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Randomized controlled trials support the antidepressant efficacy of transcranial magnetic stimulation (TMS); however, there is individual variability in the magnitude of response. Examination of response predictors has been hampered by methodological limitations such as small sample sizes and single-site study designs. Data from a multisite sham-controlled trial of the antidepressant efficacy of TMS provided an opportunity to examine predictors of acute outcome. An open-label extension for patients who failed to improve provided the opportunity for confirmatory analysis. Treatment was administered to the left dorsolateral prefrontal cortex at 10 pulses per second, 120% of motor threshold, for a total of 3000 pulses per day. Change on the Montgomery–Asberg Depression Rating Scale after 4 weeks was the primary efficacy outcome. A total of 301 patients with nonpsychotic unipolar major depression at 23 centers were randomized to active or sham TMS. Univariate predictor analyses showed that the degree of prior treatment resistance in the current episode was a predictor of positive treatment outcome in both the controlled study and the open-label extension trial. In the randomized trial, shorter duration of current episode was also associated with a better outcome. In the open-label extension study, absence of anxiety disorder comorbidity was associated with an improved outcome, but duration of current episode was not. The number of prior treatment failures was the strongest predictor for positive response to acute treatment with TMS. Shorter duration of current illness and lack of anxiety comorbidity may also confer an increased likelihood of good antidepressant response to TMS.

Background/Purpose Approximately one third of adults in the United States complete a Medical Advance Directive in their lifetime. However, few complete a Psychiatric Advance Directive (PAD), despite the high prevalence of psychiatric illness. PADs help those with mental illness specify their care preferences during periods of acute psychiatric illness. Given the minimal research regarding PAD usage, the use of PADs in clinical practice remains poorly understood. This study aims to use electronic health record (EHR) data to investigate and describe PAD usage in a large, county health system. Methods EHR data for all patients 18 years and older with a 2022 inpatient or observation discharge were retrieved. A sample of these patients who had scanned Advance Directive documents were reviewed to assess for the presence of a PAD. Results A total of 41,421 patients were included in this EHR analysis. No PAD documents were found in this population. Conclusion Although the PAD template was published on the hospital website, we found no evidence of completed PADs at our facility. Further work is needed to educate providers on the importance of PADs and promote appropriate and inclusive PAD usage at the health system level. Relevance to Clinical Practice This research identifies a significant gap in PAD utilization and emphasizes the potential for increased PAD use in clinical care. It highlights current obstacles to PAD implementation while offering actionable next steps for how PADs can fit into the larger flow of patient care. Highlights Despite Psychiatric Advance Directives (PADs) existing as an Advance Care document to help increase patient empowerment and improve psychiatric care, these documents are rarely utilized. In parallel to the lack of PAD utilization, there is an apparent lack of knowledge of what these documents are and how they can be helpful for individuals with mental illness. Additional education for providers and patients is needed to increase PAD utilization in order to support greater autonomy and empowerment for those experiencing a mental health crisis.

Simultaneously acquiring functional Near Infrared Spectroscopy (fNIRS) during Transcranial Magnetic Stimulation (rTMS) offers the possibility of directly investigating superficial cortical brain activation and connectivity. In addition, the effects of rTMS in distinct brain regions without quantifiable behavioral changes can be objectively measured. Healthy, nonmedicated participants age 18–50 years were recruited from the local community. After written informed consent was obtained, the participants were screened to ensure that they met inclusion criteria. They underwent two visits of simultaneous rTMS/fNIRS separated by 2 to 3 days. In each visit, the motor cortex and subsequently the prefrontal cortex (5 cm anterior to the motor cortex) were stimulated (1 Hz, max 120% MT, 10 s on with 80 s off, for 15 trains) while simultaneous fNIRS data were acquired from the ipsilateral and contralateral brain regions. Twelve healthy volunteers were enrolled with one excluded prior to stimulation. The 11 participants studied (9 male) had a mean age of 31.8 (s.d. 10.2, range 20–49) years. There was no significant difference in fNIRS between Visit 1 and Visit 2. Stimulation of both the motor and prefrontal cortices resulted in a significant decrease in oxygenated hemoglobin (HbO2) concentration in both the ipsilateral and contralateral cortices. The ipsilateral and contralateral changes showed high temporal consistency. Simultaneous rTMS/fNIRS provides a reliable measure of regional cortical brain activation and connectivity that could be very useful in studying brain disorders as well as cortical changes induced by rTMS.

