A randomized effectiveness trial of collaborative care for patients with panic disorder in primary care.

BACKGROUND: Effectiveness studies have tested interventions to improve quality of care for depression in primary care, but none, to our knowledge, have been completed for panic disorder (PD) in this setting. This study sought to test the clinical effectiveness of PD pharmacotherapy embedded in a disease management framework of "collaborative care" (CC). METHODS: One hundred fifteen patients with PD from 3 primary care clinics were randomized to CC or "usual care" (UC). Patients in CC (n = 57) received educational videotapes and pamphlets; pharmacotherapy with the selective serotonin reuptake inhibitor paroxetine; 2 psychiatrist visits and 2 telephone calls in the first 8 weeks; and up to 5 telephone calls between 3 and 12 months' follow-up. Usual care patients (n = 58) were treated by their primary care physician. Telephone assessments of panic, anxiety sensitivity, depression, and disability variables were performed at 3, 6, 9, and 12 months' follow-up. Adequacy of pharmacotherapy was assessed with an algorithm based on a review of efficacy studies. RESULTS: Patients in CC were more likely to receive adequate (type, dose, duration) medication and more likely to adhere to this medication at 3 and 6 months. Random regression analyses showed that CC patients improved significantly more over time compared with UC patients on anxiety, depression, and disability measures, with the greatest effects at 3 and 6 months. CONCLUSIONS: Compared with UC, CC interventions significantly improved both quality of care and clinical and functional outcomes in primary care PD patients. Clinical differences were greatest in the first 6 months, corresponding to the greater quality of care and the greater intensity of intervention.

Panic disorder in primary care: biopsychosocial differences between recognized and unrecognized patients.

Studies suggest that the recognition of depression by primary care physicians (PCPs) is most likely in more symptomatic and impaired patients. As part of a randomized effectiveness study in primary care patients with panic disorder, we examined the baseline characteristics of study patients who were recruited by waiting room screen procedure (n=69) versus patients who were referred to the study by their PCP (n=41). Patients referred by their physicians had a significantly higher frequency of panic attacks, more intense attacks, and more anticipatory anxiety on the Panic Disorder Severity Scale, while screen-identified patients were more medically ill and had worse physical functioning on the SP36. There were no differences in anxiety sensitivity, phobic avoidance, depression, other SF36 measures, disability, or medical service utilization. In conclusion, differences in referred versus screened patients are mostly specific for panic attack-related symptoms, consistent with the notion that patients with more prominent physical symptoms (i.e., panic attacks) are more often recognized and referred in busy clinical settings. The better medical status and physical functioning of referred patients may indicate greater physician recognition of panic in patients who appear less medically ill. However, the many clinical and functional similarities between these two patient samples suggests that symptomatic primary care patients with panic may not always be identified by their PCPs and argues for the value of population-based screening for panic in primary care.

Nefazodone treatment of major depression in alcohol-dependent patients: a double-blind, placebo-controlled trial.

Depression is the most common comorbid psychiatric illness in patients with alcohol dependence. This double-blind study tested the efficacy of nefazodone versus placebo for the treatment of depression in actively drinking alcohol-dependent patients who were also participating in weekly group treatment for alcoholism. Sixty-four subjects with major depression disorder and alcohol dependence with a history of at least one prior episode of depression when not drinking were randomly assigned to receive 12 weeks of either nefazodone or placebo and participated in a weekly psychoeducational group on alcoholism. Subjects were assessed every 2 weeks for depression, anxiety, side effects, and drinking frequency. Subjects taking nefazodone were significantly more likely to complete the study (62%) than those taking placebo (34%). Analyses of covariance using drinks per week as a time-dependent covariate showed lower Hamilton Rating Scale for Depression scores at week 8 for end-point analysis and at weeks 8 and 12 for completers. The endpoint analysis demonstrated a significantly greater response in the nefazodone group (48%) than in the placebo group (16%). Both groups showed a similarly significant decrease in the average number of alcoholic drinks consumed per day over the course of the study. Although the number of adverse effects was significantly greater for the nefazodone group, there were no severe adverse events, and nefazodone was well tolerated. Nefazodone is a safe and effective antidepressant to use in a population of alcohol-dependent patients with depression who have a high degree of comorbidity. Nefazodone treatment was superior to placebo in alleviating depression in these patients but did not add any advantage over the psychoeducational group in terms of drinking outcomes.

