Neurotransmitter and hormonal background of hostility in anorexia nervosa.

Marked hostility toward relatives, therapists and friends is very frequently observed in anorexia nervosa (AN) as expression of outward-directed aggressiveness which interferes with the therapeutic programs of the patients. With the purpose to investigate this aspect of the disorder and its biological background, we studied in anorexics some neurotransmitter-hormonal secretions which are known to modulate aggressivity-hostility by measuring plasma concentrations of total (TT) and free testosterone (FT), total estrogens (TE), the TT/E and FT/TE ratios, and the serotonergic function by measuring basal prolactin (PRL) levels and responses to stimulation with the specific serotonin (5-HT)-releasing agent D-fenfluramine (D-Fen). In 13 women with AN, 5 of the restricted (AN-R) and 8 of the bingeing/purging type (AN-BP) in an active phase of the disease, and in 13 healthy controls matched for sex and age, we measured hostility by the SCL-90 scale (subscale items 11, 24, 63, 67, 74, 81). Basal TT, FT, TE, TT/TE, FT/TE, PRL values and PRL responses to D-Fen and to saline administration were measured radioimmunologically in AN patients and controls. Hostility was significantly higher in AN patients than in controls, TT, FT and TE concentrations were significantly lower in AN patients than in controls, TT/TE ratio was significantly higher in AN patients than in controls, and FT/TE ratio was not different in the two groups. In AN patients and controls, hostility correlated positively with TT and FT values. Basal PRL values and responses to D-Fen administration were significantly lower in anorexics than in controls, but they did not correlate with the degree of hostility in either patients or controls. In conclusion, hostility is higher than normal in anorexics, and its severity seems to be linked to the secretion of FT and not to the alterations in the 5-HT function.

Central dopaminergic function in anorexia and bulimia nervosa: a psychoneuroendocrine approach.

Data on central dopamine (DA) function in patients with Anorexia Nervosa (AN) and Bulimia Nervosa (BN) are contradictory. To tentatively clarify the brain secretory state of the amine and its relationship with the nutritional impairments and/or the psychopathological aspects of the two disorders, we measured the responses of growth hormone (GH) to acute stimulation with apomorphine (APO), a selective D-1 and D-2 receptor agonist, in 16 AN patients, 8 restricted (AN-R) and 8 bingeing-purging (AN-BP), in 7 BN patients and in 8 healthy controls (CTR). Interference of impairment of the somatotropic axis in the GH response to APO stimulation was excluded by measuring the GH and insulin-like growth factor-1 (IGF-1) basal levels and GH responses to growth hormone-releasing hormone (GHRH) stimulation. Psychological aspects of patients and controls were investigated by the rating scales Eating Disorder Inventory (E.D.I.), Bulimic Investigation Test Edinburgh (B.I.T.E)., and Yale-Brown Cornell Eating Disorder Scale (YBC-ED). Basal GH levels were significantly higher and those of IGF-1 lower in AN-R than in AN-BP, BN and CTR subjects. GH responses to GHRH stimulation were significantly higher in AN-R than in AN-BP and BN patients and in CTR. GH responses to APO stimulation were significantly lower in AN-R and AN-BP than in BN and CTR subjects, suggesting that at the hypothalamic level there is a subsensitivity of postsynaptic D-2 receptors and possibly a presynaptic DA hypersecretion. The altered GH responses to APO stimulation did not correlate with the Body Mass Index, while they correlated negatively with E.D.I. scores.

CO2-induced panic attacks: a twin study.

OBJECTIVE: The authors investigated the role of genetic factors in 35% CO2-induced panic attacks. METHOD: Ninety twins recruited from the general population were challenged with one-vital-capacity inhalations of 35% CO2-65% O2. Probandwise concordance rates were calculated and rates compared for monozygotic and for dizygotic twins. RESULTS: A significantly higher concordance was found for 35% CO2-induced panic attacks among monozygotic than dizygotic twins (55.6% versus 12.5%). CONCLUSIONS: These results suggest a relevant role of genetic factors in 35% CO2-induced panic attacks.

Growth hormone response to growth hormone-releasing hormone stimulation in obsessive-compulsive disorder.

Two groups of 30 patients with obsessive-compulsive disorder and 30 age- and sex-matched healthy control subjects were given a growth hormone-releasing hormone (GHRH) stimulation test to determine: (1) whether the downstream function of the somatotropic axis (growth hormone = GH, somatomedin-C = SMD-C) was impaired; (2) what might be the central alteration responsible for such impairment; and (3) whether alterations might be linked to the etiopathogenesis of the disease. Basal values of GH and SMD-C were the same in patients and control subjects, but GH responses to GHRH stimulation were significantly lower in patients than in control subjects. The absence of a pathology of basal GH and SMD-C concentrations indicates that the blunted GH responses to GHRH stimulation are not due to a negative feedback mechanism and suggests that a central neurotransmitter-neuropeptide pathology might be involved in the phenomenon.

Plasma interleukin-1 beta and tumor necrosis factor concentrations in obsessive-compulsive disorders.

