Burden of EPS in commercial patients with schizophrenia initiating atypical antipsychotics.

OBJECTIVES: Extrapyramidal symptoms (EPS) affect 15% to 30% of patients with schizophrenia treated with antipsychotics and have been associated with poor outcomes. This study examined the incidence and economic burden of EPS in patients with schizophrenia initiating atypical antipsychotics (AAPs). STUDY DESIGN: Retrospective analysis of secondary deidentified administrative claims database. METHODS: Patients with schizophrenia initiating AAPs with no prior EPS were identified in the MarketScan Commercial and Medicare Supplemental databases from January 1, 2012, to December 31, 2018. Incidence of EPS (diagnosis or medication use) was assessed in the year following AAP initiation. Annual all-cause and schizophrenia-related health care resource utilization (HCRU) and costs were assessed in cohorts who did or did not develop EPS in the year following first EPS claim (EPS cohort) or randomly assigned index date (non-EPS cohort). Multivariate regression was used to compare all-cause and schizophrenia-related total health care costs and inpatient admissions between cohorts. RESULTS: A total of 3558 patients with schizophrenia newly initiating AAPs were identified; 22.1% developed EPS in the year following AAP initiation (incidence: 26.9 cases per 100 person-years). Multivariate analyses revealed that patients with EPS had 34% higher odds of all-cause (odds ratio [OR], 1.3361; 95% CI, 1.0770-1.6575; P < .01) and 84% increased odds of schizophrenia-related (OR, 1.8436; 95% CI, 1.0434-2.4219; P < .0001) inpatient admission compared with the non-EPS cohort. The EPS cohort also evidenced significantly higher adjusted all-cause ($26,632 vs $21,273; P < .001) and schizophrenia-related ($9018 vs $4475; P < .0001) costs compared with the non-EPS cohort. CONCLUSIONS: The 20% of patients who developed EPS in the year following AAP initiation evidenced significantly increased HCRU and costs over the postindex period. Schizophrenia therapies with reduced EPS risk are needed to improve patient care.

The incidence and economic burden of extrapyramidal symptoms in patients with schizophrenia treated with second generation antipsychotics in a Medicaid population.

BACKGROUND: Extrapyramidal symptoms (EPS) are common side-effects of second-generation antipsychotics (SGA), that can negatively impact patient quality-of-life, and are associated with increased morbidity and mortality. This study examined the incidence and burden of EPS in patients with schizophrenia initiating SGAs. METHODS: Patients with schizophrenia initiating SGAs were identified in the MarketScan Multi-state Medicaid database from 1 January 2012 to 31 December 2018. Incidence of EPS (identified via ICD-9/ICD-10 diagnoses and medications) was assessed during the 12-months following SGA initiation. Cohorts with and without EPS were defined. Multivariate models were used to examine all-cause and schizophrenia-related hospitalizations and total costs in the 12 months following the first EPS claim (EPS) or randomly assigned index date (Non-EPS) while controlling for multiple baseline covariates. Logistic regression was used for hospitalization and two-part models were used for skewed cost data. RESULTS: A total of 11,642 patients with schizophrenia filled a prescription for an SGA; of which, 2,468 (21.2%) experienced EPS in the first year. The age- and gender-matched EPS group and non-EPS group included 2,295 and 5,607 patients, respectively. Multivariate analyses confirmed that EPS patients had 25% higher odds of all-cause (OR = 1.25; 95% CI = 1.11-1.40) and 75% increased odds of schizophrenia-related (OR = 1.75; 95% CI = 1.53-2.00) inpatient admissions compared to non-EPS patients. Multivariate adjustment of post-period costs between groups also found significant differences in both all-cause (EPS: $27,408 vs. non-EPS: $22,489, p < 0.001) and schizophrenia-related (EPS:$12,833 vs. non-EPS:$8,077, p < 0.0001) costs between the EPS and non-EPS cohorts. CONCLUSIONS: Over one-fifth of patients initiating treatment with atypical antipsychotics in this study developed EPS in the 12 months following SGA initiation. Extrapyramidal side-effects associated with atypical antipsychotics increase the risk of hospitalization and contribute to higher healthcare costs. For patients with schizophrenia, treatment options that minimize the risk of EPS may reduce the economic burden associated with the disease.