Relationship between borderline personality disorder and Axis I diagnosis in severity of depression and anxiety.

BACKGROUND: This study tested the hypothesis that subjects with borderline personality disorder irrespective of the presence or absence of an Axis I mood or anxiety disorder would exhibit greater severity of depression and anxiety than subjects with either a personality disorder other than borderline personality disorder or no personality disorder. METHOD: Two hundred eighty-three subjects from an outpatient psychiatry clinic were administered the following assessments: the Structured Clinical Interview for DSM-III-R (SCID) for Axes I and II, the Hamilton Rating Scales for Depression and Anxiety, the Beck Depression Inventory, and the Spielberger State-Trait Anxiety Inventory. Subjects were categorized into borderline personality disorder, other personality disorder, and no personality disorder categories and into present versus absent categories on Axis I diagnosis of depression and of anxiety. A 2-factor multiple analysis of variance compared personality disorder status and Axis I diagnosis on severity of depression by observer rating and self-report. The analysis was repeated for anxiety. RESULTS: As hypothesized, significant main effects were found for borderline personality disorder and for both depression and anxiety. Subjects with borderline personality disorder showed greater severity on both depression and anxiety rating scales than did patients with another personality disorder, who showed greater severity than did patients with no personality disorder. Axis I diagnosis was also associated with greater severity on depression or anxiety rating scales. These differences were found for both observer ratings and self-report. An interaction was also found for depression: Subjects with borderline personality disorder but without an Axis I diagnosis of depression rated themselves as more severely depressed on the Beck Depression Inventory than did subjects with another or no personality disorder who also had an Axis I diagnosis of depression. CONCLUSION: Implications from the study are discussed including the need to assess for borderline personality disorder in research studies of depression and anxiety and to integrate treatments for borderline personality disorder into depression and anxiety treatment to maximize clinical outcomes.

Relationship between a GABAA alpha 6 Pro385Ser substitution and benzodiazepine sensitivity.

OBJECTIVE: In humans, interindividual variation in sensitivity to benzodiazepine drugs may correlate with behavioral variation, including vulnerability to disease states such as alcoholism. In the rat, variation in alcohol and benzodiazepine sensitivity has been correlated with an inherited variant of the GABAA alpha 6 receptor. The authors detected a Pro385Ser [1236C > T] amino acid substitution in the human GABAA alpha 6 that may influence alcohol sensitivity. In this pilot study, they evaluated the contribution of this polymorphism to benzodiazepine sensitivity. METHOD: Sensitivity to diazepam was assessed in 51 children of alcoholics by using two eye movement measures: peak saccadic velocity and average smooth pursuit gain. Association analysis was performed with saccadic velocity and smooth pursuit gain as dependent variables and comparing Pro385/Ser385 heterozygotes and Pro385/Pro385 homozygotes. RESULTS: The Pro385Ser genotype was associated with less diazepam-induced impairment of saccadic velocity but not with smooth pursuit gain. CONCLUSIONS: The Pro385Ser genotype may play a role in benzodiazepine sensitivity and conditions, such as alcoholism, that may be correlated with this trait.

Does ketamine-mediated N-methyl-D-aspartate receptor antagonism cause schizophrenia-like oculomotor abnormalities?

