Search

OBJECTIVE: Epidemiologic surveys have found that the incidence and prevalence of panic disorder decline in later life. The goal of this study was to determine whether aging has an effect on healthy subjects' responses to the panicogenic agent cholecystokinin tetrapeptide (CCK-4). METHOD: The study used a double-blind, placebo-controlled design: 40 subjects 20–35 years old and 40 subjects 65 years old or older were randomly assigned to receive an intravenous bolus of either 50 µg of CCK-4 or normal saline. RESULTS: When given CCK-4, older subjects had significantly fewer and less intense symptoms of panic, shorter duration of symptoms, and less of an increase in heart rate than did younger subjects. CONCLUSIONS: This study found an age-related change in responsiveness to CCK-4. Further research to delineate the mechanism of this change is warranted. (Am J Psychiatry 1998; 155:283–285)

BackgroundLipids appear to mediate depressive vulnerability in the elderly, however, sex differences and genetic vulnerability have not been taken into account in previous prospective studies.MethodsDepression was assessed in a population of 1040 women and 752 men aged 65 years and over at baseline and after 7-year follow-up. Clinical level of depression (DEP) was defined as having either a score of 16 and above on the Centre for Epidemiology Studies Depression scale or a diagnosis of current major depression on the Mini International Neuropsychiatric Interview. Lipid levels, apolipoprotein E and serotonin transporter linked promoter region (5-HTTLPR) genotypes were evaluated at baseline.ResultsMultivariate analyses adjusted by socio-demographic and behavioral variables, measures of physical health including ischemic pathologies, and genetic vulnerability indicated gender-specific associations between dyslipidemia and DEP, independent of the use of lipid lowering agents or apolipoprotein E status. Men with low LDL-cholesterol levels had twice the risk of prevalent and incident DEP whereas in women low HDL-cholesterol levels were found to be significantly associated with increased prevalent DEP (OR = 1.5) only. A significant interaction was observed between low LDL-cholesterol and 5-HTTLPR genotype, men with s/s or s/l genotype being at increased risk of DEP (OR = 6.0 and 2.7, respectively). No significant gene-environment interaction was observed for women.ConclusionsDEP is associated with higher atherogenic risk in women (low HDL-cholesterol), whereas the reverse is observed in men (low LDL-cholesterol). Late-life depression may have a complex gender-specific etiology involving genetic vulnerability in men.

Even if schizophrenia is known to affect social interaction, reasons of such impairment remain unclear. Social motor coordination has been suggested as being an important embodiment of healthy social exchanges. Therefore, we examined whether social motor coordination is affected by schizophrenia. Investigating patients unintentionally and intentionally coordinated with control participants, we found that schizophrenia decreased intentional but not unintentional coordination. A model is proposed to describe and understand such impairments.

Obsessive compulsive-disorder (OCD) is a group of highly debilitating condition characterized by intrusive troubling thoughts, repetitive, compulsive behaviors or mental rituals. A notable percentage of patients are refractory to pharmacological treatment and cognitive behaviour therapy. Increasing attention has been paid to the efficacy of Deep Brain Stimulation (DBS) therapies in alleviating pharmacoresistant psychiatric disorders including OCD.ObjectivesThe aim of this prospective study was to determine the efficacy of DBS using several targets in a pharmacoresistant OCD population with heterogeneous symptoms.MethodsFive patients (3 males) have been included in the study. Patients were classified according to their prominent features as follows: contamination/cleaning, symmetry/checking, exactness/counting and forbidden thoughts.The entire surgical procedure was performed under general anaesthesia. Direct targeting based on stereotactic MRI without microelectrode recordings was done. A combination of two of the following targets was simultaneously implanted for all patients: subthalamic nucleus, accumbens nucleus and bed nucleus of stria terminalis, limbic globus pallidus internus.Patients were assessed pre-and postoperatively using the Yale-Brown Obsessive Compulsive Scale.ResultsMean age at surgery was of 42.6±12.68 years. Mean follow-up with DBS was of 21±14.88 months.Mean preoperative Y-BOCS scores was 31.6±2.70 and of 11±7.97 (p=0,057, Wilcoxon signed Rank test).ConclusionSubthalamic nucleus and accumbens nucleus targets seem to be comparable in alleviating several subtypes of compulsions (checking, cleaning, counting) as well as obsessions. Further investigations are required to assess the role of limbic globus pallidus in improving pharmacoresitant OCD. Implanted system was well accepted without triggering new obsessions.

