Biomedical subjects
Publications and source records attributed to M R Liebowitz.
In an open trial, five of eight panic disorder patients and none of five control subjects panicked after inhalation of two breaths of 35% CO2 and 65% O2; none panicked after placebo. Using 35% CO2 to induce panic is safe, simple, and well tolerated and may provide a valuable laboratory model of panic.
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In the last decade anxiety disorders have been the focus of intensive research in the psychiatric community, resulting in a rapid growth in our understanding of these illnesses. Diagnostic, biological, and psychopharmacological investigations have revealed important distinctions among these disorders which enable the clinician to make well-informed therapeutic choices and frequently ameliorate or even eliminate anxiety symptoms and related phobic behaviour. The principles of treatment can be simply stated: 1. Careful diagnostic evaluation through history and exclusion of medical and psychiatric conditions which mimic anxiety disorders. 2. Treatment selection based on diagnosis and formulation with the patient of the goals and expected outcome of pharmacotherapy. 3. Systematic application of each drug treatment in sufficient dosage and for an adequate duration permitting progression to the next agent when results are not optimal. 4. Addition of non-pharmacological interventions, usually behavioural therapy, to decrease phobic behaviour. 5. Development of a maintenance or discontinuation strategy tailored to the needs of the patient.
Fluoxetine is a new antidepressant with pharmacologic effects apparently limited to blockade of neuronal serotonin reuptake. We entered 20 patients who met DSM-III criteria for either panic disorder or agoraphobia with panic attacks into an open, uncontrolled pilot study of fluoxetine. Four responded to placebo in the week before fluoxetine administration and were dropped from the study. Of the remaining 16 patients, nine were nonresponders and seven were responders, with complete cessation of their panic attacks. Eight of the nine nonresponders were unable to tolerate the side effects of fluoxetine. In contrast, all of the responders (and one nonresponder) experienced minimal side effects. Fluoxetine may be effective in the treatment of panic attacks, perhaps implicating the serotonergic system in the pathophysiology of panic disorder. Future studies should use very low doses of fluoxetine to initiate treatment.
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Alkalosis is prominent among the many physiologic and biochemical effects of sodium lactate infusion. Though this is partially due to the conversion of lactate to bicarbonate, the metabolic component, it may also be secondary to hyperventilation before and during the infusion, the respiratory component. We analyzed pH, carbon dioxide pressure, bicarbonate, and inorganic phosphate from patients with panic disorder and agoraphobia with panic attacks and from normal controls both before and during lactate infusion. Our findings extend earlier work demonstrating that many such patients are chronic hyperventilators. Both metabolic and respiratory alkalosis develop in all subjects during lactate infusion, but only hyperventilation-induced hypocapnia differentiates patients at the point of lactate-induced panic from nonpanicking patients and normal controls. Finally, low inorganic phosphate levels at baseline appear associated with patients who will panic during the subsequent lactate infusion. This last unexpected finding may reflect hyperventilation or an abnormality in intracellular glycolysis.
Forty-three patients with panic disorder or agoraphobia with panic attacks and 20 control subjects received 0.5 M racemic sodium lactate intravenous infusions, single-blind as to duration and sequence. During the procedure, pulse; blood pressure; blood L-lactate and pyruvate; plasma ionized calcium, phosphate, prolactin, epinephrine, norepinephrine, and cortisol levels; and venous PCO2, pH, and bicarbonate were measured in an attempt to clarify the mechanism of lactate-induced panic attacks. During the infusion, 72% of the patients but none of the control subjects had panic attacks. The laboratory findings suggest that peripheral catecholamine surge is not the mechanism by which lactate causes panic, although elevated epinephrine may be a predisposing factor. Heightened central noradrenergic activity was present in many but not all of the attacks. Contrary to previous hypotheses, neither depression of ionized calcium nor induction of metabolic alkalosis appears sufficient to cause panic during lactate infusion.
An open clinical trial of alprazolam therapy of patients with panic disorder or agoraphobia with panic attacks was undertaken to clarify certain issues not resolved by previous studies. These included the proportion of patients who significantly improve with alprazolam; the relative time courses for improvement in panic attacks, anticipatory anxiety, and phobic avoidance; whether successful alprazolam treatment alters vulnerability to panic with sodium lactate infusion; and what factors predict response to alprazolam in panic patients. Thirty patients meeting DSM-III criteria for panic disorder or agoraphobia with panic attacks completed a 12-week open clinical trial, and 22 were considered responders. In responders, panic attacks showed rapid improvement, whereas improvement of anticipatory anxiety and phobic avoidance was more variable. Successful alprazolam therapy appeared to block lactate vulnerability. High pretreatment Hamilton Anxiety Scale scores were associated with poor treatment response. The data suggest that alprazolam is an effective treatment for panic disorder and agoraphobia with panic attacks, and acts by directly blocking panic attacks.
