Response to sodium lactate infusion in alcoholics with panic attacks

The authors studied the response to sodium lactate infusion of 12 alcoholics with a history of panic attacks, 10 alcoholics without a history of panic attacks, and 16 nonalcoholic patients with panic disorder. The rate of lactate-induced panic was significantly higher in alcoholics with panic attacks than in alcoholics without panic attacks. Alcoholics with panic attacks were similar to nonalcoholic patients with panic disorder in their response to lactate. These findings support the specificity of lactate-induced panic for panic states and suggest that panic attacks in alcoholics resemble those in nonalcoholics. Lactate infusion may prove useful in the diagnosis of panic disorder in alcoholics.     

A laboratory procedure for the induction of flashbacks

The authors administered infusions of lactate intravenously to seven patients with a DSM-III diagnosis of posttraumatic stress disorder, six of whom also met DSM-III criteria for panic disorder. The lactate infusions resulted in flashbacks in all seven patients and panic attacks in six patients. The authors conclude that with further development intravenous lactate infusion may be used to study flashbacks and other dissociative phenomena and to determine the relationship between flashbacks and panic anxiety.     

Clinical characteristics and response to sodium lactate of patients with infrequent panic attacks

Nine patients with panic attacks too infrequent to meet DSM-III criteria for panic disorder were compared to 20 panic disorder patients with respect to clinical characteristics and response to sodium lactate infusion. The two groups showed similar clinical characteristics and response to lactate. The authors conclude that patients with infrequent panic attacks are clinically and biologically similar to those with panic disorder and discuss implications for the diagnosis of panic states.     

Response to lactate infusion in generalized anxiety disorder

Intravenous sodium lactate infusion provokes symptoms of panic in patients with panic disorder at a significantly higher rate than in normal controls. Lactate sensitivity has been postulated to be specific for patients with panic attacks regardless of frequency of attacks or coexisting diagnoses. The authors present results of a pilot study of lactate infusions in patients with generalized anxiety disorder (GAD) without any history of panic attacks. Patients with GAD reacted more like panic disorder patients than like normal controls in anxiety and symptom scores during lactate infusion and in the rate of positive responses to lactate. Although preliminary, these findings raise questions regarding the specificity of lactate sensitivity and the relationship of GAD to panic disorder.     

Nonfearful panic disorder in neurology patients validated by lactate challenge

OBJECTIVE: Nonfearful panic disorder meets the DSM-III-R criteria for panic disorder but is not associated with subjective fear and anxiety. The authors determined its prevalence in a group of neurology patients and assessed its diagnostic validity as a panic disorder subtype by evaluating the response of the patients with nonfearful panic disorder to sodium lactate and antipanic pharmacotherapy. METHOD: The subjects were all neurology patients referred over 1 year to a university hospital's psychiatric consultation service because of negative medical workups for their symptoms (N = 48). Patients who met the DSM-III-R criteria for panic disorder but did not report subjective anxiety or fear during panic episodes were diagnosed as having nonfearful panic disorder. Afterward, each of those patients received a sodium lactate infusion and, 5 hours later, a sodium chloride infusion. They were then treated with antipanic medication and followed for at least 6 months. RESULTS: Of the 48 neurology patients referred for psychiatric evaluation, 11 (23%) met the criteria for panic disorder, and all 11 met the criteria for nonfearful panic disorder. All 11 responded positively to lactate but not to placebo, and they each experienced an at least 75% reduction in symptoms during the 6-month follow-up period. Detailed case reports of three of these patients are presented. CONCLUSIONS: These findings support the construct and predictive diagnostic validity of nonfearful panic disorder as a subtype of panic disorder and suggest that a lack of attention to this group leads to both the underestimation of the prevalence of panic disorder and to the withholding of potentially successful treatments for this group.     

Lactate infusions in major depression without panic attacks

Sodium lactate infusion provokes panic attacks in panic disorder patients but not in normal controls. We have previously shown that patients who develop panic disorder during a major depressive episode are similar to panic disorder patients in their rate of panic attacks with lactate. In the present pilot study, nine patients with major depression without panic attacks underwent lactate infusions. These patients differed significantly from panic disorder patients but not from controls in their response to lactate. This argues for the specificity of lactate sensitivity for the phenomenon of panic attacks and gives further evidence for biological differences between panic and depression.     