Magnetic seizure therapy, in which seizures are elicited with a high-frequency magnetic field, is under development as a new treatment for major depressive disorder. Its use may be justified if it produces the antidepressant effects of electroconvulsive therapy (ECT), coupled with limited cognitive side-effects. To evaluate the usefulness of a new 100 Hz magnetic seizure therapy device. We induced seizures with 100 Hz magnetic transcranial stimulation in 11 patients with major depressive disorder during one session of a regular course of ECT. Recovery times after seizures induced by magnetic seizure therapy and ECT were compared. Seizures could be elicited in 10 of the 11 patients. Stimulation over the vertex produced tonic-clonic activity on 9 out of 11 occasions. Stimulation over the prefrontal midpoint elicited seizures on 3 out of 7 occasions. The mean duration of magnetically induced seizures was 31.3 s, ranging from 10 to 86 s. All patients had an exceptionally quick recovery of orientation: mean of 7 min 12 s (s.d.=2 min 7 s, range 4 min 20 s to 9 min 41 s). The recovery times were on average 15 min 35 s shorter with magnetic seizure therapy than with ECT in the same patients (paired-samples t-test: P<0.0001). Patients reported feeling less confused after magnetic seizure therapy. Side-effects were confined to myoclonic movements, associated with the use of etomidate. The new 100 Hz magnetic stimulator elicits seizures in the majority of patients when administered over the vertex. Magnetic seizure therapy was associated with shorter recovery times and less confusion following treatment. Subsequent work will be required to assess the safety and effectiveness of magnetic seizure therapy in the treatment of depression.

The objective of this post-hoc exploratory analysis was to examine the relationship between age and measures of cortical excitability and inhibition. Forty-six participants (24 with major depressive disorder and 22 healthy controls) completed MT, SICI, ICF, and CSP testing in a cross-sectional protocol. Of these 46 participants, 33 completed LICI testing. Multiple linear robust regression and Spearman partial correlation coefficient were used to examine the relationship between age and the TMS measures. In the overall sample of 46 participants, age had a significant negative relationship with motor threshold (MT) in both the right (r s = -0.49, adjusted p = 0.007; β = -0.08, adjusted p = 0.001) and left (r s = -0.42, adjusted p = 0.029; β = -0.05, adjusted p = 0.004) hemispheres. This significant negative relationship of age with MT was also observed in the sample of depressed youth in both the right (r s = -0.70, adjusted p = 0.002; β = -0.09, adjusted p = 0.001) and left (r s = -0.54, adjusted p = 0.034; β = -0.05, adjusted p = 0.017) hemispheres, but not in healthy controls. In the sample of the 33 participants who completed LICI testing, age had a significant negative relationship with LICI (200 ms interval) in both the right (r s = -0.48, adjusted p = 0.05; β = -0.24, adjusted p = 0.007) and left (r s = -0.64, adjusted p = 0.002; β = -0.23, adjusted p = 0.001) hemispheres. This negative relationship between age and LICI (200 ms interval) was also observed in depressed youth in both the right (r s = -0.76, adjusted p = 0.034; β = -0.35, adjusted p = 0.004) and left (r s = -0.92, adjusted p = 0.002; β = -0.25, adjusted p = 0.001) hemispheres. These findings suggest that younger children have higher MTs. This is more pronounced in depressed youth than healthy controls. LICI inhibition may also increase with age in youth.

