Morbid Anxiety: Identification and Treatment.

Due to their prevalence, chronicity, and poorly understood pathophysiology, anxiety disorders remain an important public health problem. Despite clear diagnostic guidelines and the availability of excellent evidence-based treatments, most anxiety patients remain underrecognized and inadequately treated. This clinical synthesis highlights changes to anxiety disorder diagnosis that became effective with DSM-5. The article also provides some clinical perspective on clarifying differential diagnostic problems and building an alliance with the anxious patient. The quality and strength of the evidence base for current anxiolytic medications options (selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, benzodiazepines, and other agents), antianxiety psychotherapies (cognitive-behavioral therapy and brief dynamic therapies), and combination treatments are discussed. A brief update on newer treatment strategies, such as cognitive enhancement, complementary therapies, and neuromodulation, is included. Future directions for anxiety nosology and treatment are summarized, including the National Institute of Mental Health Research Domain Criteria initiative and the promising role of personalized medicine.

The Neurobiology of Panic: A Chronic Stress Disorder.

Panic disorder is an often chronic and impairing human anxiety syndrome, which frequently results in serious psychiatric and medical comorbidities. Although, to date, there have been many advances in the diagnosis and treatment of panic disorder, its pathophysiology still remains to be elucidated. In this review, recent evidence for a neurobiological basis of panic disorder is reviewed with particular attention to risk factors such as genetic vulnerability, chronic stress, and temperament. In addition, neuroimaging data are reviewed which provides support for the concept of panic disorder as a fear network disorder. The potential impact of the National Institute of Mental Health Research Domain Criteria constructs of acute and chronic threats responses and their implications for the neurobiology of panic disorder are also discussed.

Trends in Use and Cost of Second-Generation Antipsychotics Among Children and Teens in Indiana Medicaid, 2004-2012.

OBJECTIVE: To replicate and extend a study by the Agency for Healthcare Research and Quality (AHRQ) and Rutgers on antipsychotic use among youths in Medicaid, the authors analyzed Indiana Medicaid claims from 2004 to 2012, extending the earlier study by focusing on second-generation antipsychotics, including both fee-for-service (FFS) and non-FFS patients, and analyzing cost trends. METHODS: The authors evaluated the impact of several Indiana Medicaid policy changes on medication utilization and cost among children enrolled for at least one month during 2004-2012 (N=683,716-793,637), using an exhaustive antipsychotic list to search the database. RESULTS: Annual utilization rates for antipsychotics were 2%-3% but were much higher among foster children (10%-15%). Policies implemented in 2007 or later were associated with a significant plateauing of utilization in 2008-2012. CONCLUSIONS: Growth of second-generation antipsychotic utilization and costs was similar to trends described in the AHRQ-Rutgers study. Several containment strategies appeared effective in addressing these trends.

Cortical and subcortical gamma amino acid butyric acid deficits in anxiety and stress disorders: Clinical implications.

Anxiety and stress disorders are a major public health issue. However, their pathophysiology is still unclear. The gamma amino acid butyric acid (GABA) neurochemical system has been strongly implicated in their pathogenesis and treatment by numerous preclinical and clinical studies, the most recent of which have been highlighted and critical review in this paper. Changes in cortical GABA appear related to normal personality styles and responses to stress. While there is accumulating animal and human neuroimaging evidence of cortical and subcortical GABA deficits across a number of anxiety conditions, a clear pattern of findings in specific brain regions for a given disorder is yet to emerge. Neuropsychiatric conditions with anxiety as a clinical feature may have GABA deficits as an underlying feature. Different classes of anxiolytic therapies support GABA function, and this may be an area in which newer GABA neuroimaging techniques could soon offer more personalized therapy. Novel GABAergic pharmacotherapies in development offer potential improvements over current therapies in reducing sedative and physiologic dependency effects, while offering rapid anxiolysis.

A controlled trial of quetiapine XR coadministration treatment of SSRI-resistant panic disorder.