Efficacy and Safety of Dasotraline in Children With ADHD: A Laboratory Classroom Study.

Objective: To evaluate the efficacy and safety of dasotraline for treatment of ADHD in children. Method: Children (ages 6-12 years; N = 112) with ADHD were randomized, double-blind, to 14 days of once-daily evening doses of dasotraline 4 mg or placebo. ADHD symptom severity was measured at baseline and Day 15 in seven, 30-min classroom sessions using the Swanson, Kotkin, Agler, M-Flynn, and Pelham (SKAMP) and the Permanent Product Measure of Performance (PERMP) math test. Results: Significant improvement was observed for dasotraline versus placebo in the SKAMP-combined score (-3.2 vs. +2.0; p < .001; effect size = 0.85) and SKAMP and PERMP subscale scores. The three most common adverse events for dasotraline (vs. placebo) were insomnia (19.6% vs. 3.6%), headache (10.7% vs. 8.9%), and decreased appetite (10.7% vs. 3.6%). Conclusion: In this laboratory classroom study, dasotraline 4 mg was found to be an efficacious and generally well-tolerated treatment for ADHD in children aged 6 to 12 years.

The selective orexin-2 receptor antagonist seltorexant improves sleep: An exploratory double-blind, placebo controlled, crossover study in antidepressant-treated major depressive disorder patients with persistent insomnia.

BACKGROUND: Insomnia is common in patients with major depressive disorder. Although antidepressants improve mood, insomnia often persists as a result of physiological hyperarousal. The orexin-2 receptor is increasingly being recognized as a new target for the treatment of persistent insomnia in major depressive disorder . AIM: This exploratory study investigated the effects of seltorexant on objective sleep parameters and subjective depressive symptoms in antidepressant treated major depressive disorder patients with persistent insomnia. METHODS: Twenty male and female patients received a single dose of 10, 20, 40 mg seltorexant and placebo with a washout period of seven days in a double-blind four-way crossover study. Effects on latency to persistent sleep, total sleep time and sleep efficiency were assessed with polysomnography. Subjective changes in mood were explored by the Quick Inventory of Depressive Symptomatology Self-Report. Safety was recorded and suicidal ideation and behavior were assessed with the Columbia Suicide Severity Rating Scale. RESULTS: Latency to persistent sleep was significantly shorter for all doses of seltorexant compared to placebo. Placebo least square mean was 61.05 min with least square mean ratios treatment/placebo (80% confidence interval) of 0.32 (0.24-0.44), 0.15 (0.11-0.2) and 0.17 (0.12-0.23) 19.69, 9.2, 10.15 for 10, 20 and 40 mg seltorexant respectively, (all p<0.001). Total sleep time was significantly longer for all doses of seltorexant compared to placebo. Sleep efficiency was significantly improved. The Quick Inventory of Depressive Symptomatology Self-Report demonstrated a trend to mood-improvement for the 40 mg group. CONCLUSIONS: Seltorexant showed a statistically significant, dose-dependent decrease in latency to persistent sleep, and increase in total sleep time and sleep efficiency combined with a tendency toward subjectively improved mood.

A randomized Phase 2 study to evaluate the orexin-2 receptor antagonist seltorexant in individuals with insomnia without psychiatric comorbidity.