Evidence from histological and pharmacological challenge studies indicates that N-methyl-D-aspartate (NMDA) receptor hypofunction may play an important role in the pathophysiology of schizophrenia. Our goal was to characterize effects of NMDA hypofunction further, as related to schizophrenia-associated neuropsychological impairment. We administered progressively higher doses of ketamine (target plasma concentrations of 50, 100, 150, and 200 ng/ml) to 10 psychiatrically healthy young men in a randomized, single-blind, placebo-controlled design and assessed oculomotor, cognitive, and symptomatic changes. Mean ketamine plasma concentrations approximated target plasma concentrations at each infusion step. Verbal recall, recognition memory, verbal fluency, pursuit tracking, visually guided saccades, and fixation all deteriorated significantly during ketamine infusion; lateral gaze nystagmus explained some, but not all, of the smooth pursuit abnormalities. We concluded that ketamine induces changes in recall and recognition memory and verbal fluency reminiscent of schizophreniform psychosis. During smooth pursuit eye tracking, ketamine induces nystagmus as well as abnormalities characteristic of schizophrenia. These findings help delineate the similarities and differences between schizophreniform and NMDA-blockade-induced cognitive and oculomotor abnormalities.

Predictors and outcome of discharge against medical advice from the psychiatric units of a general hospital.

OBJECTIVE: The study examined predictors of discharge against medical advice (AMA) and outcomes of psychiatric patients with AMA discharges, as measured by poorer symptom ratings at discharge and higher rates of rehospitalization. METHODS: A total of 195 patients discharged AMA from general hospital psychiatric units were compared retrospectively with 2,230 regularly discharged patients. AMA status was defined as signing out against medical advice, being absent without leave, or being administratively discharged. All patients received standardized assessments within 24 hours of admission and at discharge. Demographic characteristics, psychiatric history, DSA-IV psychiatric and substance use diagnoses, and scores on an expanded 32-item version of the Psychiatric Symptom Assessment Scale were compared. RESULTS: The groups did not differ in primary psychiatric diagnoses. Patients discharged AMA were significantly less likely to be Caucasian or to be functionally impaired due to physical illness. They were more likely to live alone, have a substance use diagnosis, use more psychoactive substances, and have more previous hospitalizations. Patients discharged AMA had significantly shorter lengths of stay, higher rehospitalization rates, and more severe symptoms at discharge, even when length of stay was taken into account. The differences between the groups in male gender and young age were better accounted for by a greater likelihood of substance abuse in these groups. CONCLUSIONS: The results suggest a profile of patients who may be discharged AMA. Such patients have worse outcomes and are more likely to be high utilizers of inpatient resources. Aggressive identification of patients likely to be discharged AMA and early discharge planning for appropriate outpatient treatment are recommended.

Psychedelic effects of ketamine in healthy volunteers: relationship to steady-state plasma concentrations.

BACKGROUND: Ketamine has been associated with a unique spectrum of subjective "psychedelic" effects in patients emerging from anesthesia. This study quantified these effects of ketamine and related them to steady-state plasma concentrations. METHODS: Ketamine or saline was administered in a single-blinded crossover protocol to 10 psychiatrically healthy volunteers using computer-assisted continuous infusion. A stepwise series of target plasma concentrations, 0, 50, 100, 150, and 200 ng/ml were maintained for 30 min each. After 20 min at each step, the volunteers completed a visual analog (VAS) rating of 13 symptom scales. Peripheral venous plasma ketamine concentrations were determined after 28 min at each step. One hour after discontinuation of the infusion, a psychological inventory, the hallucinogen rating scale, was completed. RESULTS: The relation of mean ketamine plasma concentrations to the target concentrations was highly linear, with a correlation coefficient of R = 0.997 (P = 0.0027). Ketamine produced dose-related psychedelic effects. The relation between steady-state ketamine plasma concentration and VAS scores was highly linear for all VAS items, with linear regression coefficients ranging from R = 0.93 to 0.99 (P < 0.024 to P < 0.0005). Hallucinogen rating scale scores were similar to those found in a previous study with psychedelic doses of N,N-dimethyltryptamine, an illicit LSD-25-like drug. CONCLUSIONS: Subanesthetic doses of ketamine produce psychedelic effects in healthy volunteers. The relation between steady-state venous plasma ketamine concentrations and effects is highly linear between 50 and 200 ng/ml.