BACKGROUND: Open-label quetiapine coadministration with SSRI therapy, in a diagnostically mixed sample of comorbid anxiety patients, offered additional anxiolytic benefit. Therefore, we designed the following controlled trial to confirm these findings in a comorbid, SSRI-resistant, panic disorder (PD) patient sample. METHODS: This was a single-site, double-blind, placebo-controlled (PLAC), randomized, parallel group (2 groups), 8-week, quetiapine extended release (XR) coadministration trial. SSRI resistance was determined either historically or prospectively. Patients were randomized if they remained moderately ill (CGI-S score ≥ 4). Change in the PDSS scale total score was the primary efficacy outcome measure. Responders were identified as those with a ≥50 % decrease from their baseline PDSS score. In the early weeks of therapy, XR was flexibly and gradually titrated from 50 to 400 mg/day. RESULTS: 43 patients were screened in total, and 26 of these were randomized and evaluable. 21 patients (78 % of the randomized group) completed the trial (10 XR; 11 PLAC). The endpoint quetiapine XR mean daily dose ± SD was 150 ± 106 mg. While, in the sample as a whole, there was improvement in PDSS scores across the 8-week trial (ANOVA main effect of time, F = 10.9, df 8,192, p < 0.0001), the treatment × time interaction effect was not statistically significant (F = 0.8, df 8,192, p = 0.61). There was no between-group difference in responder frequency at endpoint. CONCLUSIONS: This proof-of-concept RCT did not support the efficacy of this treatment strategy for SSRI-resistant PD. Quetiapine XR was generally well-tolerated. Important limitations were the small sample size, and the relatively low average dose of quetiapine XR used. ClinicalTrials.gov ID#: NCT00619892.

Double-blind, placebo-controlled, pilot trial of paliperidone augmentation in serotonin reuptake inhibitor-resistant obsessive-compulsive disorder.

OBJECTIVE: This pilot study explored the efficacy and tolerability of paliperidone augmentation of serotonin reuptake inhibitors (SRIs) in adults with treatment-resistant obsessive-compulsive disorder (OCD). METHOD: Thirty-four patients aged 24-67 years (mean = 43.7 years, SD = 11.4) who met DSM-IV criteria for OCD and remained symptomatic following 2 or more past adequate SRI trials (including their current medication) were enrolled from May 2008 to March 2012. Participants were treated for 8 weeks in a double-blind study with either paliperidone (up to 9 mg/d) or matching placebo in addition to their SRI. Blinded raters conducted outcome assessments. The primary outcome, obsessive-compulsive symptom severity, was assessed using the Yale-Brown Obsessive Compulsive Scale (YBOCS). Secondary outcomes included the Clinical Global Impressions-Severity of Illness and -Improvement scales. RESULTS: Paliperidone administration resulted in significant baseline-to-posttreatment reductions in obsessive-compulsive symptoms as measured by the YBOCS (P < .01, d = 0.66), although placebo administration also resulted in medium-sized, trend-level significant YBOCS changes (P = .05, d = 0.53). In exploratory analyses examining between-group differences, tests for paliperidone superiority relative to placebo were not significant (P = .14, d = 0.34); however, a numerical trend toward significant between-group differences was found, with a reduction of 7.98 points on the YBOCS for the paliperidone group compared to a reduction of 4.02 points for the placebo group. Paliperidone was generally well tolerated and not associated with significant weight gain (mean [SD] weight: paliperidone, pretreatment 84.70 [27.08] kg, posttreatment 84.84 [18.99] kg; vs placebo, pretreatment 77.50 [25.33] kg, posttreatment 77.43 [19.90] kg; P = .21). CONCLUSIONS: These results suggest that paliperidone augmentation is well tolerated and has potential efficacy in the short-term treatment of some patients with SRI-resistant OCD. Well-powered, randomized, controlled studies are necessary to more definitively address the efficacy of this treatment strategy. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00632229.

Increased resting-state functional connectivity between the anterior cingulate cortex and the precuneus in panic disorder: resting-state connectivity in panic disorder.