BACKGROUND: Seltorexant is a potent and selective antagonist of the orexin-2 receptor that is being developed for the treatment of insomnia and major depressive disorder. AIMS: The primary objective was to investigate the effect of seltorexant on sleep efficiency after single and multiple dose administration in subjects with insomnia disorder without psychiatric comorbidity. Secondary objectives included evaluation of total sleep time, latency to persistent sleep, and wake after sleep onset. Subjects received 40 mg of seltorexant for five days during Period 1 and placebo during Period 2 or vice versa in this randomized, two-way crossover study. Objective sleep parameters were evaluated by polysomnography over 8 h on Day 1/2 (single dose) and on Day 5/6 (multiple doses). Subjective sleep parameters were assessed by questionnaires. RESULTS: Twenty-seven subjects completed the study. The mean changes in sleep efficiency (% (SD)) of seltorexant from placebo at Day 1/2 were 5.8 (9.2), and 7.9 (9.8) at Day 5/6 ( p < 0.001 at both time points); in total sleep time (min (SD)) 27.7 (44.3) and 37.9 (47.1), respectively; in latency to persistent sleep (min (SD)) -18.8 (21.3) and -29.9 (27.7), respectively; and in wake after sleep onset (min (SD)) -11.1 (36.4) and -11.3 (46.5). The most common adverse events were headache and somnolence. CONCLUSIONS: Sleep efficiency was increased with seltorexant treatment compared with placebo. Treatment with seltorexant resulted in a prolonged total sleep time, shorter latency to persistent sleep and wake after sleep onset. There were no unexpected safety findings.

The effects of interleukin-6 neutralizing antibodies on symptoms of depressed mood and anhedonia in patients with rheumatoid arthritis and multicentric Castleman's disease.

Cytokines, including interleukin-6 (IL-6), modulate neuronal plasticity and stress coping. Depressive symptoms and major depressive disorder (MDD) have been associated with changes in cytokines and their signaling. The current study examined the effect of IL-6 monoclonal antibody administration on depressive symptoms in patients with rheumatoid arthritis (RA) or multicentric Castleman's disease (MCD). The data were obtained from two phase 2, double-blind, placebo-controlled trials designed to test the efficacy of sirukumab in RA (N=176) or of siltuximab in MCD (N=65), and were analyzed post hoc to investigate the effects of these IL-6 antibodies on depressive symptoms. The SF-36 questionnaire items on depressed-mood and anhedonia were combined as the measure for depressive symptoms. The study participants were grouped by the presence/absence of prevalent depressed mood and anhedonia (PDMA, meaning either depressed mood or anhedonia was present at least 'most of the time' and the other at least 'some of the time' for four weeks) at baseline; 26.1% of the RA sample and 15.4% of the MCD sample met criteria for PDMA at baseline. Compared with placebo, sirukumab and siltuximab produced significantly greater improvements on depressive symptoms. To account for an effect on mood due to changes in RA or MCD, the analysis was (1) adjusted for symptom severities using DAS28-CRP for RA and MCDOS for MCD alone or together with bodily pain and physical functioning, and (2) performed within RA and MCD non-responders. Improvement in depressive symptoms remained significant in the treated group for both drugs. The significance over placebo was also observed in the siltuximab study. The improvement in depressive symptoms by sirukumab correlated positively with the baseline soluble IL-6 receptor levels. The data together suggest that the IL-6 antibodies improve depressive symptoms in patients with RA and MCD. Further studies are needed to elucidate to what extents the IL-6 antibodies improve depressive symptoms through improving primary disease dependent and independent mechanisms, especially in RA patients, and the brain mechanisms underlying depressive symptom improvements.

Longitudinal Predictive Validity of the DSM-5 Anxious Distress Specifier for Clinical Outcomes in a Large Cohort of Patients With Major Depressive Disorder.

