Evidence that decreased function of lymphocyte beta adrenoreceptors reflects regulatory and adaptive processes in panic disorder with agoraphobia.

OBJECTIVE: This study was designed to clarify the nature of the reduced function of the peripheral beta adrenoceptor system observed in panic disorder with agoraphobia. The authors hypothesized that this phenomenon reflected a regulatory and adaptive process. METHODS: Lymphocyte beta adrenoreceptor density and affinity, basal lymphocyte cAMP level, and isoproterenol-stimulated cAMP generation were measured in 27 untreated outpatients with panic disorder with agoraphobia and 24 healthy comparison subjects. Lymphocyte beta receptor attributes were again assessed in patients after 4 weeks of double-blind treatment with adinazolam (slow-release form) or placebo. Panic frequency, agoraphobic symptoms, overall anxiety, and improvement with treatment were assessed with standard rating instruments. RESULTS: Multivariate statistics revealed significantly lower beta receptor density and isoproterenol-stimulated cAMP generation in patients than in comparison subjects. beta receptor density tended to normalize after adinazolam but not after placebo. Pretreatment beta receptor density was lower in treatment responders than nonresponders. Patients with mild agoraphobia had lower cAMP responsivity than patients with moderate or severe agoraphobia. CONCLUSIONS: Decreased function of lymphocyte beta receptors in panic disorder with agoraphobia is expressed as both decreased density and decreased cAMP responsivity. This pattern of changes, and the tendency for receptor density to normalize with treatment, is consistent with an active, regulatory process rather than a structural deficit in the beta receptor system. Preliminary clinical findings suggest that these changes may reflect adaptive processes associated with a favorable clinical course in panic disorder with agoraphobia.

Relationships between thyroid indices and symptoms of anxiety in depressed outpatients.

Scores on rating scales measuring symptoms of depression, panic anxiety, state anxiety, trait anxiety, and agoraphobic avoidance were correlated, using multivariate statistics, with total thyroxine- and thyrotropin-releasing hormone concentrations in outpatients with major depression. A significant inverse relationship was demonstrated between agoraphobic avoidance and total thyroxine concentrations in female patients. No other symptom ratings were significantly associated with these thyroid indices. The depressed patients scored in the clinically significant range for agoraphobic symptoms. Assessment of agoraphobic avoidance may help identify a clinically and biologically distinct subgroup of depressed patients.

Effects of single dose haloperidol administration on plasma homovanillic acid levels in normal subjects.

Homovanillic acid (HVA), an oxidative metabolite of dopamine, has been shown in a number of studies to reflect severity of symptoms and to predict response to neuroleptic treatment in schizophrenic patients. In several clinical studies, HVA levels have been shown to have a positive relationship with symptom severity and to decline over time upon treatment with antipsychotic agents. The magnitude of this decline appears to be related to the degree of symptom reduction in patients so treated. However, administration of dopamine postsynaptic antagonists should be expected to increase synaptic dopamine availability, thereby increasing HVA concentrations, according to traditional models of drug action. While in some studies, this appears to be the case, we saw no evidence of an early phase of HVA elevation after administration of 4- and 10-milligram doses of haloperidol to human volunteers. Rather, HVA levels declined during the period of absorption and attainment of peak haloperidol levels. Baseline HVA levels of 51.6 +/- 3.83 pmoles/ml and 56.8 +/- 5.70 pmoles/ml (after 4 mg and 10 mg., respectively) declined to minima of 35.6 +/- 1.67 pmoles/ml and 26.3 +/- 5.34 pmoles/ml respectively, at 3-4 hours after haloperidol administration. A trend was noted for the 10-mg dose to produce a greater decline than the 4-mg dose, which was most apparent at 4 hours after drug administration. The shape of both curves did not appear to be substantially different than expected on the basis of diurnal variation. These preliminary findings support the concept that dopamine turnover in humans is not increased and may be decreased by short-term administration of conventional neuroleptics.

Beta receptor density in human lymphocyte membranes: changing with aging?

The number of beta adrenergic binding sites (Bmax) in human lymphocyte membranes has been reported to decrease, remain the same, or increase with age. In order to address this issue, we used two highly specific beta receptor ligands with lymphocytes from healthy aged (range: 51-90 years) and young (19-39 years) subjects in two separate studies. Because depression can reduce Bmax, potential aged subjects were excluded if they had high scores on tests for depression. Bmax was higher in the aged group of each study (33% higher in the first, p less than .01, and 72.5% in the second, p less than .02); the results were similar in both studies. Antagonist affinity did not differ between young and aged groups in either study. We suggest that some of the discrepancies in the literature could be due to differences in age ranges used or to inclusion of depressed subjects in prior studies.