BACKGROUND: The structural and functional abnormalities of the anterior cingulate cortex (ACC) have been reported in panic disorder (PD). Patients with PD have shown decreased gamma-aminobutyric acid (GABA) concentration in the ACC. The GABA concentration in the ACC was found to be associated with default mode network (DMN) activity in normal human subjects. Therefore, it was hypothesized that the DMN would show abnormal activity in PD. METHODS: We identified and compared the functional connectivity maps with seed region of interest (ROI) located in the perigenual area of ACC between the 11 patients with panic disorder and age- and sex-matched normal control subjects. Combining magnetic resonance spectroscopy (MRS) and resting fMRI, we investigated the correlation between the GABA concentration in the seed ROI and the index of functional connectivity between ACC and the area showing group differences. RESULTS: The patients with PD showed increased functional connectivity between ACC and precuneus compared to control subjects. The functional connectivity between the ACC and the precuneus negatively correlated with the GABA concentration of the ACC. LIMITATIONS: The relatively small sample size and seed based analysis with the selection of a single ROI limits the generalizability of the result. CONCLUSIONS: Increased functional connectivity in the two medial nodes of the resting-state default mode network, the ACC and the precuneus, might play an important role in the pathophysiology of panic disorder. The treatment aimed to normalize the functional connectivity between ACC and precuneus might have clinical benefits in PD.

Decreased GABA levels in anterior cingulate cortex/medial prefrontal cortex in panic disorder.

Changes of various brain metabolites including γ-aminobutyric acid (GABA), measured by 1H-magnetic resonance spectroscopy (MRS), have been reported in panic disorder (PD). Deficits in GABA have been implicated in the pathophysiology of PD. Furthermore, it has been suggested that cortical metabolite changes in PD are familial. Eleven PD patients, including five with and six without a PD family history, and eight age- and gender-matched healthy controls without a family history of psychopathology were recruited. Each subject underwent MRS exams and behavioral assessments (resting visual analog anxiety level and the Panic Disorder Severity Scale). GABA was detected with a MEGA-PRESS J-editing sequence and fitted to minimize macromolecule contaminations. A significant decrease in GABA, expressed as the ratio of GABA over total creatine (GABA/tCr), was detected in the anterior cingulate cortex (ACC)/medial prefrontal cortex (mPFC) in PD patients (p<0.05), which tends to be pronounced in patients with a PD family history. No other patient/control differences in metabolites were noted in the ACC/mPFC or occipital cortex (OCC). Overall, our results indicate that deficits in GABA levels in PD patients vary by brain regions and possibly by family history status.

Adherence, persistence of use, and costs associated with second-generation antipsychotics for bipolar disorder.

OBJECTIVE: A retrospective study using Medicaid claims identified patients with bipolar disorder for whom oral second-generation antipsychotics were prescribed and compared rates of adherence, persistence of use, and costs across five groups of patients taking aripiprazole, olanzapine, quetiapine, risperidone, or ziprasidone. METHODS: Medicaid claims data for 2,446 bipolar patients were analyzed from eight states. The 18-month observation period included the six months before and the 12 months after the index prescription date. Adherence was defined as a medication possession ratio >80%. Persistence of use was measured by the number of days of medication therapy before a 30-day gap. Mental health-related prescription costs, total prescription costs, total mental health-related costs, and total costs were assessed. Ziprasidone was the comparator. RESULTS: Clinically recommended doses of second-generation antipsychotic medications were prescribed for 45% of the patients (N = 1,102). Of these, 58% (N = 642 of 1,102) were adherent with the prescribed medication, with no significant differences between medication groups. Median time to nonpersistence of use averaged 96 days. Patients taking olanzapine were about 35% more likely than patients taking ziprasidone to discontinue taking their medication (hazard ratio = 1.34, 95% confidence interval = 1.02-1.76, p = .04). Mental health-related prescription costs and total prescription costs were lower for risperidone than ziprasidone. No statistically significant differences were found between the groups for all mental health-related costs or total costs. CONCLUSIONS: Among patients in a sizeable Medicaid cohort for whom a second-generation antipsychotic medication was prescribed, less than half had a clinically recommended dose, and less than two-thirds with a clinically recommended dose were adherent to the medication, confirming that many patients with bipolar disorder do not receive clinically recommended doses of second-generation antipsychotics.

Multicenter, randomized, double-blind, active comparator and placebo-controlled trial of a corticotropin-releasing factor receptor-1 antagonist in generalized anxiety disorder.