OBJECTIVE: While the new DSM-5 anxious distress specifier is of great clinical importance, no evidence exists for its longitudinal predictive validity for clinical outcomes in patients with major depressive disorder (MDD). We examined the longitudinal validity of this specifier and validated it against DSM-IV-based comorbid anxiety disorder diagnoses. METHODS: Data are from 1,080 patients with current MDD at baseline (September 2004 to February 2007), of which 911 participated in the 2-year follow-up (September 2006 to April 2009). Patients are from the Netherlands Study of Depression and Anxiety, which is an ongoing longitudinal cohort study, and were sampled from the community, primary care, and outpatient specialized care settings. The specifier was constructed in the existing sample by 5 matching self-report items. Predictive outcomes were 2-year chronicity, time to remission of MDD, and functional disability. Discriminant performance and convergent validity of the specifier were also assessed. RESULTS: The specifier was present in 54.2% of the sample. The specifier significantly outperformed anxiety disorders in predicting chronicity (OR = 1.96, P < .001, vs OR = 1.11, P = .49), time to remission of MDD (HR = 0.75, P = .002, vs HR = 0.94, P = .55), and functional disability (B = 10.03, P < .001, vs B = 2.53, P = .07). The specifier significantly discriminated in clinical characteristics, had convergent validity for anxiety characteristics, and poorly overlapped with DSM-IV-based anxiety disorder diagnoses (Cohen κ = .09). CONCLUSIONS: The short anxious distress specifier outperforms DSM-IV-based anxiety disorder diagnoses as a longitudinal predictor for clinical outcomes in patients with MDD.

Anxious distress predicts subsequent treatment outcome and side effects in depressed patients starting antidepressant treatment.

Evidence has shown that the DSM-5 anxious distress specifier captures a clinically valid construct that predicts a worse clinical course. Although of importance for treatment planning and monitoring, however, the specifier's ability to predict treatment outcome is unknown. This is the first study to examine the ability of the DSM-5 anxious distress specifier to predict treatment response and side effects in depressed patients who recently initiated antidepressant treatment. Patients were from the Netherlands Study of Depression and Anxiety, an ongoing longitudinal cohort study. Baseline, 1-year and 2-year follow-up data were used from 149 patients (18-65 years) with current Major Depressive Disorder (MDD) who recently started adequately dosed antidepressant medication. Five self-report items were used to construct the DSM-5 anxious distress specifier. Treatment outcomes were depression severity after 1 year and 2 years, remission of MDD after 2 years and antidepressant side effects during treatment. For comparison, analyses were repeated for comorbid DSM-IV-based anxiety disorders as a predictor. In depressed patients who received antidepressant treatment, the anxious distress specifier (prevalence = 59.1%) significantly predicted higher severity (1 year: B = 1.94, P = 0.001; 2 years: B = 1.63, P = 0.001), lower remission rates (OR = 0.44, P = 0.0496) and greater frequency of side effects (≥4 vs. 0: OR = 2.74, P = 0.061). In contrast, the presence of comorbid anxiety disorders did not predict these treatment outcomes. The anxious distress specifier significantly predicts poorer treatment outcomes as shown by higher depression severity, lower remission rates, and greater frequency of antidepressant side effects in patients with MDD on adequate antidepressant treatment. Therefore, this simple 5-item specifier is of potential great clinical usefulness for treatment planning and monitoring in depressed patients.

Clinical Relevance of Sleep Duration: Results from a Cross-Sectional Analysis Using NHANES.

STUDY OBJECTIVES: To assess the clinical relevance of sleep duration, hours slept were compared by health status, presence of insomnia, and presence of depression, and the association of sleep duration with BMI and cardiovascular risk was quantified. METHODS: Cross-sectional analysis of subjects in the US National Health and Nutrition Examination Surveys using adjusted linear and logistic regressions. RESULTS: A total of 22,281 adults were included, 37% slept ≤ 6 hours, 36% were obese, and 45% reported cardiovascular conditions. Mean sleep duration was 6.87 hours. Better health was associated with more hours of sleep. Subjects with poor health reported sleeping 46 min, (95% CI -56.85 to -35.67) less than subjects with excellent health. Individuals with depression (vs. not depressed) reported 40 min less sleep, (95% CI -47.14 to -32.85). Individuals with insomnia (vs. without insomnia) reported 39 min less sleep, (95% CI -56.24 to -22.45). Duration of sleep was inversely related to BMI; for every additional hour of sleep, there was a decrease of 0.18 kg/m(2) in BMI, (95% CI -0.30 to -0.06). The odds of reporting cardiovascular problems were 6.0% lower for every hour of sleep (odds ratio = 0.94, 95% CI [0.91 to 0.97]). Compared with subjects who slept ≤ 6 h, subjects who slept more had lower odds of reporting cardiovascular problems, with the exception of subjects ≥ 55 years old who slept ≥ 9 hours. CONCLUSIONS: Long sleep duration is associated with better health. The fewer the hours of sleep, the greater the BMI and reported cardiovascular disease. A difference of 30 minutes of sleep is associated with substantive impact on clinical well-being.

