Lack of Efficacy of JNJ-18038683 on Cognitive Impairment in Patients With Stable Bipolar Disorder.

BACKGROUND: The serotonin type 7 (5-HT7) receptor is one of 14 5-HT receptors. It has received attention for its possible role in mood disorders and cognition. The 5-HT7 receptor antagonist, JNJ-18038683, has been reported to be effective in rodent models of depression and REM sleep. Also, 5-HT7 receptor blockade has been postulated to be a key component of cognitive enhancement in a number of drugs. Bipolar disorder (BD) usually endures cognitive impairment (CI); however, no treatment for CI in BD has been approved. This study aimed to evaluate the efficacy of JNJ-18038683 to improve the CI of BD compared to a placebo. METHODS: We conducted a placebo-controlled, 8-week trial of JNJ-18038683 in BD patients. Each patient's data were analyzed and reassessed blindly with a comprehensive neuropsychological battery, depression and hypomania ratings, and overall social and work function measures. RESULTS: Of 60 patients, 38 (63%) were female, 43 (72%) had BD type 1, and most patients were Caucasian and married. The overall time effect for the combined group shows statistically significant improvement from baseline to week 8 for most of the neurocognitive battery measures. This indicates a significant improvement in psychopathology and cognition during the study time in both JNJ-18038683 and placebo groups, but no difference between groups. CONCLUSIONS: This study showed no efficacy for the improvement of CIBD or mood symptoms with JNJ-18038683 compared to the placebo.

Cranial electrotherapy stimulation for the treatment of chronically symptomatic bipolar patients.

OBJECTIVE: The aim of this study was to determine if cranial electrotherapy stimulation (CES) is beneficial in chronically symptomatic bipolar (CSBP) subjects. METHODS: A retrospective chart review of all consecutive CSBP subjects who were prescribed CES collected demographic and clinical information. RESULTS: The Clinical Global Impression improved significantly [mean (SD), 2.7 (0.6) at baseline vs 2.0 (0.0), t = 0, P < 0.001], but mood symptoms change minimally. There were very few adverse effects of CES. CONCLUSIONS: Patients with CSBP continue to experience symptoms with CES but also are modestly improved.

Effect of pharmacogenomic testing on pediatric mental health outcome: a 6-month follow-up.

Aim: This retrospective, case-control study evaluated the effect of pharmacogenomic testing (PGT) on the management of pediatrics with anxiety, major depressive disorder (MDD) and attention-deficit/hyperactivity disorder (ADHD). Methods: The authors examined psychiatric diagnoses, medication histories, CYP450 profiles, SLC6A4, HTR2A, COMT and MTHFR. Results: The authors found no difference in clinical improvement between the two groups. However, the number of medication changes was significantly larger after PGT. The treatment response in MDD and anxiety was not different between the groups, while ADHD treatment response was substantially improved in PGT and correlated with COMT status. Conclusion: PGT had some value with ADHD with doubtful benefit for MDD or anxiety disorders. Accordingly, pediatric indications must be weighed against cost, utility and clinician experience. Limitations included sample size and selection bias.

Left prefrontal transcranial magnetic stimulation for treatment-resistant depression in adolescents: a double-blind, randomized, sham-controlled trial.

