Nottingham study of neurotic disorder.
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Biomedical subjects
Publications and source records attributed to D F Klein.
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Thirty-one patients with DSM-III panic disorder or agoraphobia with panic attacks, 13 normal controls, and 12 patients with other anxiety disorders were studied during ventilatory challenge with room air hyperventilation and 5% carbon dioxide inhalation. Patients also underwent sodium lactate infusion. Among the patients with panic disorder, 58% panicked with sodium lactate, 39% with 5% CO2, and 23% with room air hyperventilation. Of the other patients, four panicked with sodium lactate, none with 5% CO2, and one with room air hyperventilation. One normal control panicked with both sodium lactate and 5% CO2. Panic with CO2 was associated with an exaggerated ventilatory response and increases in plasma norepinephrine level and diastolic blood pressure. Patients with panic disorder may have hypersensitive CO2 receptors that, when triggered, evoke a subjective panic associated with an exaggerated ventilatory response and consequent hypocapnic alkalosis.
One hundred nineteen patients who met specific criteria for atypical depression completed six weeks of double-blind, randomly assigned treatment with phenelzine sulfate, imipramine hydrochloride, or placebo. The overall response rates were 71% with phenelzine, 50% with imipramine, and 28% with placebo. Phenelzine was widely superior to placebo and also showed superiority to imipramine. Phenelzine superiority appeared even greater after an additional six-week continuation phase. Imipramine was only moderately effective in this atypical depressive sample. Unexpectedly, the superiority of either phenelzine or imipramine to placebo was largely confined to patients in subsets of the study sample who were prospectively judged to also have a history of spontaneous panic attacks and/or show hysteroid dysphoric features. This is consonant with some but not other recent findings and requires replication. Overall, the concept of atypical depression as a subtype that is preferentially responsive to monoamine oxidase inhibitors is supported.
The effect of stimulants on growth has been controversial. Among hyperactive children receiving long-term methylphenidate hydrochloride treatment, we examined the effects of methylphenidate withdrawal on the growth of hyperactive children randomly assigned to be taken off, or remain on, the medication regimen over two consecutive summers. After one summer, no group difference in height was found, but weight was higher in the group that had been taken off methylphenidate therapy. In contrast, two summers of being off methylphenidate treatment had a significant positive effect on height but not on weight. The results document a linkage between exposure to methylphenidate and reduction in growth velocity. However, they do not address whether the medication has long-term effects on height.
Existing data suggests dramatic efficacy for all tested tricyclics in disorders involving spontaneous panic attacks; moderate efficacy for clomipramine but not other tricyclics in obsessive-compulsive patients; possible, but as yet not well established, tricyclic efficacy in generalized anxiety; and lack of efficacy in simple phobias. Further studies in all DSM-III Anxiety Disorders are both warranted and required to answer the nosological, pathophysiological and treatment questions raised by these findings.
Social functioning was assessed in 189 nonmelancholically depressed outpatients. Patients were then treated for 6 weeks in a double-blind trial of phenelzine, imipramine, or placebo and functioning was reassessed. Before treatment, younger, more severely depressed, more chronically depressed patients and those with a DSM-III diagnosis of major depression plus dysthymic disorder were more functionally impaired than patients without these characteristics. Chronically depressed patients who responded to treatment reported significantly improved functioning while nonresponders did not. These results suggest that for some chronically depressed patients, impaired functioning results at least partly from the Axis I mood disorder instead of being entirely attributable to Axis II character pathology.
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Forty-seven nonmelancholic depressed outpatients were infused with sodium lactate to explore the relationship between history of panic attacks and lactate-induced panic. Lactate panic was rated without knowledge of history of panic. Fifteen of 29 patients (52%) with a history of spontaneous panic experienced panic attacks in response to lactate. Only 1 of 18 patients (6%) without a history of spontaneous panic experienced a lactate-induced panic attack--a highly significant difference. The likelihood of lactate panic was related to frequency of spontaneous panic attacks. The implications of these findings for understanding the relationship of panic attacks and depression are discussed.