Efficacy and safety of an adjunctive mGlu2 receptor positive allosteric modulator to a SSRI/SNRI in anxious depression.

This phase 2a, randomized, multicenter, double-blind, proof-of-concept study was designed to evaluate, efficacy, safety and tolerability of JNJ-40411813/ADX71149, a novel metabotropic glutamate 2 receptor positive allosteric modulator as an adjunctive treatment for major depressive disorder (MDD) with significant anxiety symptoms. Eligible patients (18-64 years) had a DSM-IV diagnosis of MDD, Hamilton Depression Rating Scale-17 (HDRS17) score of ≥ 18, HDRS17 anxiety/somatization factor score of ≥ 7, and an insufficient response to current treatment with a selective serotonin reuptake inhibitor or serotonin-norepinephrine reuptake inhibitor. The doubly-randomized, 8-week double-blind treatment phase was comprised of two 4-week periods, from which a combined test statistic was generated, with pre-determined weights assigned to each of the 2 treatment periods. Period 1: patients (n=121) were randomly assigned (1:1) to JNJ-40411813 (n=62; 50mg to 150 mg b.i.d, flexibly dosed) or placebo (n=59); Period 2: placebo-treated patients (n=22) who continued to meet entry severity criteria were re-randomized (1:1) to JNJ-40411813 or placebo, while other patients underwent sham re-randomization and continued on their same treatment. Of 121 randomized patients, 100 patients (82.6%) were completers. No efficacy signal was detected on the primary endpoint, the 6-item Hamilton Anxiety Subscale (HAM-A6, p=0.51). Efficacy signals (based on prespecified 1-sided p<0.20) were evident on several secondary outcome measures of both depression (HDRS17 total score, 6-item subscale of HDRS17 assessing core depressive symptoms [HAM-D6], and Inventory of Depressive Symptomatology [IDS-C30]) and anxiety (HDRS17 anxiety/somatization factor, IDS-C30 anxiety subscale). Although well-tolerated, the results do not suggest efficacy for JNJ-40411813 as an adjunctive treatment for patients with MDD with significant anxious symptoms in the dose range studied.

An open-label extension study of the safety and efficacy of risperidone in children and adolescents with autistic disorder.

