Pursuing personalized medicine for depression by targeting the lateral or medial prefrontal cortex with Deep TMS.

BACKGROUNDMajor depressive disorder (MDD) can benefit from novel interventions and personalization. Deep transcranial magnetic stimulation (Deep TMS) targeting the lateral prefrontal cortex (LPFC) using the H1 coil was FDA cleared for treatment of MDD. However, recent preliminary data indicate that targeting the medial prefrontal cortex (MPFC) using the H7 coil might induce outcomes that are as good or even better. Here, we explored whether Deep TMS targeting the MPFC is noninferior to targeting the LPFC and whether electrophysiological or clinical markers for patient selection can be identified.METHODSThe present prospective, multicenter, randomized study enrolled 169 patients with MDD for whom antidepressants failed in the current episode. Patients were randomized to receive 24 Deep TMS sessions over 6 weeks, using either the H1 coil or the H7 coil. The primary efficacy endpoint was the change from baseline to week 6 in Hamilton Depression Rating Scale scores.RESULTSClinical efficacy and safety profiles were similar and not significantly different between groups, with response rates of 60.9% for the H1 coil and 64.2% for the H7 coil. Moreover, brain activity measured by EEG during the first treatment session correlated with clinical outcomes in a coil-specific manner, and a cluster of baseline clinical symptoms was found to potentially distinguish between patients who can benefit from each Deep TMS target.CONCLUSIONThis study provides a treatment option for MDD, using the H7 coil, and initial guidance to differentiate between patients likely to respond to LPFC versus MPFC stimulation targets, which require further validation studies.TRIAL REGISTRATIONClinicalTrials.gov NCT03012724.FUNDINGBrainsWay Ltd.

Repetitive transcranial magnetic stimulation for smoking cessation: a pivotal multicenter double-blind randomized controlled trial.

Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive brain stimulation method increasingly used to treat psychiatric disorders, primarily depression. Initial studies suggest that rTMS may help to treat addictions, but evaluation in multicenter randomized controlled trials (RCTs) is needed. We conducted a multicenter double-blind RCT in 262 chronic smokers meeting DSM-5 criteria for tobacco use disorder, who had made at least one prior failed attempt to quit, with 68% having made at least three failed attempts. They received three weeks of daily bilat-eral active or sham rTMS to the lateral prefrontal and insular cortices, followed by once weekly rTMS for three weeks. Each rTMS session was administered following a cue-induced craving procedure, and participants were monitored for a total of six weeks. Those in abstinence were monitored for additional 12 weeks. The primary outcome measure was the four-week continuous quit rate (CQR) until Week 18 in the intent-to-treat efficacy set, as determined by daily smoking diaries and verified by urine cotinine measures. The trial was registered at ClinicalTrials.gov (NCT02126124). In the intent-to-treat analysis set (N=234), the CQR until Week 18 was 19.4% following active and 8.7% following sham rTMS (X2 =5.655, p=0.017). Among completers (N=169), the CQR until Week 18 was 28.0% and 11.7%, respectively (X2 =7.219, p=0.007). The reduction in cigarette consumption and craving was significantly greater in the active than the sham group as early as two weeks into treatment. This study establishes a safe treatment protocol that promotes smoking cessation by stimulating relevant brain circuits. It represents the first large multicenter RCT of brain stimulation in addiction medicine, and has led to the first clearance by the US Food and Drug Administration for rTMS as an aid in smok-ing cessation for adults.

Quetiapine augmentation in obsessive-compulsive disorder resistant to serotonin reuptake inhibitors: an open-label study.