Patients present unique combinations of familial relationships, developmental idiosyncrasies, social aberrations, affective states, cognitive abilities, symptoms, defects, and maladaptations. Psychopharmacological treatments form a useful approach to cutting through this complexity to the core pathophysiology. Focusing on disorders that can be brought to complete remission by medication suggests that retarded and agitated depressions, manic and angry hyperactive paranoid states, panic disorder, emotionally unstable character disorders and schizophrenias are governed by the degree of derangement of an affective-activation control system. Defects in this control system are best conceptualized in cybernetic terms rather than in terms of the current rheostat models. Conceptualization of cybernetic defects allows for understanding of psychopathological developments as well as give a framework for pharmacological benefits. One aspect of the activation-affective disorders, are disorders of two types of pleasure regulatory mechanism, here referred to as appetitive and consummatory. The relationship of disorders of these hedonic control mechanisms to affective states and those of drug abuse are considered. This schema also affirms a close relationship between the bipolar affective disorders and the schizophrenias.
Sixty patients with probable atypical depression--defined as meeting Research Diagnostic Criteria for depressive illness, having reactive mood, and having one of four associated symptoms (hyperphagia, hypersomnolence, leaden feeling, and sensitivity to rejection)--took part in a study contrasting phenelzine, imipramine, and placebo. Phenelzine was found to be superior to imipramine and placebo. These results were compared to results from a sample of 120 patients with identical characteristics, except that they had more than one associated atypical symptom (full atypical syndrome). The size of the drug effect was comparable in patients with full atypical and partial atypical syndromes.
To assess the role of peripheral epinephrine in social anxiety, the authors infused 11 patients meeting DSM-III criteria for social phobia with intravenous epinephrine over 60 minutes. Although the mean plasma epinephrine level increased from 113 to 928 pg/ml, only one of the 11 patients experienced observable anxiety; this finding suggests that an increase in plasma epinephrine level alone is inadequate to cause social anxiety. Of the variables measured, only the average minute volume correlated with self-rated anxiety. Ventilatory indexes might be better correlates of subjective anxiety than other physiological variables.
Seven patients with schizophrenia and panic attacks all showed marked improvement of positive and negative schizophrenic symptoms when alprazolam was openly added to antipsychotic medication. Panic attacks may identify alprazolam-responsive schizophrenic patients and may define a distinct pathophysiologic subgroup.
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In 17 healthy young men who had a parent with documented early coronary disease, ratings of type A behaviour correlated with upregulated lymphocyte beta 2 receptor density and inversely with the ratio of platelet alpha 2 to lymphocyte beta 2 receptor density ratio. This indicates a correlation of type A behaviour with receptor-based determinations of increased peripheral alpha-adrenergic balance, consistent with increased coronary arterial vasoconstriction, perhaps leading to coronary artery disease.
We explored a causal sequence between panic and avoidance to provide recommendations for psychotherapy, pharmacotherapy, and their combination in treating agoraphobia. We produced a two-way [( imipramine hydrochloride vs placebo] by [office-based behavioral therapy vs in vivo exposure]) design by amalgamating two studies. We assessed agoraphobic patients for panic and avoidance at these time points: baseline (week 0), midcourse (week 13), and termination (week 26). The causal sequence model was tested by path analysis. Imipramine was superior to placebo in lowering panic and avoidance at both postbaseline time points. Exposure was superior to office-based treatment in lowering avoidance only at week 13. Exposure appeared to produce quicker improvement of avoidance than office-based therapy, but relapse occurred if this improvement was not supported by medication. Exposure did not benefit panic. We believe patients should be informed that imipramine is superior to exposure in inducing a panic-free state. Exposure without imipramine is of benefit only in reducing avoidance, but adding imipramine to exposure is necessary for panic control and substantially improves exposure and exposure maintenance.
Acute Panic Inventory (API) scores were obtained from 26 normal controls and 89 patients with either panic disorder or agoraphobia with panic attacks before and during lactate infusions. Retrospective ratings of the patients' usual spontaneous attacks were much higher, by API, than ratings of moments of severe stress by the controls. Point of panic API scores, as well as increments of panic scores over prelactate scores, were higher for patients who experienced lactate panics than for both controls and patients who did not panic.
In previous articles we have reported on the total Acute Panic Inventory (API) score during lactate-induced panic. Even patients with panic disorder who do not panic during lactate infusion have higher API scores during the infusion than normal controls. In this post hoc analysis, we wished to determine whether specific API items were more sensitive to the beneficial effects of antipanic medication, either at baseline or during the infusion, in these lactate-insensitive panic patients. Four of the 17 items showed specific drug blockade of baseline severity. Five additional items showed specific drug blockade of lactate exacerbation of symptom severity. Medication apparently had no effect on severity of the remaining eight items. We suggest that the nine symptoms that responded to drug therapy are associated with hyperventilation. The study indicates that antipanic drugs may have a specific effect in blunting hyperventilation.