Determinants of suicidal ideation: the role of substance use disorders.

BACKGROUND: This study tested the hypothesis that the amount of psychoactive substance consumed (frequency and/or quantity), life problems resulting from this use, and a DSM-IV diagnosis of substance abuse/dependence are independent risk factors associated with increased suicidal ideation in a population of psychiatric inpatients with major depressive disorder. METHOD: 891 hospitalized patients with a primary diagnosis of nonpsychotic major depressive disorder (MDD) received a standardized, psychiatrist-administered assessment battery. To examine the relationship between admission suicidality and demographic, psychiatric history, and admission variables, chi-square analyses were used for categorical data and one-way ANOVAs were used for continuous indices. Stepwise hierarchical multiple regression analyses were performed to determine the set of variables that was independently related to admission suicidality level. RESULTS: There was general agreement between our findings and previous literature in regard to the association between severity of Axis I diagnosis, depressed mood, hopelessness, male gender, unemployment, involuntary treatment, and alcohol/drug problems and higher suicidal ideation. In our sample of hospitalized patients with unipolar major depressive disorder, higher current drug and/or alcohol dependency and high current use of alcohol or other substances of abuse were independently associated with higher levels of suicidal ideation. CONCLUSION: This association with higher suicidal ideation lends support to the importance of treating patients for both alcohol/drug problems and depression in an effort to decrease their risk for future suicide. We hope that our findings will improve the care that patients with dual diagnoses receive.

Relationships between neuropsychological and oculomotor measures in schizophrenia patients and normal controls.

Establishing the relationship between oculomotor and neuropsychological impairments might facilitate a more coherent description of schizophrenia-associated neurocognitive deficits. Therefore, we assessed several aspects of neuropsychological and oculomotor function in 25 medicated schizophrenia patients and 24 age-matched controls. Neuropsychological tasks included the Wisconsin Cart Sort Test (WCST), the Trail Making Test (TMT), the Rey Auditory Verbal Learning Test, and finger tapping speed. Oculomotor functions assessed included smooth pursuit, initiation of smooth pursuit, predictive pursuit, fixation, visually guided saccades, remembered saccades, and antisaccades. Among the schizophrenia patients, predictive pursuit performance correlated significantly with finger tapping (dominant hand), TMT (both parts), and one WCST measure (categories completed). The only other significant correlation among the schizophrenia patients was between antisaccade performance and part A of the TMT. Perseverative errors during the WCST and antisaccade performance were the only measures significantly correlated among the normals. Closely related neurocognitive deficits may be responsible for impairments in TMT, WCST, predictive pursuit, and antisaccade performance in schizophrenia.

Cardiovascular and catecholamine response to orthostasis in panic and obsessive-compulsive disorder and normal controls: effects of anxiety and novelty.

OBJECTIVE: Studies of the cardiovascular and catecholamine response to orthostatic challenge in panic disorder patients have yielded conflicting results. Failure to control for the effects of both anxiety and novelty, which contribute to subjects' response to orthostatic challenge in control patients, could possibly account for this. METHODS: The blood pressure, pulse, plasma norepinephrine and epinephrine responses to orthostasis were examined in patients with panic disorder, obsessive-compulsive disorder (to control for nonspecific anxiety effects), and controls, on two separate days a week apart (to control for novelty). RESULTS: All measures showed robust and significant increases with orthostatic challenge that were generally similar across groups. Pressure responses were greater on average on the first compared with the second day and panic disorder patients had higher plasma norepinephrine levels throughout the study and a diminished diastolic blood pressure response on the first day. CONCLUSIONS: These findings in general support the absence of consistent peripheral autonomic nervous system differences in response to orthostatic challenge in panic disorder patients.