BACKGROUND: The response of obsessive-compulsive disorder (OCD) to serotonin reuptake inhibitors (SRIs) is often inadequate. Case series reporting successful augmentation with risperidone and olanzapine led us to investigate quetiapine in OCD that was resistant to SRI treatment. METHOD: In this 8-week, 2-site (S1, S2), open-label trial, 30 adults (16 at S1 and 14 at S2) with a DSM-IV diagnosis of OCD, SRI-resistant, received augmentation with quetiapine, with the dose doubled every 2 weeks from 25 mg to 200 mg/day. Primary outcome was measured with the Yale-Brown Obsessive Compulsive Scale (YBOCS). A response was defined as a > or = 25% decrease from the baseline YBOCS score. RESULTS: Significant differences between the sites in patient characteristics (7/14 at S2 were hoarders, i.e., more treatment resistant, vs. 1/16 at S1; p = .01) and in quetiapine treatment (mean +/- SD dose of 116 +/- 72 mg/day at S2 vs. 169 +/- 57 mg/day at S1; p = .039) necessitated separate analysis of results. At S1, the mean +/- SD YBOCS score fell significantly from 27.7 +/- 7.0 to 23.3 +/- 8.4 (t = 2.96, df = 15, p = .01), and the responder rate was 31% (5/16). At S2, the mean YBOCS score did not decrease significantly, and the responder rate was 14% (2/14). Most adverse medication events were mild or moderate. Two subjects (13%) at S1 and 3 (21%) at S2 withdrew due to adverse events. CONCLUSION: The results at S1 resemble those reported with other atypical antipsychotics and suggest that quetiapine augmentation may benefit treatment-resistant OCD. The poorer results at S2 may reflect the large proportion of hoarders or the less intense treatment. Longer, higher dose, large, double-blind, placebo-controlled comparison trials of atypical antipsychotics are needed.

St John's wort versus placebo in obsessive-compulsive disorder: results from a double-blind study.

Although St John's wort (Hypericum perforatum) is one of the most widely used and studied herbal medicines for depression, less is known about its efficacy in anxiety disorders, in spite of the fact that patients with anxiety disorders are among the most likely to self-medicate using alternative treatments. Pharmacokinetic evidence for the serotonergic, domaminergic and GABAminergic activity of hypericum, and a recent successful open-label study, suggests that it may be effective for obsessive-compulsive disorder (OCD). Sixty subjects were randomized to 12 weeks of treatment with St John's wort (LI 160) or matching placebo. Subjects with Hamilton Depression Scale scores of 16 or above were excluded. A flexible-dose schedule was utilized (600-1800 mg/day). The mean change on the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) with St John's wort (3.43) was not significantly different than the mean change found with placebo (3.60) (P=899). No significant differences were found on any of the Y-BOCS subscales. The percentage of patients rated as 'much' or 'very much' improved at endpoint was not significantly different between St John's wort (17.9%) and placebo (16.7%) (P=0.905). Only one patient from each group discontinued due to adverse events [sinus infection (St John's wort); confusion (placebo)]. The results fail to support the efficacy of St John's wort for OCD.

Augmentation of serotonin reuptake inhibitors in refractory obsessive-compulsive disorder using adjunctive olanzapine: a placebo-controlled trial.

BACKGROUND: The purpose of this study was to explore the efficacy of adding an atypical antipsychotic, olanzapine, to a serotonin reuptake inhibitor (SRI) in treatment-refractory obsessive-compulsive disorder (OCD). METHOD: Twenty-six patients aged between 18 and 65 (mean = 41.2, SD = 11.9) years meeting DSM-IV criteria for OCD, who had not responded to SRIs, were treated for 6 weeks in a double-blind, placebo-controlled augmentation study with either olanzapine (up to 20 mg/day) or placebo. Severity of illness was assessed biweekly by the Yale-Brown Obsessive Compulsive Scale (Y-BOCS). Analysis of covariance with baseline Y-BOCS score included as a covariate was used to compare improvement in Y-BOCS scores in the 2 groups. Response was defined as a 25% or greater improvement in Y-BOCS score. Data were collected between April 2001 and May 2003. RESULTS: Outcome was assessed for all patients using the last observation carried forward. Subjects in the olanzapine group had a mean decrease of 4.2 (SD = 7.9) in Y-BOCS score compared with a mean increase in score of 0.54 (SD = 1.31) for subjects in the placebo group (F = 4.85, df = 2,23; p =.04). Six (46%) of 13 subjects in the olanzapine group showed a 25% or greater improvement in Y-BOCS score compared with none in the placebo group. The final mean dose of olanzapine was 11.2 (SD = 6.5) mg/day. Medication was well tolerated. Only 2 (15%) of 13 subjects who received olanzapine discontinued because of side effects: sedation (N = 1) or weight gain (N = 1). CONCLUSION: These results provide preliminary evidence that adding olanzapine to SRIs is potentially efficacious and well tolerated in the short-term treatment of patients with refractory OCD. Controlled studies with larger sample sizes are necessary to more definitively address this treatment strategy.

