Irving M. Reti

Efficacy and safety of deep transcranial magnetic stimulation for major depression: a prospective multicenter randomized controlled trial

Major depressive disorder (MDD) is a prevalent and disabling condition, and many patients do not respond to available treatments. Deep transcranial magnetic stimulation (dTMS) is a new technology allowing non‐surgical stimulation of relatively deep brain areas. This is the first double‐blind randomized controlled multicenter study evaluating the efficacy and safety of dTMS in MDD. We recruited 212 MDD outpatients, aged 22–68 years, who had either failed one to four antidepressant trials or not tolerated at least two antidepressant treatments during the current episode. They were randomly assigned to monotherapy with active or sham dTMS. Twenty sessions of dTMS (18 Hz over the prefrontal cortex) were applied during 4 weeks acutely, and then biweekly for 12 weeks. Primary and secondary efficacy endpoints were the change in the Hamilton Depression Rating Scale (HDRS‐21) score and response/remission rates at week 5, respectively. dTMS induced a 6.39 point improvement in HDRS‐21 scores, while a 3.28 point improvement was observed in the sham group (p=0.008), resulting in a 0.76 effect size. Response and remission rates were higher in the dTMS than in the sham group (response: 38.4 vs. 21.4%, p=0.013; remission: 32.6 vs. 14.6%, p=0.005). These differences between active and sham treatment were stable during the 12‐week maintenance phase. dTMS was associated with few and minor side effects apart from one seizure in a patient where a protocol violation occurred. These results suggest that dTMS constitutes a novel intervention in MDD, which is efficacious and safe in patients not responding to antidepressant medications, and whose effect remains stable over 3 months of maintenance treatment.

Selective expression of Narp, a secreted neuronal pentraxin, in orexin neurons

Recent studies have provided compelling evidence demonstrating that orexin (also known as hypocretin) neurons play a central role in the pathophysiology of narcolepsy. However, targeted deletion of orexin does not fully mimic the functional deficits induced by selective ablation of these neurons; implying that other secreted signaling molecules expressed in these neurons mediate key aspects of their function. In this study, we demonstrate that orexin neurons display robust expression of neuronal activity‐regulated pentraxin (Narp), a secreted neuronal pentraxin, implicated in regulating clustering of α‐amino‐3‐hydroxy‐5‐methylisoxazole‐4‐propionate (AMPA) receptors. Furthermore, we have found that hypothalamic melanin‐concentrating hormone (MCH) neurons, which form a peptidergic pathway thought to oppose the effects of the orexin system, express another neuronal pentraxin, NP1. Thus, these findings suggest that these pathways utilize neuronal pentraxins, in addition to neuropeptides, as synaptic signaling molecules.

Influences of parenting on normal personality traits

There is a considerable literature linking aspects of experienced parenting to later personality disorders. Because dimensionally measured personality disorders are associated with variations in normal personality traits, it is important to understand the contribution of parenting experienced in childhood to later normal personality traits. In this report, 742 community-based individuals, subjects from the Hopkins Epidemiology of Personality Disorders Study, were assessed for normal personality traits, as measured by the Revised NEO Personality Inventory (NEO-PI-R) and the Temperament and Character Inventory (TCI), and for parental behavior experienced as children, as measured by the Parental Bonding Instrument (PBI). The PBI dimensions were significantly, but moderately, correlate with measures of normal personality, the strongest associations being with the NEO-PI-R factors, neuroticism and conscientiousness, and with the TCI factors, self-directedness and harm avoidance. Subjects who reported lower parental care and higher parental intrusiveness were more likely to be higher in neuroticism, lower in conscientiousness, lower in self-directedness, and higher in harm avoidance. Also, trends emerged suggesting both parent-specific and gender-specific differences in the relationship between the PBI dimensions and normal adult personality traits. As variations in normal personality traits are associated with dimensionally measured personality disorders, it is conceivable that the role of parenting in later personality disorder may be mediated by associations between parenting and normal personality traits.

H-coil repetitive transcranial magnetic stimulation for the treatment of bipolar depression: an add-on, safety and feasibility study

Abstract Objectives. The H1-Coil is a novel transcranial magnetic stimulation (TMS) device capable of inducing a magnetic field with a deeper and wider distribution than standard coils. This pilot study evaluated the safety and feasibility of the H1-Coil as adjuvant treatment for bipolar depression (BPD). Methods. Nineteen patients diagnosed as having BPD and under treatment with psychotropic medication were enrolled in the study. They received daily prefrontal repetitive TMS (rTMS: 20 Hz, 2 s on, 20 s off, totaling 1680 stimuli) every weekday for four consecutive weeks. The primary outcome measure was the change from baseline in the Hamilton Depression Rating Scale (HDRS-24) score a week after the last treatment session. Results. A significant mean decrease of 12.9 points in the HDRS-24 scale (P< 0.001) was found. Response rate was 63.2% and remission rate was 52.6%. Treatment was well tolerated in terms of headache and overall discomfort, and there were no significant change in cognitive functioning or mood switches. One patient had a short induced generalized seizure without complications. Conclusions. An add-on H-coil rTMS treatment protocol in BPD subjects indicated improvement in bipolar depression symptoms. Sham-control studies to further determine the efficacy and safety of the H-Coil for BPD are warranted.