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Phenelzine was administered to 11 patients meeting DSM-III criteria for social phobia in open clinical trials. Seven of 11 showed marked improvement, while the remaining four experienced moderate benefit. These findings, which require replication in controlled trials, suggest that in addition to other actions, phenelzine has a direct effect in reducing interpersonal hypersensitivity.
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Thirty-one of 43 patients with panic disorder or agoraphobia with panic attacks and none of 20 normal controls panicked in response to infusions of sodium lactate. Before receiving lactate, patients showed higher heart rates than controls and also signs of hyperventilation. During lactate infusion, patients who did not panic, nevertheless, developed higher lactate and pyruvate levels and greater ionized calcium and pH changes than controls. Lactate-induced panic attacks were regularly accompanied by biological changes consistent with hyperventilation and central noradrenergic activation and irregularly by elevation of plasma norepinephrine and cortisol levels. Panic attacks were not associated with changes in epinephrine or calcium levels or pH. Baseline arousal increased the likelihood of panic during lactate infusion. It is hypothesized that lactate-induced panic primarily involves central noradrenergic discharge with inconsistent peripheral manifestations.
While other anxiety disorders have recently become the subjects of increasing investigation, social phobia remains, except among behavior therapists, relatively unstudied. As a result, major uncertainties exist concerning classification, prevalence, severity, etiology, assessment, and treatment of social phobia. Existing findings do suggest that in its own right and as a comparison for other anxiety disorders, social phobia should prove a fertile area for psychobiological and clinical investigation.
An algorithm for transcribing Research Diagnostic Criteria diagnoses for depressive disorders to similar categories in the DSM-III was applied to 103 depressed outpatients previously diagnosed by Research Diagnostic Criteria. All had Hamilton Depression Rating Scale scores of 18 or less. Among 64 patients completing a six-week, double-blind study comparing desipramine hydrochloride with placebo, desipramine was significantly more effective than placebo in patients with DSM-III major depression but not in those with dysthymic disorder. Among patients with major depression, a significant drug-placebo response difference was demonstrated even in those without melancholia. These findings support the clinical usefulness of the DSM-III in the treatment of depressed outpatients. Independent of DSM-III diagnosis, however, evidence of panic attacks seemed to identify patients who benefited from desipramine therapy. This suggests that the DSM-III hierarchy, which excludes consideration of panic in patients with major depression, may require revision.
To examine the biochemical effects of 10-30 mg/day L-deprenyl, measurement of 24-hr urinary output of phenylethylamine (PEA), 3-methoxy 4-hydroxy phenylethyleneglycol (MHPG), and L-deprenyl's amphetamine metabolites were carried out before and during the treatment of atypical depressives. Platelet monoamine oxidase (MAO) activity was also assessed. With L-deprenyl 10-30 mg/day, the expected MAO B inhibition occurred, as indicated by significant increase in urinary PEA excretion and virtual disappearance of platelet MAO activity. Twenty-five to 33% of the daily dose of L-deprenyl was recovered as urinary methamphetamine or amphetamine. Excretion of MHPG was significantly decreased with L-deprenyl 10-20 mg/day. Overall, the results suggest that L-deprenyl's antidepressant effects are mediated by some mechanism other than, or in addition to, MAO B inhibition.
Preliminary reports have indicated that platelet monoamine oxidase (MAO) activity is elevated in patients with anxiety disorder. We compared MAO activity in 20 drug-free patients with panic disorder with 20 age- and sex-matched normal controls. MAO activity in patients was significantly higher than in normals. MAO activity was not correlated with age or plasma catecholamine levels. The authors speculate about the possible significance of elevated MAO activity in patients with panic disorder.
Sodium lactate precipitates panic in 70-100% of clinically ill patients with panic disorders. The lactate vulnerability of remitted patients is unknown. In this study, 13 panic patients completed three sequential sodium lactate infusions: one before treatment, a second when panic free on tricyclic antidepressants (TCA), and a third when in remission and unmedicated for 1 to 6 months. Three out of 13 patients panicked at the third infusion as compared to 0/13 infused on TCA and 7/12 at pretreatment infusion. This result (1) indicates that lactate vulnerability can exist in clinically well, unmedicated patients, and (2) raises the possibility that lactate vulnerability may be a trait characteristic. Further studies are needed before definite conclusions can be drawn.
Recent evidence suggests that hyperventilation may be associated with spontaneous panic attacks in patients with panic disorder. This is reflected in abnormal patterns of blood gas and blood pH levels in these patients. In this study, absolute levels and variances of pH, pCO2, and bicarbonate were compared between controlled patients before and after successful pharmacological treatment. The results indicate that successful treatment of panic disorder results in a normalization of pH, pCO2, and bicarbonate levels.