OBJECTIVE: The purpose of this study was to evaluate the long-term safety and efficacy of risperidone in treating irritability and related behaviors in children and adolescents with autistic disorders. METHODS: In this 6 month (26 week) open-label extension (OLE) study, patients (5-17 years of age, who completed the previous fixed-dose, 6 week, double-blind [DB] phase) were flexibly dosed with risperidone based on body weight. The maximum allowed dose was 1.25 mg/day for those weighing 20 to <45 kg, and 1.75 mg/day for those weighing ≥ 45 kg. The study primarily assessed risperidone's safety; efficacy was assessed as a secondary end-point. RESULTS: Fifty-six (71%) out of 79 enrolled patients completed the OLE; the most common discontinuations were for insufficient response (7 [9%]) or adverse events (AE) (5 [6%]). The most common (≥ 5% frequency in the total group) AEs were increased appetite (11% [n=9]); increased weight and vomiting (9% [n=7] each); sedation, pyrexia, and upper respiratory tract infection (8% [n=6] each); nasopharyngitis (6% [n=5]); and somnolence and fatigue (5% [n=4] each). Extrapyramidal AEs were reported in 6 (8%) patients. Increase in mean weight (11-15%) and body mass index (5-10%) occurred; one patient discontinued because of weight increase. One potentially prolactin-related AE (irregular menstruation) was reported. The risperidone high-dose group had the greatest mean improvement in sleep visual analog scale (24.6). All groups showed additional improvement in efficacy scale scores during the OLE. CONCLUSIONS: During this OLE, safety findings with risperidone treatment (maximum weight-based dose of 1.25 mg/day or 1.75 mg/day) were consistent with those observed in the DB phase, and with the current safety information for risperidone in autistic, psychiatric, and behavioral disorders. Patients experienced some additional improvement in irritability and related behaviors. CLINICAL TRIALS REGISTRY: This phase-4 study is registered at ClinicalTrials.gov (NCT00576732).

Metabolic and body mass parameters after treatment with JNJ-37822681, a novel fast-dissociating D2 receptor antagonist, vs olanzapine in patients with schizophrenia.

BACKGROUND: The highly selective and fast dissociating D2 receptor antagonist JNJ-37822681 may be associated with lower risk for weight gain and undesirable metabolic effects compared with available antipsychotics. METHODS: In this double-blind, randomized study, patients were randomly assigned (1:1:1:1:1) to 12 weeks of JNJ-37822681 (10 mg, 20 mg, or 30 mg, twice daily) or olanzapine (10 mg/d during week 1; 15 mg/d after week 1), or 6 weeks of placebo (followed by 6 weeks of olanzapine, 15 mg/d). Metabolic and body mass parameters were assessed at weeks 6 and 12. RESULTS: For metabolic parameters, at week 6 none of the JNJ-37822681 groups demonstrated significant change vs placebo; however, significant changes (P < .05) were observed in the olanzapine vs placebo group in triglycerides, low-density lipoprotein (LDL) and very-LDL cholesterol, and free fatty acids. For all JNJ-37822681 groups, mean weight changes at week 12 (-0.3 [10 mg], + 0.3 [20 mg], + 0.8 kg [30 mg]) were significantly less (P < .001) than for the olanzapine group (+ 2.7 kg). A higher percentage of overweight or obese patients (baseline body mass index: ≥25 kg/m2) receiving olanzapine had ≥7% increase in weight than those receiving JNJ-37822681 (9.8% vs 2.3%, respectively). CONCLUSIONS: JNJ-37822681 treatment was associated with a more favorable outcome on weight and metabolic adverse effects vs olanzapine for treating schizophrenia; the 10 mg twice-daily dose demonstrated minimal to no weight gain.

Risperidone dosing in children and adolescents with autistic disorder: a double-blind, placebo-controlled study.

Efficacy and safety of 2 risperidone doses were evaluated in children and adolescents with autism. Patients (N = 96; 5-17 years), received risperidone (low-dose: 0.125 mg/day [20 to <45 kg], 0.175 mg/day [>45 kg] or high-dose: 1.25 mg/day [20 to <45 kg], 1.75 mg/day [>45 kg]) or placebo. Mean baseline (range 27-29) to endpoint change in Aberrant Behavior Checklist-Irritability (primary endpoint) was significantly greater in the high-dose-(-12.4 [6.5]; p < 0.001), but not low-dose (-7.4 [8.1]; p = 0.164) group, versus placebo (-3.5 [10.7]). Clinical Global Impressions-Severity and Children's Yale-Brown Obsessive Compulsive Scale scores improved significantly only in the high-dose group, consistent with ABC-I results. Somnolence, sedation and increased appetite occurred more frequently in high-versus low-dose groups. Overall, increased appetite occurred most frequently.