Elevated brain lactate responses to neural activation in panic disorder: a dynamic 1H-MRS study

Converging evidence suggests that patients with panic disorder have a metabolic disturbance that may influence the regulation of arousal systems and confer vulnerability to 'spontaneous' panic attacks. The consistent finding of elevated brain lactate responses to various metabolic challenges in panic disorder appears to support this model, although the mechanism of this effect is not understood. Several mechanisms have been proposed to account for elevated brain lactate responses in panic disorder, including (1) brain hypoxia due to excessive cerebral vasoconstriction, and (2) a metabolic disturbance affecting lactate metabolism. Recent studies have shown that neural activation (for example, sensory stimulation) causes local lactate accumulation in the presence of increased oxygen availability. The current study used proton magnetic resonance spectroscopic measures of visual cortex lactate changes during visual stimulation in 15 untreated patients with panic disorder and 15 matched volunteers to critically test these two proposed mechanisms of elevated brain lactate responses in panic disorder. Visual cortex lactate/N-acetylaspartate increased during visual stimulation in both groups. The increase was significantly greater in the panic patients than in the comparison group. There were no group differences in end-tidal pCO(2). The finding that visual stimulation leads to significantly greater visual cortex lactate responses in panic patients is not predicted by the hypoxia model. These results suggest that a metabolic disturbance affecting the production or clearance of lactate is the cause of the elevated brain lactate responses consistently observed in panic disorder and provide further support for metabolic models of vulnerability to this illness.     

Lactate- and isoproterenol-induced panic attacks in panic disorder patients and controls

In a double-blind study using sodium lactate and isoproterenol infusions to provoke panic attacks, 73 of 86 panic disorder patients and 10 of 45 controls panicked with lactate, and 58 of 86 patients and 4 of 45 controls panicked with isoproterenol. We measured baseline and peak anxiety ratings in 10 controls with lactate-induced panic attacks, 31 controls who did not panic during lactate infusions, and 63 panic disorder patients who did panic during lactate infusions. The controls who panicked with lactate had robust increases in their anxiety ratings very similar to the increases experienced by patients who panicked with lactate.     

The diagnostic utility of lactate sensitivity in panic disorder

Lactate infusion is the most extensively studied of the pharmacological challenge tests in panic disorder. We assessed the value of this test in the diagnosis and subtyping of panic in clinical and research settings. Analysis of lactate infusion studies to date suggests that patients with panic attacks are significantly more sensitive to lactate than are healthy controls or patients with other psychiatric disorders without panic attacks. However, the usefulness of lactate infusion is limited by the lack of standardized, objective criteria for lactate-induced panic and uncertainty as to the sensitivity and specificity of the test for current, clinically significant panic attacks. Except in rare cases, the clinical history is likely to be of more value than lactate response in diagnosing panic disorder. Determination of the role of the test in subtyping patients with panic disorder awaits further study of the diagnostic, prognostic, genetic, and pathophysiologic significance of lactate sensitivity.     

Response to sodium lactate in panic disorder: relationship to presenting clinical variables

Sodium lactate infusion provokes more physiological and psychological symptoms of panic in patients with panic attacks than in normal controls. The relationship between response to sodium lactate infusion and presenting clinical characteristics was examined in 50 patients with panic disorder or agoraphobia with panic attacks. Lactate-induced panic was significantly related only to a patient-reported family history of panic. Rating of physical symptoms during lactate infusion, but not overall response to lactate, was significantly correlated with Symptom Checklist-90 somatization scores. In general, lactate response does not identify clinically distinct subpopulations of patients with panic disorder.     

Elevated serum lactate following hyperventilation during glucose infusion in panic disorder

Early investigators reported that patients with anxiety syndromes associated with panic attacks produced more lactate during exercise than control subjects. These studies suggested a metabolic difference between patients and controls. However, the possibility that patients were simply less fit than controls could not be excluded. In this study, serum lactate was measured in panic disorder patients in response to a metabolic challenge not involving exercise. Voluntary hyperventilation during iatrogenic hyperglycemia led to an increase in serum lactate. The increase in serum lactate was significantly greater in panic disorder patients than in controls. Hyperventilation provoked panic attacks in 4 of 8 patients and none in 6 controls. There was no evidence of a relationship between the increase in lactate or the associated decrease in phosphate and the level of anxiety produced by this procedure.     

Increased response to a putative panicogenic nocebo administration in female patients with panic disorder

Experimental challenge studies may generate and test hypotheses regarding the pathophysiology of panic disorder and may serve to identify pathophysiologically relevant subtypes. It has been suggested that gender-related differences may be relevant in the development and maintenance of panic disorder. In a randomized double blind design the effects of placebo and sodium lactate administration in 14 female and 16 male patients with panic disorder and 23 healthy control subjects were compared using the Acute Panic Inventory (API) score and derived formal criteria for a panic attack. Panic attack frequency following sodium lactate was 76.6% in the patient group. Although control subjects had a lacate-induced increase in the API score as well, this effect was much weaker. No panic attacks occurred in patients with panic disorder or healthy control subjects receiving a placebo. However, a gender effect was observed in the putative panicogenic placebo condition: female patients with panic disorder had more subthreshold panic anxiety as measured with the API score. The data give evidence for an increased nocebo response in female patients with panic disorder.     