Effects of haloperidol on recall and information processing in verbal and spatial learning.

1. Normal male subjects were tested with either a multi-trial word list learning test or a spatial analogue prior to administration of either 4 mg. or 10 mg. of oral haloperidol. Six hours after drug administration subjects who had previously received the verbal test were administered the spatial test, and vice versa, so for each test there was a no-drug control group, a group tested after receiving 4 mg. of haloperidol, and a group tested after a 10 mg. dose. 2. Both the verbal and spatial learning tests yield multidimensional measures of components of memory and learning, including measures sensitive to effort-demanding and more automatic information processing operations. 3. Results showed no differences for either test among the pre-drug control group and the 4 mg. and 10 mg. groups, with only one minor exception. 4. The lack of significant results cannot be attributed to insensitivity of the test instruments used, since previous studies have documented sensitivity to a number of clinical conditions and to aging. 5. Results have implications regarding clinical effects of haloperidol. A theory that links dopaminergic functioning with effortful information processing underlying memory and learning was not supported.

Lymphocyte beta-adrenoreceptor density in patients with unipolar depression and normal controls.

Values of binding maximum (Bmax) and dissociation constant (Kd) of (-)3-[125I]iodocyanopindolol (ICYP) were determined in beta-adrenergic receptors of membranes of peripheral lymphocytes in 32 patients with unipolar depression (DSM-III-R) and 31 normal controls. Results were analyzed by a two-way Analysis of Covariance method. A significant difference was noted for group assignment (patient versus control, p less than 0.05). Mean Bmax (fmol ICYP bound/mg lymphocyte membrane fraction total protein) of patients was 31.9 +/- 3.84 (SE) and controls 46.3 +/- 3.92 (SE). A significant interaction was found between group membership and gender (p less than 0.05). In the female patient group (n = 14), mean Bmax was 30.5 +/- 5.79 (SE); in female controls, mean Bmax was 56.0 +/- 5.15 (SE). Differences between male patients and male controls were not significant. Mean values of Kd (pmol/liter) showed a trend for patient values to be lower than control values [69.0 +/- 13.66 (SE) versus 108.5 +/- 14.42 (SE), respectively]. A significant inverse relationship was noted between lymphocyte beta-receptor Bmax and frequency of panic attacks during the depressive episode in 18 patients (p = 0.05). No relationship was found between values of Kd and frequency of panic attacks in these patients. Thus, preliminary evidence is provided for relationships among altered beta-adrenergic receptor binding, gender, and indices of panic-anxiety in unipolar depressed patients.

Effect of haloperidol on a symbol digit substitution task in normal adult males.

Two groups of normal male volunteers were administered oral haloperidol at two dose levels: 4 mg (n = 12), and 10 mg (n = 9). Subjects were administered the Symbol-Digit Substitution Test (SDST) prior to drug administration (0 hours) and at the following intervals after administration: 1, 3, 4, 6, 14, 24, and 36 hours. Overall performance of the 10-mg group was poorer than that of the 4-mg group. Both groups showed a significant time-dependent decrease in performance, with the effects for the 10-mg group being apparent earlier and lasting longer. The time course for this decrease corresponded to the time course of elevation of prolactin by haloperidol in these subjects. Performance on the Flexibility of Closure Test was unimpaired in subjects receiving 10 mg haloperidol, indicating that the impairment in performance on the SDST was not exclusively due to nonspecific factors such as sedation or psychomotor retardation. Extrapyramidal side effects could have contributed to impairment on the SDST, but the time course of these effects was different than that of performance impairment. Results indicate that haloperidol may have dose-dependent differential adverse effects on task performance when administered on a short-term basis, although little is known about the exact nature of these effects and their relationship to antipsychotic activity of the drug. Even though these effects may clear with repeated administration, their presence even for a short time may contribute adversely to the risk-benefit profile of neuroleptic medication.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of oral administration of haloperidol on plasma thyrotropin concentrations in men.

To investigate the effects of neuroleptics on plasma thyrotropin (TSH) concentrations, haloperidol tablets were administered orally to 34 normal male volunteers. Seventeen of the subjects received 4 mg; the other 17 received 10 mg. Plasma samples were collected at baseline and 1, 3, 4, 6, 14, 24, 36, 48, 72 and 96 hr after drug administration. Plasma TSH was assayed by a double antibody radioimmunoassay procedure. A significant change in plasma TSH occurred for all subjects (p less than 0.001). By multivariate analysis of variance, the dose x time interaction was not significant. However, a significant dose x time interaction was detected in a univariate analysis. After haloperidol 10 mg a statistically significant rise in TSH occurred at 3-4 hr, which corresponded to the time of attainment of maximal plasma haloperidol concentrations. A significant but modest correlation between plasma haloperidol and TSH was present at 3 hr (0.373; p less than 0.05). TSH concentrations at 14 hr after the 10 mg dose were not significantly correlated with simultaneous or peak plasma haloperidol concentrations. Consequently, only the release of TSH occurring at 3-4 hr after the 10 mg dose was attributed to the drug's effects.

