxicating substances does differentiate teenage suicide victims, as only a small proportion of black teenagers had used cocaine or alcohol prior to death compared to almost half of all whites.

Carbon-11 HOMADAM: a novel PET radiotracer for imaging serotonin transporters.

UNLABELLED: Carbon-11-labeled N,N-dimethyl-2-(2'-amino-4'-hydroxymethylphenylthio)benzylamine (HOMADAM) was synthesized as a new serotonin transporter (SERT) imaging agent. METHODS: Carbon-11 was introduced into HOMADAM by preparation of N-methyl-2-(2'-amino-4'-hydroxymethylphenylthio)benzylamine followed by alkylation with carbon-11 iodomethane. Binding affinities of HOMADAM and the radiolabeling substrate, N-methyl-2-(2'-amino-4'-hydroxymethylphenylthio)benzylamine, were determined in cDNA transfected cells expressing human SERT, dopamine transporters (DAT) and norepinephrine transporters NET using [3H]citalopram, [(125)I]RTI-55 and [3H]nisoxetine, respectively. MicroPET brain imaging was performed in monkeys. Arterial plasma metabolites of HOMADAM were analyzed in a rhesus monkey by high-performance liquid chromatography (HPLC). RESULTS: HOMADAM displayed high affinity for the SERT (Ki = 0.6 nM). N-methyl-2-(2'-amino-4'-hydroxymethylphenylthio)benzylamine displayed moderate affinity for the SERT (Ki = 15.11 nM). The affinities of HOMADAM for the DAT and NET were 2000- and 253-fold lower, respectively, than for the SERT. [11C]HOMADAM was prepared from [11C]iodomethane in approximately 25% radiochemical yield (decay-corrected to end of bombardment). MicroPET brain imaging studies in monkeys demonstrated that [11C]HOMADAM uptake was selectively localized in the midbrain, thalamus, pons, caudate, putamen and medulla. The midbrain-to-cerebellum, pons-to-cerebellum, thalamus-to-cerebellum and putamen-to-cerebellum ratios at 85 min were 4.2, 2.8, 2.3 and 2.0, respectively. HOMADAM binding achieved quasi-equilibrium at 45 min. Radioactivity in the SERT-rich regions of monkey brain was displaceable with R,S-citalopram. Radioactivity in the DAT-rich regions of monkey brain was not displaceable with the DAT ligand RTI-113. Radioactivity in the SERT-rich regions of monkey brain was displaceable with the R,S-reboxetine, a NET ligand with a high nanomolar affinity for SERT. Arterial plasma metabolites of HOMADAM were analyzed in a rhesus monkey by HPLC and displayed a single peak that corresponded to unmetabolized HOMADAM. CONCLUSION: HOMADAM is an excellent candidate for PET primate imaging of brain SERTs.

Ethnic differences in patterns of suicide across the life cycle.

OBJECTIVE: The authors analyzed suicide across the life cycle of different ethnic groups in an urban population equally divided between blacks (44.6%) and whites (48.1%). METHOD: Two data sets were used: 1) all suicides in Fulton County, Ga., from January 1994 through December 2002 and 2) all U.S. suicides reported by the National Center for Injury Prevention in 1999 and 2000. RESULTS: The population rates for suicide in Fulton County were 1.22 per 100,000 black females, 10.74 per 100,000 black males, 9.89 per 100,000 white females, and 21.04 per 100,000 white males. In Fulton County, age at completed suicide was more than a decade lower in blacks than in whites. The median age of black victims was 32 years, with an interquartile range (IQR) of 23-45, and the median for whites was 44 years (IQR=31-58); the difference was significant. The mean ages of victims who were black (mean=36.1 years, SD=17.0) and of "other" race (mean=35.7, SD=14.3) were significantly lower than the mean for whites (mean=46.2, SD=18.5). The national data were similar, but minorities accounted for an even smaller percentage of suicides. Median age at completed suicide for African Americans nationally was 34 years (IQR=24-45) compared to 44 years (IQR=32-58) for Caucasians. CONCLUSIONS: African Americans commit suicide at rates much lower than those for whites, but they do so when much younger and they have a narrow, age-defined window of vulnerability. Age-specific psychopathological processes and protective factors may define suicide risk for each demographic group.

Reduction of episodes of seclusion and restraint in a psychiatric emergency service.

The authors developed a comprehensive plan focusing on the early identification and management of problematic behaviors in an effort to reduce seclusion and restraint in a psychiatric emergency service and to increase adherence to hospital standards for its use. Hospital data for nine months before and nine months after the implementation of the plan were retrospectively reviewed. Two key factors that were believed to increase the likelihood of episodes of seclusion and restraint were ineffectual management of problematic behavior and inadequate monitoring. The plan, when instituted, was associated with a 39 percent reduction of instances of seclusion and restraint. Compliance with hospital standards increased to 100 percent.

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.

Serotonin transporter: a potential substrate in the biology of suicide.

Suicide is a serious public health problem in the US, yet its neurobiological underpinnings are poorly understood. Suicide is highly correlated with depressive symptoms, and considerable evidence suggests that depression is associated with a relative deficiency in serotonergic neurotransmission. Serotonergic circuits also mediate impulsivity, a trait obviously relevant to suicide. These findings, taken together, suggest that alterations in the serotonergic system might contribute to suicidal behavior, serving as an impetus for researchers to scrutinize the serotonin transporter (SERT) as a potential substrate for the pathophysiology of suicide. Using post-mortem brain tissue, platelets, and DNA from suicide completers and attempters have not provided unequivocal evidence for a pre-eminent role for the SERT in the pathophysiology of suicide. This paper provides a review of several studies that have evaluated the role of the SERT in the pathophysiology of suicide.

The relationship of restrictions on state hospitalization and suicides among emergency psychiatric patients.

OBJECTIVE: This study explored the relationship between mandated decreases in transfers to a state hospital from a large urban psychiatric emergency facility and the occurrence of suicide in the catchment area served. METHODS: During 1996, new admission criteria that emphasized psychiatric diagnosis and potential benefit from hospitalization and that restricted the admission of recidivistic patients and of those with a primary diagnosis of a substance use disorder were phased in. Data on the number of patients seen in a psychiatric emergency service and the number transferred to the state hospital were obtained for the period 1994-1998. Data on all completed suicides in the county served by the hospital were also obtained. RESULTS: During 1994 and 1995, a total of 9,308 patients were transferred to the state hospital. In 1997 and 1998, a total of 4,072 patients were transferred. The number of patients seen in the emergency service remained constant throughout the study period. No change was noted in the absolute number or the rate of suicide in the county after the new admission criteria were implemented. A total of 164 suicides were recorded in 1994-1995 (12 per 100,000 population per year), compared with 152 in 1997-1998 (ten per 100,000 population per year). CONCLUSIONS: Transfers to the state hospital were reduced by 56 percent, with no change in the suicide rate. This finding suggests that the availability of inpatient psychiatric hospitalization may not have a direct effect on the suicide rate.