Electroconvulsive therapy (ECT) is an effective treatment for major depression. Optimising efficacy and minimising cognitive impairment are goals of ongoing technical refinements. To compare the efficacy and cognitive effects of a novel electrode placement, bifrontal, with two standard electrode placements, bitemporal and right unilateral in ECT. This multicentre randomised, double-blind, controlled trial (NCT00069407) was carried out from 2001 to 2006. A total of 230 individuals with major depression, bipolar and unipolar, were randomly assigned to one of three electrode placements during a course of ECT: bifrontal at one and a half times seizure threshold, bitemporal at one and a half times seizure threshold and right unilateral at six times seizure threshold. All three electrode placements resulted in both clinically and statistically significant antidepressant outcomes. Remission rates were 55% (95% CI 43-66%) with right unilateral, 61% with bifrontal (95% CI 50-71%) and 64% (95% CI 53-75%) with bitemporal. Bitemporal resulted in a more rapid decline in symptom ratings over the early course of treatment. Cognitive data revealed few differences between the electrode placements on a variety of neuropsychological instruments. Each electrode placement is a very effective antidepressant treatment when given with appropriate electrical dosing. Bitemporal leads to more rapid symptom reduction and should be considered the preferred placement for urgent clinical situations. The cognitive profile of bifrontal is not substantially different from that of bitemporal.

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.

: Transcranial magnetic stimulation (TMS) research has suggested dysfunction in cortical glutamatergic systems in adolescent depression, while proton magnetic resonance spectroscopy ( H-MRS) studies have demonstrated deficits in concentrations of glutamatergic metabolites in depressed individuals in several cortical regions, including the anterior cingulate cortex (ACC). However, few studies have combined TMS and MRS methods to examine relationships between glutamatergic neurochemistry and excitatory and inhibitory neural functions, and none have utilized TMS-MRS methodology in clinical populations or in youth. This exploratory study aimed to examine relationships between TMS measures of cortical excitability and inhibition and concentrations of glutamatergic metabolites as measured by H-MRS in depressed adolescents. : Twenty-four adolescents (aged 11-18 years) with depressive symptoms underwent TMS testing, which included measures of the resting motor threshold (RMT), cortical silent period (CSP), short-interval intracortical inhibition (SICI), and intracortical facilitation (ICF). Fourteen participants from the same sample also completed H-MRS in a 3 T MRI scanner after TMS testing. Glutamate + glutamine (Glx) concentrations were measured in medial ACC and left primary motor cortex voxels with a TE-optimized PRESS sequence. Metabolite concentrations were corrected for cerebrospinal fluid (CSF) after tissue segmentation. Pearson product-moment and Spearman rank-order correlations were calculated to assess relationships between TMS measures and [Glx]. : In the left primary motor cortex voxel, [Glx] had a significant positive correlation with the RMT. In the medial ACC voxel, [Glx] had significant positive correlations with ICF at the 10-ms and 20-ms interstimulus intervals (ISIs). : These preliminary data implicate glutamate in cortical excitatory processes measured by TMS. Limitations included small sample size, lack of healthy control comparators, possible age- and sex-related effects, and observational nature of the study. Further research aimed at examining the relationship between glutamatergic metabolite concentrations measured through MRS and the excitatory and inhibitory physiology measured through TMS is warranted. Combined TMS-MRS methods show promise for future investigations of the pathophysiology of depression in adults as well as in children and adolescents.

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. 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. 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. Unmedicated participants with LLD activate additional areas within frontostriatal-limbic brain circuitry when performing the SST at a level comparable to a healthy cohort.

Studies have shown that age is a determinant in the course of major depressive disorder. Age has been associated with depression severity; it has also been associated with varying depressive symptomatology. The authors explore the relationships between current age and depression severity, course of illness, presenting symptom features, and comorbid symptoms. Baseline clinical and sociodemographic information was collected on 1,498 participants enrolled in the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) Study. Five age cohorts (18–25, 26–35, 36–50, 51–65, and 66–75) were compared on both sociodemographic and clinical factors. Depressive symptoms were measured with the 30-item clinician-rated Inventory of Depressive Symptomatology. Clinically meaningful differences were found among age cohorts on several clinical and depressive symptom features. Older patients (51–65 and 66–75) endorsed longer durations of illness, more major depressive episodes, a later age at onset of their first major depressive episode, and more general medical comorbidities. Older patients had more middle and terminal insomnia, less irritability, and less hypersomnia. They were less likely to hold negative views of themselves or of their future and were less likely to report previous suicide attempts. Older patients were less likely to endorse symptoms consistent with generalized anxiety disorder, social phobia, panic disorder, and drug abuse. These cross-sectional data indicate that different age-cohorts present with varying sociodemographic and clinical characteristics, as well as general-medical and psychiatric comorbid conditions.