Treatment-resistant depression (TRD) is prevalent and associated with a substantial psychosocial burden and mortality. There are few prior studies of interventions for TRD in adolescents. This was the largest study to date examining the feasibility, safety, and efficacy of 10-Hz transcranial magnetic stimulation (TMS) for adolescents with TRD. Adolescents with TRD (aged 12-21 years) were enrolled in a randomized, sham-controlled trial of TMS across 13 sites. Treatment resistance was defined as an antidepressant treatment record level of 1 to 4 in a current episode of depression. Intention-to-treat patients (n = 103) included those randomly assigned to active NeuroStar TMS monotherapy (n = 48) or sham TMS (n = 55) for 30 daily treatments over 6 weeks. The primary outcome measure was change in the Hamilton Depression Rating Scale (HAM-D-24) score. After 6 weeks of blinded treatment, improvement in the least-squares mean (SE) HAM-D-24 scores were similar between the active (-11.1 [2.03]) and sham groups (-10.6 [2.00]; P = 0.8; difference [95% CI], - 0.5 [-4.2 to 3.3]). Response rates were 41.7% in the active group and 36.4% in the sham group (P = 0.6). Remission rates were 29.2% in the active group and 29.0% in the sham group (P = 0.95). There were no new tolerability or safety signals in adolescents. Although TMS treatment produced a clinically meaningful change in depressive symptom severity, this did not differ from sham treatment. Future studies should focus on strategies to reduce the placebo response and examine the optimal dosing of TMS for adolescents with TRD.

Treatment-Resistant Depression in Adolescents: Clinical Features and Measurement of Treatment Resistance.

Objective: To describe the clinical characteristics of adolescents with antidepressant treatment-resistant major depressive disorder (MDD) and to examine the utility of the Antidepressant Treatment Record (ATR) in categorizing treatment resistance in this population. Methods: Adolescents with treatment-resistant MDD enrolled in an interventional study underwent a baseline evaluation with the ATR, Children's Depression Rating Scale-Revised (CDRS-R), and Clinical Global Impressions-Severity (CGI-S) scales. Demographic and clinical characteristics were examined with regard to ATR-defined level of resistance (level 1 to ≥3) using analysis of variance and χ2 tests. Results: In adolescents with treatment-resistant MDD (N = 97), aged 12-21 years, most were female (65%), white (89%), and had recurrent illness (78%). Patients were severely ill (median CGI-S score of 5), had a mean CDRS-R score of 63 ± 10, and 17.5% had been hospitalized for depression-related symptoms. Fifty-two patients were classified as ATR 1, whereas 32 were classified as ATR level 2 and 13 patients as ≥3, respectively. For increasing ATR-defined levels, illness duration increased from 12.0 (range: 1.5-31.9) to 14.8 (range: 1.8-31.7) to 19.5 (range: 2.5-36.2) months and the likelihood of treatment with serotonin norepinephrine reuptake inhibitors (SNRIs) and dopamine norepinephrine reuptake inhibitors (DNRIs) similarly increased (p = 0.006 for both SNRIs and DNRIs) as did the likelihood of treatment with mixed dopamine serotonin receptor antagonists (χ2 = 17, p < 0.001). Conclusions: This study underscores the morbidity and chronicity of treatment-resistant MDD in adolescents. The present characterization of related clinical features describes the use of nonselective serotonin reuptake inhibitors in adolescents with treatment-resistant depression and raises the possibility that those with the greatest medication treatment resistance are less likely to have had recurrent episodes. The study also demonstrates the utility of the ATR in categorizing treatment resistance in adolescents with MDD.

Risk for emerging bipolar disorder, variants, and symptoms in children with attention deficit hyperactivity disorder, now grown up.