A double-blind, randomized, placebo-controlled study with JNJ-37822681, a novel, highly selective, fast dissociating D2 receptor antagonist in the treatment of acute exacerbation of schizophrenia.

JNJ-37822681 is a novel, highly selective dopamine D2 receptor antagonist characterized by a rapid dissociation rate from the dopamine D2 receptor. This profile was hypothesized to confer antipsychotic efficacy and improved tolerability. In this 12-week study, the efficacy and safety of JNJ-37822681 were evaluated in patients with an acute exacerbation of schizophrenia, randomly assigned (1:1:1:1:1) to JNJ-37822681 (10-, 20- or 30-mg bid), olanzapine (15 mg once-daily), or placebo (for 6 weeks followed by olanzapine for 6 weeks). Of 498 randomized patients, 298 (60%) completed the study. All JNJ-37822681 dose groups and the olanzapine group showed significantly greater reduction in PANSS total score from baseline to week 6 versus placebo (all p-values < 0.001). Least-squares adjusted mean changes from baseline to week 6 in PANSS total score were: -6.4 (placebo); -18.4 (10 mg JNJ-37822681), -17.7 (20 mg JNJ-37822681), -20.0 (30 mg JNJ-37822681) and -22.9 (olanzapine). All JNJ-37822681 groups showed significant improvement versus placebo from baseline to week 6 in the PANSS subscales, Marder factors, Clinical Global Impression of Severity, and in the Subjective Well-Being on Neuroleptics scale (all p-values < 0.05). The most common treatment-emergent adverse events with JNJ-37822681 were insomnia (17%) and akathisia (13%). Incidences of extrapyramidal symptoms were dose-related and were comparable for JNJ-37822681 10 mg bid and olanzapine groups. All JNJ-37822681 dose groups showed lesser weight gain compared with olanzapine. The efficacy and tolerability profile of the JNJ-37822681 10 mg bid was consistent with the study hypothesis.

Neural circuitry of submissive behavior in social anxiety disorder: A preliminary study of response to direct eye gaze.

Fear of eye gaze is common in social anxiety disorder (SAD) and may represent an evolutionarily conserved submissive behavior. SAD subjects and healthy volunteers who underwent functional magnetic resonance imaging showed significant differences in neural activity in amygdala, fusiform, insula, anterior cingulate and prefrontal cortex in response to direct versus averted gaze. Neural response to direct gaze may identify brain regions important in the pathophysiology of SAD.

Acute occupancy of brain serotonin transporter by sertraline as measured by [11C]DASB and positron emission tomography.

BACKGROUND: In vivo determination of serotonin transporter (5-HTT) occupancy by selective serotonin reuptake inhibitors (SSRI) using positron emission tomography (PET) can aid in determination of dosing. Previous studies used chronic SSRI administration that may down-regulate 5-HTT and used the cerebellum as reference region despite measurable 5-HTT. We examine the reference region and occupancy after acute sertraline dosing. METHODS: We conducted autoradiography of human postmortem cerebellum to determine an optimal reference region. We quantified 5-HTT binding using [(11)C]DASB and arterial input functions in 17 healthy volunteers. Baseline PET scans were followed by a scan 4-6 days after 25 mg to 100mg of daily sertraline. Several modeling methods and outcome measures were assessed. RESULTS: Cerebellar gray matter is the optimal reference region. Occupation of 5-HTT sites saturates at low plasma sertraline levels (K(D) = 1.9 ng/ml) with maximal occupancies of 106.8 +/- 8.3% across all brain regions. There is a weak correlation between oral sertraline and plasma sertraline. Occupancy measures vary based on the reference region and outcome measure used. CONCLUSIONS: Occupancy studies and postmortem autoradiography can help define the optimal reference region. Reference tissue modeling using the optimal reference region returns the same occupancy measures as those determined using an arterial input function.

Prediction of panic response to a respiratory stimulant by reduced orbitofrontal cerebral blood flow in panic disorder.