Plasma interleukin-1 beta (Il-1 beta) and tumor necrosis factor-alpha (TNF-alpha) concentrations were measured twice, at a 48-hour interval, in 27 drug-free obsessive-compulsive patients (12 women and 15 men) and in 27 sex-age-matched healthy controls. Il-1 beta and TNF-alpha concentrations were significantly lower in patients than in controls, whereas there were no differences in either group between men and women, between the samples of the two days, or, in the patients, between those who had and those who had not been previously treated with psychopharmacologic drugs.

Dopamine function in obsessive-compulsive disorder: growth hormone response to apomorphine stimulation.

Indirect observations suggest that the dopaminergic system may be involved in the pathophysiology of obsessive-compulsive disorder (OCD). The dopaminergic function of 15 patients with OCD and 15 age/sex-matched controls was evaluated by measuring the growth hormone (GH) responses to stimulation with the dopaminergic agonist apomorphine (APO), which increases growth hormone-releasing hormone (GHRH), GH, and somatomedine C (SMD-C) secretions. Therefore, we measured basal plasma GH and SMD-C concentrations and GH responses to GHRH stimulation to exclude that a downstream pathology of the somatotropic axis could obscure the significance of the results of the APO test. The response of prolactin (PRL) to APO inhibition were also measured. Basal plasma levels of GH, SMD-C, and PRL, GH responses to GHRH stimulation, and PRL responses to APO inhibition did not differ in the two groups of subjects. GH responses to APO stimulation were blunted in obsessive-compulsive (OC) patients. The emetic response to the same stimulation was stronger in patients than in controls. These responses suggest that in our OC patients there is a dysregulation of the dopaminergic system, which is possibly expressed in different ways in the various areas of the central nervous system.

The 35% CO2 challenge test in patients with social phobia.

Panic disorder (PD) and social phobia (SP) share many clinical, demographic and biological characteristics. To investigate the relationships between the two disorders, the responses to inhalation of a 35% carbon-dioxide (CO2) and 65% oxygen (O2) gas mixture were assessed. Sixteen patients with PD, 16 patients with SP, 13 patients with both SP and PD, seven patients with SP who experienced sporadic unexpected panic attacks and 16 healthy control subjects inhaled one vital capacity of 35% CO2 or compressed air. A double-blind, randomized, crossover design was used. PD patients and SP patients showed similar anxiogenic reactions to 35% CO2, both stronger than seen in control subjects. Patients with both disorders and SP patients with sporadic unexpected panic attacks reacted similarly to subjects with PD or SP alone. These results suggest that PD and SP share a common hypersensitivity to CO2 and thus might belong to the same spectrum of vulnerability.

Pharmacologic effect of imipramine, paroxetine, and sertraline on 35% carbon dioxide hypersensitivity in panic patients: a double-blind, random, placebo-controlled study.

The effects of short treatment (7 days) with the tricyclic antidepressant imipramine and the two selective serotonin reuptake inhibitors paroxetine and sertraline on the reactivity to inhalation of 35% CO2/65% O2 were compared in 70 panic patients who had positive responses to 35% CO2 inhalations. A double-blind, random, placebo-controlled design was applied. Each patient was given the 35% CO2 challenge on days 0 (before starting the treatment), 3, and 7. In the placebo group, there were no significant changes in the reactivity to 35% CO2 in the three sessions whereas there were significant similar reductions of reactivity to 35% CO2 in all three drug-treated groups. These results confirm the good reproducibility of 35% CO2 reactivity and the negligible effects of placebo on reactivity to CO2 and suggest that short treatments with imipramine, paroxetine, and sertraline decrease reactivity to 35% CO2, possibly as an expression of their antipanic properties.

Noradrenergic receptor sensitivity in obsessive-compulsive disorders: I. Growth hormone response to clonidine stimulation.

In 15 patients with obsessive-compulsive disorder (OCD) and in 15 healthy controls postsynaptic alpha-2-adrenoceptor sensitivity was examined by measuring the growth hormone (GH) response to growth hormone-releasing hormone (GHRH) and to clonidine stimulation. Basal values of GH and somatomedin-C (SMD-C) and mean GH responses to GHRH were the same in patients and controls, thus suggesting that a peripheral pathology of the somatotropic axis should not be present. GH responses to clonidine stimulation were blunted in patients suggesting that post-synaptic alpha-2-adrenoceptors are subsensitive, possibly due to higher than normal noradrenergic secretion.

Noradrenergic receptor sensitivity in obsessive compulsive disorder: II. Cortisol response to acute clonidine administration.

Sensitivity of pre-synaptic alpha-2- and post-synaptic alpha-1- and beta-adrenoceptors was investigated in 15 patients with obsessive-compulsive disorder (OCD) and in 15 age- and sex-matched healthy controls, by measuring cortisol responses to saline administration and to inhibition by clonidine (clon), a noradrenergic receptor agonist. Basal values of cortisol and responses to administration of saline and of clon were the same in patients and controls.

Panic attacks: a twin study.