Adult antisocial personality traits are associated with experiences of low parental care and maternal overprotection

Objective: To investigate the role of parenting in the development of adult antisocial personality traits.

Sustained Increase in Narp Protein Expression Following Repeated Electroconvulsive Seizure

The delayed response to many psychiatric treatment regimens has focused attention on identifying enduring changes in gene expression following repeated stimulation that may contribute to these responses. Recent studies have identified Narp protein as a neuronal immediate early gene product that remains elevated in the hippocampus nearly 24 hours after a single episode of electroconvulsive seizure (ECS). To examine how Narp expression responds to repeated stimulation, we have examined the effect of repeated ECS on Narp expression in the hippocampus. We report that Narp protein levels remain elevated, about six-fold higher than basal levels, at 48 hours after the last of a series of five or six ECS given every other day. As Narp protein appears to play a key role in regulating AMPA receptor clustering at synaptic sites, sustained increases in Narp may contribute to changes in excitatory synaptic transmission induced by chronic neuronal stimulation.

Monoamine oxidase A regulates antisocial personality in whites with no history of physical abuse

OBJECTIVE Preclinical and human family studies clearly link monoamine oxidase A (MAOA) to aggression and antisocial personality (ASP). The 30-base pair variable number tandem repeat in the MAOA promoter regulates MAOA levels, but its effects on ASP in humans are unclear. METHODS We evaluated the association of the variable number tandem repeat of the MAOA promoter with Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, ASP disorder (ASPD) traits in a community sample of 435 participants from the Hopkins Epidemiology of Personality Disorders Study. RESULTS We did not find an association between the activity of the MAOA allele and ASPD traits; however, among whites, when subjects with a history of childhood physical abuse were excluded, the remaining subjects with low-activity alleles had ASPD trait counts that were 41% greater than those with high-activity alleles (P < .05). CONCLUSION The high-activity MAOA allele is protective against ASP among whites with no history of physical abuse, lending support to a link between MAOA expression and antisocial behavior.

ECT for self-injury in an autistic boy

ObjectiveSelf-injurious behavior presents a significant challenge in autism, and first-line psychopharmacological and behavioral interventions have limited efficacy in some patients. These intractable cases may be responsive to electroconvulsive therapy.Clinical pictureThis article presents an eight-year-old boy with autism, mental retardation, prominent mood lability and a five-year history of extreme self-injurious behavior towards his head, averaging 109 self-injurious attempts hourly. The patient was at high risk for serious head trauma, and required usage of bilateral arm restraints and protective equipment (i.e., padding on shoulders, arms, and legs). All areas of daily functioning were profoundly impacted by dangerous self-injury.TreatmentFifteen bilateral ECT treatments resulted in excellent mood stabilization and reduction of self-injury to 19 attempts hourly, and maintenance ECT was pursued. The patient was able to return to developmentally-appropriate educational and social activities.ConclusionECT should be considered in the treatment algorithm of refractory cases of severe self-injury in autism.

Prominent Narp expression in projection pathways and terminal fields.

Narp (neuronal activity regulated pentraxin) is a secreted immediate early gene product that is induced by synaptic activity. Recent studies have indicated that Narp may be an extracellular aggregating factor for AMPA receptors. Immunohistochemical studies have revealed prominent expression of Narp in the mossy fiber pathway of the dentate gyrus, suggesting it may be released pre‐synaptically. However, invitro studies using recombinant Narp indicate that Narp may act when expressed by either pre‐ or post‐synaptic elements. To help define Narps mode of action, we have examined its localization in the habenula‐interpeduncular pathway which also displays robust Narp expression. Focusing on this pathway as well as hippocampal and cortical Narp expression, we found prominent Narp staining in projection pathways and terminal fields. In contrast, Narp expression in dendrites was minimal in these neuronal populations. These findings indicate that, under physiological conditions, Narp is targeted to the synapse from pre‐ rather than post‐synaptic elements. Our results also suggest that future studies focusing on these projection pathways that express high levels of Narp, in vivo, may help to understand the regulation and function of endogenous Narp.

rTMS for adolescents: Safety and efficacy considerations

In light of both the FDAs clearance of repetitive transcranial magnetic stimulation (rTMS) for adult major depressive disorder and concerns about safety and efficacy of existing antidepressant therapies for adolescent depression, there is increasing interest in rTMS as a novel treatment for adolescent depression. We reviewed English-language studies using rTMS in persons under the age of 18, yielding 6 published reports. Because rTMS is typically delivered at or above 1 Hz for psychiatric indications, our search was confined to these frequencies. Also included are studies involving rTMS above 1 Hz for non-psychiatric indications. Articles were retrieved from the MEDLINE database. There were 19 reported subjects under age 18 who have been administered rTMS at a frequency above 1 Hz: 10 for major depression, 5 for spastic cerebral palsy and 4 for epilepsia partialis continua. We found that most subjects responded favorably to rTMS and no adverse events have been reported. However data are insufficient for drawing firm conclusions about safety and efficacy. Further studies of rTMS as a treatment for adolescent depression are warranted.