Determinants of pharmacologic treatment failure in panic disorder.

BACKGROUND: We systematically assessed reasons for failure of pharmacologic treatment for panic disorder in patients referred to a specialty anxiety and mood disorders clinic and examined possible determinants of treatment-resistant panic disorder. METHOD: Interview data were obtained from 106 patients with DSM-III-R panic disorder seen in consultation. Data for each of 252 past medication trials included dose, duration of treatment, side effects, outcome, and reason for discontinuation. T tests and chi-square analyses were used to compare demographic and clinical characteristics of patients failing versus responding to adequate trials and those with and without intolerable medication side effects. RESULTS: Of 252 medication trials, 190 used effective antipanic medications, and only 59 (23%) were adequate in dose and duration. The most common reason for treatment failure was intolerable side effects, occurring in 51 (27%) of 190 trials using effective antipanic medications. Patients discontinuing treatment due to adverse effects had higher Hamilton Rating Scale for Anxiety scores and were less likely to have a history of substance abuse. Discontinuation due to side effects was significantly more common with tricyclic antidepressants than with benzodiazepines. True treatment resistance was reported in 14 (24%) of 59 adequate medication trials. Treatment-resistant patients were younger and had a higher lifetime rate of major depression. CONCLUSION: Although use of ineffective medications or inadequate trials were important factors, the most common reason for treatment failure was side effects, especially with tricyclic antidepressants. True treatment resistance was less common, since few medication trials were adequate in dose and duration, and may be associated with comorbidity.

Effect of benzodiazepines on plasma levels of homovanillic acid in anxious patients and control subjects.

The effects of four logarithmically increasing doses of intravenous diazepam or placebo on plasma homovanillic acid (HVA) were determined in benzodiazepine-naive patients with panic disorder (PD) or generalized anxiety disorder (GAD), and in healthy controls. Plasma HVA was measured at baseline and 3 min after the first and fourth doses of diazepam/placebo. Mean baseline plasma HVA levels were significantly lower in PD patients compared with GAD patients and controls. Although plasma HVA levels decreased significantly with time in all groups, there was no diazepam effect. This study suggests that low dopaminergic activity may occur in a subset of anxious patients (PD), and that diazepam does not significantly affect dopaminergic activity as measured by plasma HVA in humans.

Reduced benzodiazepine sensitivity in patients with panic disorder: comparison with patients with obsessive-compulsive disorder and normal subjects.

OBJECTIVE: The authors sought to replicate their previous finding of reduced response to diazepam in patients with panic disorder, to test whether this effect was specific for panic disorder, and to determine whether this reduced response was merely an artifact of resistance to sedation from anxiety-related overarousal. METHOD: The effects of four increasing intravenous doses of diazepam on saccadic eye movement velocity and accuracy (the latter being a saccadic variable that is unaffected by sedation), short-term memory, and self- and observer-rated sedation were assessed in 18 patients with panic disorder, 15 patients with obsessive-compulsive disorder, and 14 normal comparison subjects. The ratios of effect to blood level areas under the curve for both ascending and descending limbs of the effect/blood level curves were compared for each variable. RESULTS: Patients with panic disorder showed significantly less diazepam effect on saccadic velocity and accuracy for the ascending limb of the blood level curve than comparison subjects. Patients with obsessive-compulsive disorder showed similar differences from comparison subjects but only for saccadic velocity. There were no group differences in diazepam effects on memory and sedation. CONCLUSIONS: Patients with panic disorder are less sensitive than comparison subjects to diazepam. Although this difference is not an artifact of resistance to sedation, it may not be specific for panic disorder but rather may reflect a more nonspecific aspect of anxiety disorders.

Tridimensional personality traits in sons of alcoholic and nonalcoholic fathers.