The role of genetic factors in panic disorder (PD) and sporadic panic attacks (SPAs) was investigated. A total of 120 twins recruited from the general population were interviewed for the presence of anxiety disorders and SPAs. A significantly higher concordance among MZ than DZ twins was found for PD (73% vs. 0%) but not for SPAs (57% vs. 43%). These results confirm a significant role of genetic factors in PD but suggest that genetic factors might not be crucial for the development of SPAs.

Sensitivity to 35% CO2 in healthy first-degree relatives of patients with panic disorder.

OBJECTIVE: The authors tested the hypothesis that hyperreactivity to CO2 in healthy subjects represents an underlying familial vulnerability to panic disorder. METHOD: One vital-capacity inhalation of 35% CO2 and 65% O2 was administered to each of 84 patients with panic disorder, 23 healthy first-degree relatives of probands with panic disorder, and 44 healthy subjects with no family history of panic disorder. RESULTS: The first-degree relatives of the probands with panic disorder reacted significantly more than the healthy subjects and significantly less than the probands. CONCLUSIONS: These findings suggest an association between family history of panic disorder and hyperreactivity to 35% CO2 in healthy subjects.

Menstrual cycle-related sensitivity to 35% CO2 in panic patients.

In a double blind, random, cross-over design, 10 patients and seven controls inhaled one vital capacity of 35% CO2-65% O2 during their early-follicular and midluteal phases. Anxiety after CO2 intake was significantly stronger in the early-follicular phase than in the midluteal phase for patients. Controls had no anxiety reactions.

Laboratory response of patients with panic and obsessive-compulsive disorders to 35% CO2 challenges.

OBJECTIVE: The DSM-III-R anxiety disorders section includes both panic disorder and obsessive-compulsive disorder. To evaluate the relationship between these two disorders, subject responses to inhalation of a 35% CO2 and 65% O2 mixture were assessed. METHODS: Twenty-three patients with panic disorder, 23 with obsessive-compulsive disorder, 12 with both obsessive-compulsive and panic disorder, and 23 healthy comparison subjects were given a single vital capacity inhalation of 35% CO2 and 65% O2 or a placebo mixture of compressed air. A double-blind, random, crossover design was used. RESULTS: Patients with panic disorder and patients with both panic disorder and obsessive-compulsive disorder showed similar strong anxiogenic reactions to 35% CO2; while patients with obsessive-compulsive disorder alone did not differ from comparison subjects. CONCLUSIONS: These results confirm that obsessive-compulsive disorder and panic disorder are two distinct syndromes and that patients with these disorders have different sensitivity to CO2 inhalation.

Alpha 2-adrenergic receptor sensitivity in panic disorder: II. Cortisol response to clonidine stimulation in panic disorder.

The cortisol responses to acute administration of saline and of clonidine (Clon), 150 micrograms IV, were examined in 12 patients with panic disorder and agoraphobia, before and after 32 days of alprazolam therapy (2.5 mg/day), and in 12 normal controls. The responses in the Clon test corrected for the responses to saline differed in the two groups, and in patients were not changed by the therapy even though significant symptomatological improvement was achieved. The results suggest that presynaptic alpha 2- or postsynaptic alpha 1-beta-adrenoceptor sensitivity is impaired in panic disorder.

Pharmacologic effect of toloxatone on reactivity to the 35% carbon dioxide challenge: a single-blind, random, placebo-controlled study.

The effect of a short treatment (7 days) with the reversible monoamine oxidase type A inhibitor toloxatone on the reactivity to the inhalation of 35% CO2 was evaluated in 18 panic patients who responded to 35% CO2 inhalation with panic before treatment. A single-blind, placebo-controlled design was applied. Panic patients were randomly assigned to the toloxatone (N = 10) or placebo (N = 8) groups and were given the 35% CO2 challenge on days 1 (before starting the treatment), 3, and 7. Patients on placebo did not report any significant changes in their reactivity to 35% CO2 during the three sessions, whereas patients on toloxatone reported a significant attenuation of the reactivity on day 7. These results indicate that (1) anxiety provoked by the inhalation of 35% CO2 is reproducible; (2) placebo has a negligible effect on 35% CO2 reactivity; and (3) reactivity to 35% CO2 is significantly attenuated by short treatment with toloxatone, possibly related to its antipanic activity.

Carbon dioxide/oxygen challenge test in panic disorder.

The effects of a single inhalation of a 35% CO2/65% O2 gas mixture were examined in 71 patients with panic disorder with or without agoraphobia and 44 normal control subjects. Compared with the placebo condition, inhalation of air, the CO2/O2 mixture elicited a clear anxiety reaction only in panic disorder patients, who experienced a sudden rise of subjective anxiety as well as of several panic symptoms. Respiratory symptoms and the fear of dying best distinguished the patients from the control subjects. Baseline anxiety was not the key factor in explaining this differential reaction. The clinical features of panic disorder (namely, frequency of panic attacks, agoraphobia, anticipatory anxiety, and duration of illness) were not significantly related to the response to the challenge test, suggesting that CO2 reactivity might be a trait marker of panic disorder.