OBJECTIVE: Lack of appropriate top-down governance by frontal cortical regions over a hypersensitive amygdala-centered fear neurocircuitry has been hypothesized to be central in the pathophysiology of panic disorder. The aim of this study was to examine regional cerebral blood flow changes in response to anxiety/panic provocation in subjects with panic disorder and healthy comparison subjects. METHOD: Quantitative water method positron emission tomography was used to obtain brain images of five untreated subjects with panic disorder and five healthy comparison subjects before and during anxiogenic challenge with intravenous doxapram, an acute respiratory stimulant. RESULTS: Baseline perfusion of the orbitofrontal cortex predicted panic attacks: lower perfusion was associated with heightened anxiety in response to doxapram challenge. CONCLUSIONS: The orbitofrontal cortex may be important in the regulation of responding to fear and is a potential area of aberrant functioning in panic disorder.

Effects of hyperventilation on heart rate and QT variability in panic disorder pre- and post-treatment.

Panic disorder is associated with an elevated risk of cardiovascular disease and sudden death. Individuals with panic disorder have been shown to have reduced variability in heart rate and increased variability in the QT interval on electrocardiogram (ECG), patterns predictive of sudden cardiac death in certain forms of cardiomyopathy. Given that panic disorder patients often hyperventilate during a panic attack, we assessed the effects of voluntary hyperventilation on the ECG utilizing linear analyses of heart rate and QT interval variability. Sixteen symptomatic, medication-free patients underwent hyperventilation challenge. A small subgroup of eight subjects underwent re-challenge after treatment. Pre-treatment, hyperventilation resulted in a decrease in a measure of heart rate variability and an increase in the QT variability index (QTVI; QT variance normalized for mean QT, divided by heart rate variance normalized for mean heart rate). In a remitted state, the QTVI was reduced both during rest and during hyperventilation compared with the respective pre-treatment levels. These findings suggest a possible mechanism explaining increased rates of cardiovascular morbidity and mortality in panic disorder. Moreover, the reduction in QTVI observed post-treatment raises the question of whether treatment might have cardioprotective effects, at least in panic disorder patients who have particular types of co-morbid cardiac disease. Yet these results must be interpreted cautiously; they are preliminary, exploratory and observed in a very small sample without a healthy comparison group.

Neurocircuitry of anxiety disorders.

A major focus in the field of anxiety in the past decade, and an area of intense ongoing interest, is the delineation of the basic neurocircuitry underlying normal and pathologic anxiety. Preclinical work defining the basic neurocircuitry responsible for fear responding has fueled neuroimaging investigations attempting to model the neurocircuitry of the anxiety disorders. Herewith, the authors review neuroimaging findings contributing to the development and refinement of neuroanatomic models for post-traumatic stress disorder, panic disorder, and social anxiety disorder.

Molecular targets in the treatment of anxiety.

Although the cathecholamine systems have long been the focus of drug therapy in anxiety and depression, the development of novel drugs specifically aimed at new targets within these traditional neurotransmitter systems and at targets outside of these systems is now propelling the field of drug development in anxiety. A greater understanding of regional brain networks implicated in stress, anxiety, and anxious behaviors has provided localized targets for anxiolytics. Within the serotonin and norepinephrine systems, increased understanding of postsynaptic receptor regulation with chronic treatment and cross-system effects of drug therapy have been critical in furthering our understanding of effective pharmacological interventions. Receptors within the glutamate, gamma-aminobutyric acid, and neuropeptide systems provide a rich diversity of drug targets, both in localization and function. While acknowledging significant clinical and biological differences between the various anxiety disorders, an important aspect of modern neurobiological research is to look for similarities among these disorders, given that they are highly comorbid with each other and often respond to the same spectrum of treatments. Here we review current views on both traditional and new molecular targets in the treatment of anxiety, realizing that the ultimate challenge in effective anxiolytic drug development may be achieving specificity in brain regions important in generating and sustaining anxiety.