Mood alteration following oral and intravenous haloperidol and relationship to drug concentration in normal subjects.

Haloperidol was administered to 12 subjects intravenously (0.125 mg/kg) and to nine subjects orally (0.5 mg/kg). These doses produced sedation in most subjects. A minimal decrease in orthostatic blood pressure was observed. Administration of the Profile of Mood States to these subjects revealed effects on factor 4, vigor-activity, and factor 6, confusion-bewilderment, but many subjects could not complete testing due to excessive sedation. Haloperidol concentrations were obtained during testing and correlated moderately with scores of these subscales. Correlation was also noted between haloperidol concentration and chlorpromazine effect as measured by the Addiction Research Center Inventory. Extrapyramidal reactions, mainly acute dystonic reactions and akathisia, were common. Dystonia occurred in four subjects after intravenous, and three subjects, after oral administration. Akathisia occurred in eight subjects after intravenous, and three subjects after oral administration. Extrapyramidal reactions tended to occur relatively early or relatively late, at times when drug concentrations were far less than peak values.

Elimination half-life and bioavailability of haloperidol in schizophrenic patients.

Haloperidol was administered orally to 6 male schizophrenic patients and intravenously to 3. Elimination half-life (t1/2 beta) and bioavailability (F) were calculated for both groups from haloperidol serum concentrations determined by gas-liquid chromatography. Mean (+/- SD) half-lives were 17.5 +/- 8.7 hours for oral administration and 15.1 +/- 2.5 hours for intravenous; bioavailability was 0.64 +/- 0.23. These values were comparable to those found in normal volunteers.

Haloperidol kinetics after oral and intravenous doses.

Haloperidol kinetics were determined after oral and intravenous drug doses in 15 men. Mean elimination t1/2 for the subjects was 17.9 +/- 6.4 (SD) hr. After 0.125 mg/kg IV, mean distribution t1/2s in six subjects were 0.19 +/- 0.07 and 2 +/- 1 hr, and in 12 subjects mean clearance was 11.8 +/- 2.9 ml/kg/min and mean steady-state volume of distribution was 17.8 +/- 6.5 l/kg. After 0.50-mg/kg oral doses in eight subjects, mean lag time before drug absorption was 0.82 +/- 0.25 hr. Mean absorption t1/2 was 0.37 +/- 0.18 hr and mean distribution t1/2 was 0.96 +/- 0.20 hr. Bioavailability was 0.65 +/- 0.14 after oral doses. In 14 kinetic studies in nine subjects, data was analyzed by both model-dependent (open two- and three-compartment models using nonlinear regression) and model-independent (AUC and first moment curve) approaches. Results of the two were found to be in close agreement. The long elimination t1/2 of haloperidol is explained by the drug's extensive tissue distribution.

Detection of marijuana use in psychiatric patients by determination of urinary delta-9-tetrahydrocannabinol-11-oic acid.

Seventy-six male inpatients with diagnoses of schizophrenia, primary affective disorder, post-traumatic stress disorder, borderline personality disorder, other personality disorder, and primary substance abuse disorder were screened for the use of marijuana by determination of urinary delta-9-tetrahydrocannabinol-11-oic acid. Screening was performed to detect marijuana use in asymptomatic patients returning to the ward after passes, and also to elucidate changes in mental state in newly admitted patients and patients who had decompensated during hospitalization. Ward personnel found the screening procedure quite useful and incorporated it into psychotherapeutic and chemotherapeutic interventions. Although susceptible and resistant individuals were found in all diagnostic categories studied, no consistent features were found to distinguish those individuals who exhibited behavioral change in association with marijuana smoking, from those who did not.

Relationship of serum haloperidol levels to clinical response in schizophrenic patients.

The authors treated 16 outpatients and 1 inpatient who had diagnoses of schizophrenia in exacerbation with haloperidol as the sole neuroleptic agent and obtained ratings of psychopathology and serum levels of haloperidol. Improvement in schizophrenic symptoms measured by the Brief Psychiatric Rating Scale was significantly greater in patients who had mean haloperidol serum concentrations in the range of 8-18 ng/ml than in patients whose mean haloperidol serum concentration fell outside this range.