PurposeThis randomised, double-blind fixed-dose study compared the efficacy of escitalopram and paroxetine in the long-term treatment of patients with severe MDD.Methods:Patients with DSM-IV-defined MDD and baseline Montgomery-Asberg Depression Rating Scale (MADRS ≥30) were randomised in a 1:1 ratio to 24 weeks of double-blind treatment with either escitalopram (20mg) or paroxetine (40mg). The primary analysis of efficacy was an analysis of covariance of change from baseline to Week 24 in MADRS total score using the last observation carried forward (LOCF) method.Results:At endpoint (24 weeks), the mean change from baseline in total MADRS score was -25.2 for escitalopram-treated patients (n=228) and -23.1 for paroxetine-treated patients (n=223), a difference of 2.1 points (p

SummaryBehavioural changes have often been noted in patients with epilepsy. This study investigated the converse phenomenon—the occurrence of transient sensory, cognitive and affective changes resembling those described by epileptics, in affectively ill patients. Forty-four patients with affective illness, 37 with complex partial seizures, and 30 hypertensive controls were interviewed to determine the lifetime occurrence of these phenomena. Such symptoms occurred frequently in association with episodes of affective illness and epilepsy, but were rare in controls. Visual, auditory, olfactory and epigastric symptoms, illusions, jumbled thoughts and amnesia were common to both epilepsy and affective illness. Greater numbers of symptoms were associated with better response to lithium and tricyclic antidepressants. Transient sensory, cognitive, and affective phenomena may be more common in affective illness and other psychiatric conditions than is generally recognised, and may be clues to the underlying pathophysiology of these conditions.

Uhde, Thomas W., Jean-Philippe Boulenger, Peter P. Roy-Byrne, Macilla F. Geraci, Bernard J. Vittone, and Robert M. Post: Longitudinal course of panic disorder: clinical and biological considerations. Prog. Neuro-Psychopharmacol. & Biol. Psychiat. 1985, 9 (1); 39–51. 1. 1. The longitudinal course of panic disorder and its associated symptoms were investigated in thirty-eight patients. 2. 2. The temporal relationships among panic attacks, generalized anxiety, agoraphobia and depression are described. 3. 3. Similar and different biological alterations in the tricyclic-responsive disorders of primary depression and panic disorder are reviewed and discussed.

Electroencephalographic sleep recordings were compared in patients with panic disorder and normal controls. Correlation coefficients of standard sleep parameters versus ratings of anxiety, depression, and panic attack frequency were calculated in the panic-anxious patients. Overall findings are discussed in the context of previous sleep studies in patients with depressive, anxiety, and obsessive-compulsive disorders.

The effect of chronic caffeine treatment on three different binding sites in five brain areas of mice is characterized. The sites studied were the adenosine receptor, using [3H] diethylphenylxanthine, the benzodiazepine receptor, using [3H] diazepam and the adenosine uptake site, using [3H] nitrobenzylthioinosine. Significant increases were only observed in adenosine receptors with the greatest degree of change seen in the cerebellum and brain stem at both 16 and 23 days of caffeine treatment. The lack of significant effects of chronic caffeine on benzodiazepine receptors and adenosine uptake sites indicates that the caffeine effect is specific. The effect of chronic caffeine treatment on the ontogeny of adenosine receptors was also studied with the result showing a significantly accelerated development of the receptor in the caffeine treated animals. The adult adenosine receptor levels were 20-30% higher than those observed in control animals. The observed alterations in adenosine receptor number which occur as a consequence of caffeine consumption may underlie some of the behavioral effects of this cortical stimulant as well as provide insights concerning the mechanisms of tolerance to and dependence on caffeine.

The effects of two different kinds of stress (social and physical) on central adenosine receptors were investigated in mouse whole brain membranes using 1,3-diethyl-8-[3H]phenylxanthine ([3H]DPX) as a ligand. Chronic but not acute social stress induced an increase in the number of adenosine receptors similar to that induced by chronic, nontoxic doses of caffeine. Acute but not chronic social stress also induced an increase in the number of benzodiazepine receptors labeled by [3H]beta-carboline-3-carboxylate ethyl ester. The group submitted chronically to both stress and caffeine showed an increase in [3H]DPX binding relative to that found with either of these factors alone. The adenosine uptake site, labeled by [3H]nitrobenzylthioinosine, was not modified by either stress or caffeine administration.