BACKGROUND: Antagonism of corticotropin-releasing factor (CRF) receptors has been hypothesized as a potential target for the development of novel anxiolytics. This study was designed to determine the safety and efficacy of pexacerfont, a selective CRF-1 receptor antagonist, in the treatment of generalized anxiety disorder (GAD). METHOD: This was a multicenter, randomized, double-blind, placebo-controlled and active comparator trial. Two hundred and sixty patients were randomly assigned to pexacerfont 100 mg/day (after a 1 week loading dose of 300 mg/day), placebo or escitalopram 20 mg/day in a 2:2:1 ratio. The primary outcome was the mean change from baseline to end point (week 8) in the Hamilton Anxiety Scale total score. RESULTS: Pexacerfont 100 mg/day did not separate from placebo on the primary outcome measure. The half-powered active comparator arm, escitalopram 20 mg/day, demonstrated efficacy with significant separation from placebo at weeks 1, 2, 3, 6, and 8 (P<.02). Response rates for pexacerfont, placebo, and escitalopram were 42, 42, and 53%, respectively. Genetic and psychometric rating scale data was obtained in 175 randomized subjects. There was a significant association between a single nucleotide polymorphism (SNP) of the gene encoding plexin A2 (PLXNA2-2016) with the HAM-A psychic subscale score for the entire cohort at baseline (FDR-adjusted P=.015). CONCLUSIONS: Pexacerfont did not demonstrate efficacy compared to placebo for the treatment of GAD. Whether these findings are generalizable to this class of agents remains to be determined. Our preliminary genetic finding of an association between a SNP for the gene encoding plexin A2 and an anxiety phenotype in this study merits further exploration. The trial was registered at clinicaltrials.gov (NCT00481325) before enrollment.

Pharmacologic treatment of panic disorder.

Comprehensive management of panic disorder involves a wide array treatments and interventions to reduce symptoms and increase functionality. This chapter provides an overview of the pharmacologic treatment of panic disorder including aspects of assessment, treatment selection and the biologic mechanisms of the illness.

Current perspectives of the roles of the central norepinephrine system in anxiety and depression.

Norepinephrine (NE) is a major monoamine neurotransmitter that has widespread effects across multiple brain areas to regulate arousal and stress responses. The underlying function of the NE cortical system is to balance vigilance/scanning behavior with focused attention on novel environmental stimuli and the state of arousal. The central NE system is involved intrinsically with the stress response system, and dysregulation within the NE system has been implicated in the pathogenesis of anxiety and depressive disorders. Central NE activity paradoxically has either anxiogenic or anxiolytic effects, depending on whether the time course of the stress is acute or chronic, whether the stress is predictable or unpredictable, and which underlying brain regions are affected. Under conditions of chronic stress, NE system activity dysregulation of the hypothalamic-pituitary-adrenal system may turn a homeostatic stress response into a pathological stress response. Data suggest that the NE interplay with the serotonin system may exert neurobiological normalization of the pathophysiological state of anxious depression. Accordingly, pharmacological interventions targeting the NE system can result in anxiolytic, rather than anxiogenic, outcomes when used to treat patients with anxiety and depression.

A key role for orexin in panic anxiety.

Panic disorder is a severe anxiety disorder with recurrent, debilitating panic attacks. In individuals with panic disorder there is evidence of decreased central gamma-aminobutyric acid (GABA) activity as well as marked increases in autonomic and respiratory responses after intravenous infusions of hypertonic sodium lactate. In a rat model of panic disorder, chronic inhibition of GABA synthesis in the dorsomedial-perifornical hypothalamus of rats produces anxiety-like states and a similar vulnerability to sodium lactate-induced cardioexcitatory responses. The dorsomedial-perifornical hypothalamus is enriched in neurons containing orexin (ORX, also known as hypocretin), which have a crucial role in arousal, vigilance and central autonomic mobilization, all of which are key components of panic. Here we show that activation of ORX-synthesizing neurons is necessary for developing a panic-prone state in the rat panic model, and either silencing of the hypothalamic gene encoding ORX (Hcrt) with RNAi or systemic ORX-1 receptor antagonists blocks the panic responses. Moreover, we show that human subjects with panic anxiety have elevated levels of ORX in the cerebrospinal fluid compared to subjects without panic anxiety. Taken together, our results suggest that the ORX system may be involved in the pathophysiology of panic anxiety and that ORX antagonists constitute a potential new treatment strategy for panic disorder.