Lactate infusions in obsessive-compulsive disorder

Panic attacks followed sodium lactate infusions in one of seven patients with obsessive-compulsive disorder and 26 of 48 patients with panic disorder or agoraphobia with panic attacks. This suggests that lactate-induced panic is specific to the latter groups.     

Elevated serum lactate associated with panic attacks induced by hyperventilation.

Several lines of evidence suggest that lactate metabolism may be altered in panic disorder. We recently reported exaggerated increases in serum lactate in panic patients following hyperventilation during glucose infusion. In the current study, lactate metabolism was stimulated by hyperventilation following glucose ingestion in 12 panic patients and 12 controls. The seven patients who panicked during hyperventilation exhibited larger increases in serum lactate levels than nonpanicking patients or controls. The lactate response was significantly correlated with peak ratings of anxiety and panic symptoms, but not correlated with insulin or cortisol levels, heart rate, pCO2, adiposity, exercise habits, or diet. Hyperventilation-induced panic appears to be associated with metabolic changes leading to elevated serum lactate.     

Vasopressin response to lactate infusion in normals and patients with panic disorder

Infusions of sodium lactate evoke panic symptoms in patients with panic disorder but not in normal subjects. Although plasma vasopressin (AVP) is known to rise in response to other forms of stress, its response during this maneuver has not previously been reported. We measured plasma AVP in double-blind infusions of sodium lactate in 5 normal subjects, 6 patients with panic disorder, and, again in 4 patients after chronic alprazolam. In all groups administered lactate, AVP rose significantly above baseline values (p less than 0.05) though no change was seen in a control group of patients during D5NS infusion. No difference in AVP response to lactate was apparent between untreated patients (who experienced panic) and normals or chronically treated patients (who had minimal symptoms). Thus, the presence of panic symptoms induced by lactate is insufficient to provoke an abnormal pattern of AVP release.     

Phenomenological comparison of dextrose, lactate, and isoproterenol associated panic attacks

To investigate the relationship between naturally occurring and drug-induced panic attacks, we compared the phenomenology of panic attacks in 12 panic disorder patients who panicked during both placebo and lactate infusion and in 9 panic disorder patients who panicked during both placebo and isoproterenol infusions. Panic attacks during lactate and isoproterenol infusions were similar to the panic attacks during placebo infusions.     

Ventilatory physiology of patients with panic disorder

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.     

Vulnerability to sodium lactate in panic disorder patients given cognitive-behavioral therapy

Six patients with panic disorder who had panicked during sodium lactate infusion were given cognitive-behavioral treatment for 12-24 weeks. After treatment they underwent another lactate infusion, and four patients were rates as having no panic, suggesting that reduced vulnerability to lactate accompanies remission of panic. Controlled trials of cognitive-behavioral therapy and use of lactate infusion as a measure of remission are recommended.     

Behavioral biochemical and neuroendocrine concomitants of lactate-induced panic anxiety

In a single-blind study using sodium lactate infusions to provoke panic attacks, 11 of 15 patients with panic disorder panicked with lactate. None of the 15 control subjects panicked during lactate administration. Before receiving lactate, higher preinfusion anxiety levels were present in the patient group as compared to controls. Preinfusion Acute Panic Inventory (API) scores were significantly higher in patients who panicked compared to nonpanicking patients. In addition, patients who panicked during lactate infusion showed a higher mean plasma MHPG level at baseline. During lactate infusion, however, no increase in plasma MHPG was seen in patients who panicked, nor in nonpanickers and controls. Several other biochemical and hormonal variables were measured. No single biochemical or neuroendocrine variable was found to correlate with lactate-induced panic attacks. It is argued that the baseline arousal level of patients with panic disorder may be increased, which renders these patients more vulnerable to panic attacks.     

Experimental pathophysiology of panic

In this article, we review how the knowledge of the pathophysiology of panic disorder has expanded, with special emphasis on laboratory models using lactate and carbon dioxide challenges. Experiments in the late 1960s revealed that lactate infusion can induce panic attacks. A prominent feature of these attacks is hyperventilation. Because lactate infusion induces a metabolic alkalosis, one would rather expect a compensatory hypoventilation. For years hyperventilation was thought to be causally linked to panic, but it has since been proven to be a symptom rather than a cause of panic attacks. Similarly, it is not hypocapnia but hypercapnia that has proven to be capable of provoking panic attacks. Carbon dioxide challenges are comparable to lactate infusion in the degree to which they meet the criteria for an ideal model of panic disorder. Experiments with carbon dioxide in first-degree relatives of panic disorder patients and in monozygotic twins support the idea of a constitutional predisposition to panic disorder. Of the various other agents that have been used to trigger panic attacks, cholecystokinin seems particularly promising as a valid laboratory model of panic disorder and may provide valuable data regarding the mechanism of panic attacks. The false suffocation alarm theory, proposed by Klein, is an integrative hypothesis that may account for a large number of the laboratory as well as clinical observations.