The binding properties of N6-cyclohexyl [3H]adenosine ( [3H]CHA) and 1,3-diethyl-8-[3H]phenylxanthine ( [3H]DPX) in rat forebrain membrane are compared. The kinetic parameters of binding for each ligand are quite distinct, with [3H]CHA displaying two populations of binding sites (KD = 0.4 +/- 0.05 nM and 4.2 +/- 0.3 nM; Bmax = 159 +/- 17 and 326 +/- 21 fmol/mg protein), whereas [3H]DPX yielded monophasic Scatchard plots (KD = 13.9 +/- 1.1 nM; Bmax = 634 +/- 27 fmol/mg protein). The metals copper, zinc, and cadmium are potent inhibitors of [3H]CHA binding, with respective IC50 concentrations of 36 microM, 250 microM, and 70 microM. Copper is a much less potent inhibitor of [3H]DPX binding (IC50 = 350 microM). The inhibitory effect of copper on both [3H]CHA and [3H]DPX binding is apparently irreversible, as membranes pretreated with copper cannot be washed free of its inhibitory effect. The inhibitory effect of both copper and zinc on [3H]CHA binding was reversed by the guanine nucleotide Gpp(NH)p. [3H]DPX binding is only partially inhibited by zinc and cadmium (60% of specific binding remains unaffected), suggesting that this adenosine receptor ligand binds to two separate sites. Guanine nucleotides had no effect on the inhibition of [3H]DPX binding by either copper or zinc. Differential thermal and proteolytic denaturation profiles are also observed for [3H]CHA and [3H]DPX binding, with the former ligand binding site being more labile in both cases. Stereospecificity is observed in the inhibition of both [3H]CHA and [3H]DPX binding, with L-N-phenylisopropyladenosine (PIA) being 50-fold more potent than D-PIA in both cases. Evidence is therefore provided that adenosine receptor agonists and antagonists have markedly different binding properties to brain adenosine receptors.

Although several neurotransmitter systems have been implicated in the neurobiology of animal fear and human anxiety1, the focus of the present report in this regard is limited to the noradrenergic system. Several lines of evidence suggest an important role for noradrenergic function in the neurobiology of fear, anxiety, alarm and arousal (for review see Uhde et al.2,3). Redmond and Huang4 demonstrated that electrical and pharmacological activation of the noradrenergic nucleus locus coeruleus (LC) in the monkey produced fear behaviors similar to those occurring during exposure to natural threat in the wild. In addition to these behavioral manifestations of fear during LC activation, Redmond and colleagues4,5 documented temporally-related increases in the levels of noradrenaline and its metabolite, 3-methoxy-4-hydroxy-phenylethylene glycol (MHPG), in the brain, cerebrospinal fluid (CSF) and plasma.

The effects of caffeine on plasma adenosine were examined in eight healthy normal volunteers. Subjects were randomly administered on 4 separate days, in a double-blind fashion, either placebo or three different doses of caffeine (240, 480, and 720 mg). Adenosine concentrations, measured by high performance liquid chromatography, were in the micromolar range when samples were drawn into tubes containing dipyridamole to prevent adenosine reuptake by red blood cells. Plasma adenosine levels did not change after caffeine administration. The effects of caffeine on anxiety were related to changes in plasma caffeine but not plasma adenosine levels. The potential interest of caffeine as a chemical model of anxiety is discussed.

Much attention has been focused on the neurobiology of panic disorder. According to the DSM-III-R classification of panic disorders, panic attacks are given central importance in the genesis and maintenance of secondary complications such as agoraphobia, anticipatory anxiety, and, in a subgroup of patients, major depressive symptomatology. Given this perspective, it is important to understand the pathophysiology and biological correlates of “spontaneous” or “unprovoked” panic attacks.

The binding of various adenosine receptor ligands and of [3H]diazepam, as well as their inhibition of methylxanthines, have been studied in human brain cerebral cortex membranes. Caffeine and theophylline competitively inhibit binding of [3H]cyclohexyladenosine, [3H]diethylphenylxanthine, [3H]phenylisopropyladenosine and [3H]diazepam. Both caffeine and theophylline are more potent as inhibitors of adenosine receptor ligand binding compared to [3H]diazepam binding. Theophylline was more potent than caffeine in its ability to compete with adenosine receptor ligand binding while the reverse was true for [3H]diazepam binding. The meaning of these results for the mode of action of methylxantine is discussed.