Obsessive-compulsive hoarding: symptom severity and response to multimodal treatment.

BACKGROUND: Compulsive hoarding and saving symptoms, found in many patients with obsessive-compulsive disorder (OCD), are part of a clinical syndrome that has been associated with poor response to medications and cognitive-behavioral therapy (CBT). We sought to determine whether patients with the compulsive hoarding syndrome had more severe symptoms and functional impairment than nonhoarding OCD patients and whether they would respond to intensive, multimodal treatment previously found to be effective for treatment-refractory OCD. METHOD: We studied 190 consecutive patients with DSM-IV OCD treated openly for approximately 6 weeks with intensive CBT, medication, and psychosocial rehabilitation in a partial hospitalization program for severely ill OCD patients. Twenty of the 190 patients (11%) were identified as having the compulsive hoarding syndrome. All patients were assessed before and after treatment with the Yale-Brown Obsessive Compulsive Scale (YBOCS), Hamilton Rating Scale for Depression (HAM-D). Hamilton Rating Scale for Anxiety (HAM-A). and Global Assessment Scale (GAS). We compared the symptom severity and response to treatment of compulsive hoarders versus nonhoarding OCD patients. RESULTS: Compulsive hoarders were significantly older than nonhoarders (p < .001). Hoarders had significantly lower GAS scores and higher HAM-A scores than nonhoarders both before (p = .04) and after (p = .002) treatment, but had similar pretreatment YBOCS scores. Both groups improved significantly with treatment as assessed by YBOCS score (p < .001), but nonhoarders had significantly greater decreases in YBOCS scores than hoarders (p = .02). CONCLUSION: While the compulsive hoarding syndrome appears to be a distinct, more disabling, variant of OCD that does not respond as robustly to treatment, it may still improve significantly with intensive, multimodal treatment tailored to its specific features and associated deficits.

Quality of life and functional impairment in compulsive hoarding.

Compulsive hoarding patients have been found in previous studies to have substantial disability and functional impairment. However, no prior study has examined subjective and objective quality of life (QOL) in patients with compulsive hoarding. This present study compared compulsive hoarders and non-hoarding OCD patients across a variety of QOL domains. Subjects were 171 consecutive adult patients (34 compulsive hoarders, 137 non-hoarding patients with DSM-IV OCD) treated openly between 1998 and 2004 in the UCLA OCD Partial Hospitalization Program (OCD PHP), a specialized, intensive, multi-modal treatment program for treatment-refractory patients. Scores on the Quality of Life Scale and other symptom severity measures on admission were compared between compulsive hoarders and non-hoarding OCD patients. Compulsive hoarders were older and had lower global functioning than non-hoarding OCD patients. Both groups had low overall QOL scores across multiple domains. Compulsive hoarders had significantly lower levels of satisfaction with their safety than non-hoarding OCD patients, were more often the victims of both violent and non-violent crime, felt less safe in their neighborhoods, and felt less protected against attack. Compulsive hoarders were also much less satisfied with their living arrangements than non-hoarding OCD patients. No differences were found on financial variables, but the vast majority of patients in both groups were unemployed. Compulsive hoarders have lower QOL than non-hoarding OCD patients in the domains of safety and living situation. Psychosocial rehabilitation that focuses on problems with victimization, safety, employment, and financial areas may be a beneficial augmentation to treatment for compulsive hoarding.

A pilot controlled trial of bupropion XL versus escitalopram in generalized anxiety disorder.

OBJECTIVE: To compare the efficacy and safety of bupropion XL (150 to 300 mg/day) with the selective serotonin reuptake inhibitor escitalopram (10 to 20 mg/day) in outpatients diagnosed with generalized anxiety disorder (GAD). METHODS: Twenty-four participants with GAD between 18 and 64 years enrolled in a 12-week, double-blind, randomized trial. The primary efficacy measures were the Clinical Global Impression of Improvement (CGI-I) and the Hamilton Anxiety Rating Scale (HARS). RESULTS: Bupropion XL demonstrated comparable anxiolytic efficacy to escitalopram in outpatients with GAD. Both treatments were well-tolerated. CONCLUSION: Findings from this pilot project suggest that bupropion XL may be useful in treating GAD. These preliminary results warrant further research to explore the use of bupropion XL in the treatment of GAD.