AIM: To determine the prevalence of bipolar disorder (BD) and sub-threshold symptoms in children with attention deficit hyperactivity disorder (ADHD) through 14 years' follow-up, when participants were between 21-24 years old. METHODS: First, we examined rates of BD type I and II diagnoses in youth participating in the NIMH-funded Multimodal Treatment Study of ADHD (MTA). We used the diagnostic interview schedule for children (DISC), administered to both parents (DISC-P) and youth (DISCY). We compared the MTA study subjects with ADHD (n = 579) to a local normative comparison group (LNCG, n = 289) at 4 different assessment points: 6, 8, 12, and 14 years of follow-ups. To evaluate the bipolar variants, we compared total symptom counts (TSC) of DSM manic and hypomanic symptoms that were generated by DISC in ADHD and LNCG subjects. Then we sub-divided the TSC into pathognomonic manic (PM) and non-specific manic (NSM) symptoms. We compared the PM and NSM in ADHD and LNCG at each assessment point and over time. We also evaluated the irritability as category A2 manic symptom in both groups and over time. Finally, we studied the irritability symptom in correlation with PM and NSM in ADHD and LNCG subjects. RESULTS: DISC-generated BD diagnosis did not differ significantly in rates between ADHD (1.89%) and LNCG 1.38%). Interestingly, no participant met BD diagnosis more than once in the 4 assessment points in 14 years. However, on the symptom level, ADHD subjects reported significantly higher mean TSC scores: ADHD 3.0; LNCG 1.7; P < 0.001. ADHD status was associated with higher mean NSM: ADHD 2.0 vs LNCG 1.1; P < 0.0001. Also, ADHD subjects had higher PM symptoms than LNCG, with PM means over all time points of 1.3 ADHD; 0.9 LNCG; P = 0.0001. Examining both NSM and PM, ADHD status associated with greater NSM than PM. However, Over 14 years, the NSM symptoms declined and changed to PM over time (df 3, 2523; F = 20.1; P < 0.0001). Finally, Irritability (BD DSM criterion-A2) rates were significantly higher in ADHD than LNCG (χ(2) = 122.2, P < 0.0001), but irritability was associated more strongly with NSM than PM (df 3, 2538; F = 43.2; P < 0.0001). CONCLUSION: Individuals with ADHD do not appear to be at significantly greater risk for developing BD, but do show higher rates of BD symptoms, especially NSM. The greater linkage of irritability to NSM than to PM suggests caution when making BD diagnoses based on irritability alone as one of 2 (A-level) symptoms for BD diagnosis, particularly in view of its frequent presentation with other psychopathologies.

Current and emerging therapies for the management of bipolar disorders.

Bipolar disorder is a complex condition to treat because agents that may be effective for a specific phase may not be effective for other phases, or may even worsen the overall course of the illness. Over the last decade there has been an increase in research activity in the treatment of bipolar illness. There are now several agents that are well established for the treatment of acute mania (lithium, divalproex, carbamazepine, nearly all antipsychotics), acute bipolar depression (lamotrigine, quetiapine, olanzapine/fluoxetine combination), and relapse prevention (lithium, lamotrigine, divalproex, most second generation antipsychotics). There are also novel treatments that are being studied for all three phases. These include eslicarbazepine, cariprazine, MEM-1003, memantine, tamoxifen and pentazocine for acute mania; pramipexole, modafinil, armodafinil, divalproex, lurasidone, agomelatine, cariprazine, lisedexamfetamine, riluzole, RG-2417, bifeprunox, ropinirole, GSK1014802, and magnetic stimulation for bipolar depression; and asenapine, lurasidone, and cariprazine for relapse prevention. Additionally, there are accumulating data that antidepressants, particularly serotoninergic ones, are not particularly effective in acute bipolar depression and may worsen the course of the illness.

Bipolar disorder: an update.

There has been a recent increase in the number of clinical trials and treatment options for bipolar disorder. This research has resulted in new treatment options. Most second-generation antipsychotics have demonstrated efficacy in the treatment of mania, both in monotherapy and as adjuncts to mood stabilizers. For bipolar depression, nearly all randomized, placebo-controlled studies have demonstrated that antidepressants do not provide any additional benefit to ongoing mood stabilizers. Additionally, antidepressants carry a risk of destabilization of bipolar disorder with an increase in mania, cycling, and chronic irritable dysphoria. Newer non-antidepressant treatments for depression include quetiapine, lamotrigine, modafinil, and pramipexole. These agents are effective for acute treatment and appear to be effective in maintenance. The least-studied phase of bipolar disorder is the maintenance phase. The use of multiple agents appears to be superior to monotherapy in relapse prevention. Despite the many advances in the pharmacotherapy of bipolar disorder, the overall prognosis of this severe illness does not appear to have changed.