The diagnostic utility of lactate sensitivity in panic disorder.

Lactate infusion is the most extensively studied of the pharmacological challenge tests in panic disorder. We assessed the value of this test in the diagnosis and subtyping of panic in clinical and research settings. Analysis of lactate infusion studies to date suggests that patients with panic attacks are significantly more sensitive to lactate than are healthy controls or patients with other psychiatric disorders without panic attacks. However, the usefulness of lactate infusion is limited by the lack of standardized, objective criteria for lactate-induced panic and uncertainty as to the sensitivity and specificity of the test for current, clinically significant panic attacks. Except in rare cases, the clinical history is likely to be of more value than lactate response in diagnosing panic disorder. Determination of the role of the test in subtyping patients with panic disorder awaits further study of the diagnostic, prognostic, genetic, and pathophysiologic significance of lactate sensitivity.

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.

Reduced benzodiazepine sensitivity in panic disorder.

We evaluated the functional sensitivity of the gamma-aminobutyric acid-benzodiazepine supramolecular complex in 9 patients with panic disorder and 10 psychiatrically healthy control subjects by comparing the effects of four logarithmically increasing doses of intravenous diazepam on saccadic eye movement velocity, memory, and self-rated sedation. Patients with panic disorder were less sensitive than controls to diazepam using eye velocity as the dependent measure. Sedation and memory effects did not distinguish the two groups. These findings suggest that panic disorder is associated with functional subsensitivity of the gamma-aminobutyric acid-benzodiazepine supramolecular complex in brain-stem areas controlling saccadic eye movements.

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.

Biological markers in panic states: lactate-induced panic and mitral valve prolapse.

Anxious patients, and more specifically, patients experiencing panic attacks, are thought to have a significant biological component to their illness. This study looks at two promising biological markers associated with this patient population-mitral valve prolapse and lactate-induced panic. We present our findings, which further characterize clinical and biological aspects of these two markers.

Response to lactate infusion in generalized anxiety disorder.

Intravenous sodium lactate infusion provokes symptoms of panic in patients with panic disorder at a significantly higher rate than in normal controls. Lactate sensitivity has been postulated to be specific for patients with panic attacks regardless of frequency of attacks or coexisting diagnoses. The authors present results of a pilot study of lactate infusions in patients with generalized anxiety disorder (GAD) without any history of panic attacks. Patients with GAD reacted more like panic disorder patients than like normal controls in anxiety and symptom scores during lactate infusion and in the rate of positive responses to lactate. Although preliminary, these findings raise questions regarding the specificity of lactate sensitivity and the relationship of GAD to panic disorder.

Lactate vulnerability after alprazolam versus placebo treatment of panic disorder.

Thirty-six patients with panic disorder underwent sodium lactate infusion before and after 8 weeks of treatment with alprazolam or placebo. With reinfusion, those patients panic-free with chronic alprazolam treatment displayed significantly decreased reactivity to lactate, as measured by subjective symptom ratings, duration of infusion before developing peak lactate-induced symptoms, and the proportion of patients experiencing lactate-induced anxiety or panic. Patients panic-free on placebo, as well as nonresponders to alprazolam treatment, displayed some, although less striking, decreases in reactivity to lactate with reinfusion. As a group, patients clinically unchanged with placebo treatment showed no systematic change in lactate response with reinfusion. Although the small numbers of patients in each treatment outcome group prohibit drawing definitive conclusions, these findings suggest that decreases in lactate-induced panic after successful alprazolam treatment of panic may result from a combination of changes in clinical state and direct effects of the medication.

Neuroendocrine effects of diazepam in panic and generalized anxiety disorders.

The adrenocorticotropic hormone (ACTH), cortisol, and growth hormone responses to four consecutive, logarithmically increasing doses of intravenous diazepam compared with placebo given at 15-min intervals were examined in patients with panic disorder (n = 13), generalized anxiety disorder (n = 8), and healthy controls (n = 13). Diazepam caused dose-dependent decreases in cortisol and increases in GH and dose-independent decreases in ACTH. There were no patient-control differences, possibly due to either the small sample size of the experimental paradigm, which tested subjects in an upright, sitting position in mildly arousing circumstances.

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.

Lactate-induced panic in primary affective disorder.

Intravenous sodium lactate was given to seven patients with primary depression and secondary panic attacks and 26 patients with panic disorder or agoraphobia with panic attacks. The two groups had similar rates of panic response. These results challenge the diagnostic specificity of lactate-induced panic.

Response to sodium lactate infusion in alcoholics with panic attacks.