Sons of alcoholics (SOAs; n = 27) and sons of nonalcoholics (SONAs; n = 23) were compared across Tridimensional Personality Questionnaire (TPQ) and Sensation Seeking scales and measures of plasma homovanillic acid and platelet monoamine oxidase activity. SOAs and SONAs did not differ significantly on any measure. The pattern of correlations between TPQ and Sensation Seeking scales provided some support for the construct validity of TPQ measures. Scores on the TPQ Novelty Seeking scale and platelet monoamine oxidase activity were significantly inversely associated (r = -0.52, p < 0.02) among SOAs, but not among SONAs (r = -0.06).

Effect of diazepam on plasma gamma-aminobutyric acid in sons of alcoholic fathers.

A subgroup of abstinent alcoholics, display low levels of plasma gamma-aminobutyric acid (GABA). Two previous studies of plasma GABA in sons of alcoholic fathers (SOAs) have yielded conflicting results. The aim of the current study was to measure plasma GABA both at baseline and after challenge with diazepam, a GABAA receptor agonist, in a group of SOAs already shown to display decreased eye movement, memory, and sedative effects of diazepam. Twenty-seven SOAs and 23 male control subjects received four logarithmically increasing doses of diazepam or placebo in randomized order on 2 days at least 1 week apart. Plasma GABA was measured at baseline and after the last dose. There were no significant differences between SOAs and controls in baseline plasma GABA levels. In the whole sample, there were significant correlations between baseline plasma GABA and both high novelty-seeking and low-harm avoidance scores on the Tridimensional Personality Questionnaire. Both SOAs and controls displayed decreases in plasma GABA over time on both testing days, but there was no effect of diazepam on plasma GABA and no significant difference between groups in plasma GABA response to diazepam. These results suggest that neither low plasma GABA at baseline nor altered plasma GABA response to diazepam is associated with increased genetic risk for alcoholism.

Long-term course and outcome in panic disorder: a naturalistic follow-up study.

Fifty-five of 102 consecutively evaluated patients with panic disorder seen in consultation at a specialty anxiety and mood disorders clinic were reinterviewed from 15 to 60 months later after naturalistic treatment in the community. Over the follow-up period, most patients displayed improvement in panic attack frequency and severity, phobic avoidance, depression, and major role functioning, although only five (10%) were asymptomatic on all measures at follow-up. The majority of patients with impaired interpersonal functioning showed no improvement on this measure. Thirty percent of the patients were panic-free at 12 months and 28% at the time of follow-up, with 43% experiencing at least three panic-free months during the follow-up period. Comorbid agoraphobia, major depression, and Axis II disorders were associated with worse outcome on selected measures of symptomatic and functional impairment. However, the strongest predictors of overall improvement were avoidance coping for outcome at 12 months and Axis I comorbidity for outcome at the time of the follow-up evaluation.

Human oculomotor function: reliability and diurnal variation.

To provide information on test-retest reliability for seven oculomotor paradigms currently used in studies of schizophrenia and other neuropsychiatric conditions, we tested eight controls at four weekly intervals, twice in the morning (8-10 AM) and twice in the afternoon (3-5 PM). Intraclass correlation coefficients were significant (p < .05) for both AM and PM pairs of measures as well as for mean AM and PM pairs for closed-loop pursuit gain, open-loop pursuit gain (using velocity as the measure), saccadic frequency during pursuit and fixation, visually and nonvisually guided saccadic latency and velocity, antisaccadic latency, and premature reflexive saccades during the memory-guided saccade task. Acceleration as a measure of open-loop gain (for slower targets) and accuracy of saccades to a moving target were only reliable at PM testing time. Nonvisually guided saccadic accuracy and inappropriate reflexive saccades during the antisaccade task were not reliable, possibly due to the narrow range of values for these measures. Except for approximately 10% fewer saccades during pursuit and fixation in the morning, there were no consistent diurnal differences. These findings suggest that, in a small sample of subjects, most measures of oculomotor function are stable across time and may reflect underlying neurophysiologic traits.