The experiences of human fear and anxiety are discussed within the context of locus ceruleus function in animals. The rationale for studying correlates of noradrenergic function, such as 3-methoxy-4-hydroxyphenethylene glycol (MHPG), is reviewed, and data demonstrating a positive correlation between plasma free MHPG and state anxiety in normal volunteers is presented. The behavioral effects of oral caffeine (240-720 mg), intravenous clonidine (2 micrograms/kg), and oral yohimbine (20 mg) were studied in various psychiatric patients and normal volunteers. Caffeine and yohimbine had anxiogenic properties; conversely, clonidine reduced self-rated measures of anxiety across a wide spectrum of psychiatric conditions. These findings expand previous research indicating that noradrenergic hyperactivity may be associated with many types of human fear and anxiety.

• The results of a caffeine consumption inventory indicated that patients with panic anxiety disorder, but not affectively ill patients or normal controls, had levels of self-rated anxiety and depression that correlated with their degree of caffeine consumption. In addition, this self-report survey suggested that patients with panic disorder had an increased sensitivity to the effects of one cup of coffee. This apparent sensitivity to caffeine was also documented by the observation that more patients with panic disorder reported the discontinuation of coffee intake due to untoward side effects than controls. These results, based on self-reports, suggest that the hypothesis that patients with panic disorder are more reactive to caffeine should be directly tested using caffeine challenges and that the mechanisms underlying caffeine's effects on anxiety should be further explored.

We evaluated the behavioral and physiologic effects of clonidine hydrochloride, a centrally active alpha 2-adrenergic agonist, in two separate studies of patients with panic disorder. In the first study, intravenous clonidine (2 micrograms/kg) and placebo were administered on a blind basis to 12 patients with panic disorder and ten normal controls. Clonidine produced significantly greater decrements in anxiety at one hour in the patients with panic disorder than in the controls. The changes in pulse, blood pressure, and ratings of sleepiness did not differ significantly between patients and controls. In the second study, oral clonidine was administered to 18 patients in a double-blind, flexible-dose treatment trial averaging ten weeks in duration. While anxiolytic effects were noticed in some patients, these effects did not persist in the group as a whole. These two studies indicate that while clonidine has short-term anxiolytic effects in patients with panic disorder, these effects do not persist with long-term administration in most patients.

Publisher Summary A number of observations made over the past two decades have shown adenosine in cerebral systems to have properties consistent with those of neurohumoral agents. Specifically, these include (1) calcium ion (Ca2+)-dependent release of adenosine from nerve endings, (2) inactivation of the released adenosine by re-uptake or metabolism by adenosine deaminase, and (3) potent depressant effects on the release of various neurotransmitters, neuronal activity, and animal activity. In peripheral systems, adenosine is involved in a variety of metabolic processes that include lipolysis and muscle function. This chapter reviews recent developments regarding the role of adenosine as a neuromodulator. A number of observations suggest that adenosine may play a role in the antidepressant activity of tricyclic antidepressants and electroconvulsive treatment. The chapter also reviews recent advances in the characterization of the adenosine receptor and the methods required for its study.

[3H]imipramine binding to platelets was measured in 17 drug-free panic disorder patients and 14 healthy controls. No difference in Bmaxor Kdvalues was found between the two groups. Patients with a past history of major melancholic depression or severe agoraphobia had similar binding parameters as panic disorder patients without a history of depression or severe agoraphobia. The authors acknowledge Manila Geraci and Barbara Scupi for their ongoing scientific collaboration and thank Sue Rose and Patricia Hafer for their secretarial assistance in the preparation of the manuscript.

Striatal D2 dopaminergic receptors of 12 drug-free schizophrenic patients and 12 normal subjects were investigated with positron emission tomography and [76Br]bromospiperone. Patients were classified according to DSM-III criteria, and their clinical symptoms were rated according to Andreasen's negative and positive symptom scales. The ratio of striatal to cerebellar radioactivity was taken as an index of striatal D2 dopamine receptor density. There was no significant difference between the control subjects and the overall schizophrenic group and no significant relationship between this index and the symptom ratings. However, state-dependent variables could partly account for the striatal D2 receptor density variability.