The authors studied the response to sodium lactate infusion of 12 alcoholics with a history of panic attacks, 10 alcoholics without a history of panic attacks, and 16 nonalcoholic patients with panic disorder. The rate of lactate-induced panic was significantly higher in alcoholics with panic attacks than in alcoholics without panic attacks. Alcoholics with panic attacks were similar to nonalcoholic patients with panic disorder in their response to lactate. These findings support the specificity of lactate-induced panic for panic states and suggest that panic attacks in alcoholics resemble those in nonalcoholics. Lactate infusion may prove useful in the diagnosis of panic disorder in alcoholics.

Panic disorder precipitated by exposure to organic solvents in the work place.

The authors describe three cases of idiosyncratic response to occupational solvent exposure, with symptoms characteristic of panic disorder (DSM-III). The specific treatment and prognostic implications of this panic-like reaction to solvents are discussed. Sodium lactate infusion is proposed as an objective test to aid in the diagnosis.

Clinical characteristics and response to sodium lactate of patients with infrequent panic attacks.

Nine patients with panic attacks too infrequent to meet DSM-III criteria for panic disorder were compared to 20 panic disorder patients with respect to clinical characteristics and response to sodium lactate infusion. The two groups showed similar clinical characteristics and response to lactate. The authors conclude that patients with infrequent panic attacks are clinically and biologically similar to those with panic disorder and discuss implications for the diagnosis of panic states.

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.

Relapse and rebound following discontinuation of benzodiazepine treatment of panic attacks: alprazolam versus diazepam.

The authors assessed the effects of partial tapering followed by abrupt discontinuation of alprazolam, diazepam, and placebo in 40 patients with panic attacks. The anxiety scores and frequency of panic attacks of the three groups did not differ at the end of the initial 2-week taper, but 1 week after abrupt discontinuation of the remaining medication, patients formerly taking alprazolam had greater increases in anxiety but no more panic attacks than did the other patients. Because of low statistical power, differences in benzodiazepine half-lives, absence of multiple ratings, and imbalances between groups in clinical characteristics, these findings must be viewed as preliminary.

Prevalence, onset, and clinical recognition of panic states in hospitalized male alcoholics.

Alcoholism has been associated with a high prevalence of anxiety and phobic disorders. The authors ascertained the current prevalence of panic disorder and the lifetime prevalence of infrequent panic attacks in 154 male alcoholics in an inpatient alcohol treatment program. Thirteen percent (N = 20) gave a lifetime history of panic attacks and 45% (N = 9) of these had current panic disorder. Panic attacks preceded or coincided with the onset of problem drinking in 50% (N = 9) of the 18 patients with both diagnoses. Only two patients with histories of panic had been previously diagnosed, and none had been treated. Clinical implications of these findings are discussed.

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.

Benzodiazepine sensitivity in panic disorder: effects of chronic alprazolam treatment.

The aim of the current study was to determine the degree to which patients with panic disorder develop tolerance to subjective and physiological effects of benzodiazepine after chronic treatment with alprazolam. Response to acute administration of diazepam was assessed in 19 panic disorder patients receiving chronic treatment with alprazolam and 23 untreated panic disorder patients. At baseline in the laboratory, the two groups did not differ in peak saccadic eye movement velocity, saccade latency, short-term memory, plasma cortisol and growth hormone concentrations, heart rate, and self-rated levels of sedation and anxiety. Compared with untreated patients, alprazolam-treated patients displayed significantly less diazepam-induced change in peak saccadic velocity, saccade latency, growth hormone secretion, memory, and self-rated levels of sedation. There was no difference between groups in diazepam effects on plasma cortisol concentrations or self-rated anxiety. Within alprazolam-treated patients, diazepam-induced slowing of peak saccade velocity was significantly inversely correlated with illness severity, as measured by reported panic attacks per week and severity of phobic avoidance, but not with alprazolam dose, blood level, or duration of treatment. Because the alprazolam-treated group reported more panic attacks per week than the untreated panic patients, treated patients were divided into those who were asymptomatic versus those with continuing panic attacks. The subgroup of nine alprazolam-treated subjects who were asymptomatic also showed significantly less diazepam effects than the group of untreated panic disorder patients, suggesting that overall group differences were at least partially attributable to the development of tolerance to selected benzodiazepine effects with chronic alprazolam treatment.

Alcohol abuse, substance abuse, and panic disorder.

The purpose of this article is to review the literature concerning the interaction of alcohol and/or substance abuse with panic disorder, the comorbidity of these disorders, possible causal relationships, biologic relationships, and the recognition and treatment of dually disordered patients. A number of studies suggest significant comorbidity between panic disorder and alcoholism or abuse of drugs, especially cocaine and sedatives. Panic may lead to drinking or sedative use and also result from prolonged use or withdrawal of alcohol or other drugs. Possible biologic relationships involve the gamma-aminobutyric acid (GABA)-benzodiazepine receptor complex and the central noradrenergic system. Although treatment of panic in substance abusers has not been studied specifically, guidelines for recognition and management of these patients, including use of antipanic medication, are discussed.