Serotoninergic mechanisms in the treatment of obsessive-compulsive disorder.

Obsessive-compulsive disorder (OCD) is a disabling psychiatric condition affecting 1-2% of the community. Although modern drug, behavioral and psychosurgical therapies have improved the prognosis of OCD considerably, approximately 30% of patients remain treatment-refractory. Currently, selective serotonin (5-HT) reuptake inhibitors (SSRIs) are the drug treatments of choice for OCD. Accordingly, this review evaluates the evidence for a role of the serotonin (5-HT) neurochemical system in the treatment and pathophysiology of OCD. However, drug treatment approaches that modify function of interrelated neurochemical systems, such as the dopamine and glutamate systems, are also briefly discussed as they promise to complement and enhance SSRI treatment effects.

Selective serotonin reuptake inhibitor treatment for generalized anxiety disorder: a double-blind, prospective comparison between paroxetine and sertraline.

OBJECTIVE: Selective serotonin reuptake inhibitors (SSRIs) appear to be an effective class of medications for the treatment of generalized anxiety disorder. Within the SSRI class, however, there have been no comparative treatment studies for this disorder. Therefore, in the present study, we compared the efficacy and tolerability of 2 SSRIs, paroxetine and sertraline, in the treatment of generalized anxiety disorder. METHOD: In this parallel-group, double-blind, flexible-dose study, 55 patients with primary generalized anxiety disorder (DSM-IV criteria) were randomly assigned to receive either paroxetine or sertraline treatment for 8 weeks. Primary efficacy measures were the mean changes in Hamilton Rating Scale for Anxiety (HAM-A) scores as well as responder and remission rates based on the Clinical Global Impressions scale. Secondary efficacy measures consisted of the Indiana University Generalized Anxiety Measurement Scale and self-report ratings of anxiety, and quality-of-life outcome. Tolerability was assessed using the Systematic Assessment for Treatment Emergent Events questionnaire for treatment-emergent symptoms. RESULTS: The intent-to-treat sample consisted of 53 patients who received medication for at least 1 week. Of the 53 patients, 43 completed the entire 8 weeks of treatment. Both paroxetine and sertraline resulted in significant decreases in mean HAM-A scores (paroxetine = 57% +/- 28%; sertraline = 56% +/- 28%). There were no differences between medication groups on response or remission rates, and tolerability was comparable. CONCLUSIONS: Both paroxetine and sertraline appear similarly effective and well tolerated for the treatment of generalized anxiety disorder.

Impaired GABA neuronal response to acute benzodiazepine administration in panic disorder.

OBJECTIVE: Disturbances in the metabolism of the brain amino acid transmitter gamma-aminobutyric acid (GABA) may contribute to the pathophysiology of human anxiety disorders. Animal studies indicate that deletions or reductions in the expression of the gene for the GABA synthetic enzyme, glutamate decarboxylase 65 (GAD(65)), reduce basal cortical GABA levels or stress-induced release of GABA in the cerebral cortex and increase fear behaviors. Complementing these findings, the authors recently observed lower than normal cortical GABA levels in patients with panic disorder. In the current study, the authors tested the hypothesis that panic disorder patients have a deficient GABA neuronal response to benzodiazepine (clonazepam) administration. METHOD: In a parallel-group, repeated-measures design, occipital cortex GABA responses to acute oral, open-label benzodiazepine administration were tested in 10 panic disorder patients and nine healthy comparison subjects. Occipital cortex total GABA levels were measured before and after medication administration by means of a novel proton magnetic resonance spectroscopic technique. RESULTS: Panic disorder patients had a deficient GABA neuronal response (blunted reduction of occipital cortex GABA level) to acute benzodiazepine administration, compared to the healthy subjects, who exhibited a significant decrease in occipital cortex GABA levels after this intervention. The patients also appeared to have persistently low occipital cortex GABA after chronic benzodiazepine treatment. CONCLUSIONS: Overall, these data are consistent with the hypothesis that a trait-like abnormality in GABA neuronal function contributes to the pathogenesis of human panic disorder. The data raise the possibility that GAD(65) enzyme dysfunction could be a pathogenic factor in panic disorder.