Lactate-induced Panic Attacks Research Articles

Factors associated with the development of panic attack and panic disorder: Survey in the Japanese population

Environmental factors, in addition to genetic factors, may be related to the development of panic attack (PA) and panic disorder (PD). Previous studies suggested that there may be seasonal variation in the onset of PA/PD and possibly a higher prevalence of PA/PD in colder areas. Also observed were lactate-induced PA and elevated serum cholesterol in PD patients. These suggest that living environment and lifestyle, such as weather conditions, preference of food and physical exercise, might play a role in the occurrence of PA and PD. The present study explored the association of such candidate factors with the development of PA and PD in 4000 Japanese subjects, using a questionnaire. The subjects were recruited from the general population of Japan, using stratified random sampling. Logistic regression with stepwise selection of variables was employed for statistical analysis. Variables including "dislike of physical exercise", mostly in female subjects, and "living in areas with longer winter", in male subjects, were suggested for associations with PA and PD among the candidate factors. The result is preliminary but indicates that lifestyle such as like/dislike of physical exercise and environmental factors including weather conditions could play a partial role in the development of PA and PD. Further investigations are required before firm conclusions can be reached.

Stress responsive neurohormones in depression and anxiety.

Clinical and preclinical studies have gathered substantial evidence that stress response alterations play a major role in the development of major depression, panic disorder and posttraumatic stress disorder. The stress response, the hypothalamic pituitary adrenocortical (HPA) system and its modulation by CRH, corticosteroids and their receptors as well as the role of natriuretic peptides and neuroactive steroids are described. Examplarily, we review the role of the HPA system in major depression, panic disorder and posttraumatic stress disorder as well as its possible relevance for treatment. Impaired glucocorticoid receptor function in major depression is associated with an excessive release of neurohormones, like CRH to which a number of signs and symptoms characteristic of depression can be ascribed. In panic disorder, a role of central CRH in panic attacks has been suggested. Atrial natriuretic peptide (ANP) is causally involved in sodium lactate-induced panic attacks. Furthermore, preclinical and clinical data on its anxiolytic activity suggest that non-peptidergic ANP receptor ligands may be of potential use in the treatment of anxiety disorders. Recent data further suggest a role of 3alpha-reduced neuroactive steroids in major depression, panic attacks and panic disorder. Posttraumatic stress disorder is characterized by a peripheral hyporesponsive HPA-system and elevated CRH concentrations in CSF. This dissociation is probably related to an increased risk for this disorder. Antidepressants are effective both in depression and anxiety disorders and have major effects on the HPA-system, especially on glucocorticoid and mineralocorticoid receptors. Normalization of HPA-system abnormalities is a strong predictor of the clinical course, at least in major depression and panic disorder. CRH-R1 or glucorticoid receptor antagonists and ANP receptor agonists are currently being studied and may provide future treatment options more closely related to the pathophysiology of the disorders.

The neuroendocrinology of stress and the pathophysiology and therapy of depression and anxiety

Clinical and preclinical studies have gathered substantial evidence that stress response alterations play a major role in the development of major depression, panic disorder, and post-traumatic stress disorder. The stress response, the hypothalamic pituitary adrenocortical (HPA) system and its modulation by corticotropin-releasing hormones (CRH),corticosteroids,and their receptors, and the roles of natriuretic peptides and neuroactive steroids are described. We review the role of the HPA system in major depression, panic disorder, and post-traumatic stress disorder and its possible relevance for treatment. Impaired glucocorticoid receptor function in major depression is associated with an excessive release of neurohormones such as CRH, to which a number of signs and symptoms characteristic of depression can be ascribed. In panic disorder, a role of central CRH in panic attacks has been suggested. Atrial natriuretic peptide (ANP) is causally involved in sodium lactate-induced panic attacks. Furthermore, preclinical and clinical data on its anxiolytic activity suggest that nonpeptidergic ANP receptor ligands may be potentially useful in the treatment of anxiety disorders. Post-traumatic stress disorder is characterized by a peripheral hyporesponsive HPA system and elevated CRH concentrations in the CSF. This dissociation is probably related to an increased risk of this disorder. We further review recent data that describe an important role of GABA(A)-receptor modulatory,3 alpha-reduced neuroactive steroids in major depression, anxiety, and its treatment. Antidepressants are effective in both depression and anxiety disorders and have major effects on the HPA system,especially on glucocorticoid and mineralocorticoid receptors. Normalization of HPA system abnormalities is a strong predictor of the clinical course, at least in major depression and panic disorder. Currently,CRH-R1 or glucocorticoid receptor antagonists and ANP receptor agonists are being studied and may provide future treatment options more closely related to the pathophysiology of these disorders.

Release of prolactin but not of adenocorticotropic hormone increases significantly in lactate-induced panic attacks

Release of prolactin but not of adenocorticotropic hormone increases significantly in lactate-induced panic attacks

Prolactin but not ACTH increases during sodium lactate-induced panic attacks

Paradoxically, the pituitary–adrenal axis is not activated during sodium lactate-induced panic. We measured the response of another stress-sensitive hormone, prolactin, to standard lactate and placebo infusion in a double-blind randomised design in eight patients with panic disorder and eight matched normal controls. Prolactin release was significantly elevated ( P<0.05) in panickers compared with non-panickers, whereas ACTH secretion was not activated at all. This differential stress response needs further investigation.

LY354740, a potent group II metabotropic glutamate receptor agonist prevents lactate-induced panic-like response in panic-prone rats

LY354740 is a potent and selective agonist at the group II metabotropic glutamate receptors and is shown to be an effective inhibitor of glutamate release with significant anxiolytic and drug withdrawal alleviating properties in certain animal models. Rats with chronic inhibition of GABA synthesis in the dorsomedial hypothalamus (DMH) are highly anxious and exhibit panic-like responses to peripheral lactate infusions similar to patients with panic disorder. Using these panic-prone rats, we tested the efficacy of LY354740 in preventing the lactate-induced panic-like response, comparing it to alprazolam, a clinically effective anti-panic drug. Rats were fitted with femoral arterial and venous catheters and implanted with Alzet pumps infusing the GABA synthesis inhibitor l-allylglycine into the DMH. After four days of recovery, they were confirmed to be panic-prone to lactate infusions as indicated by increases in heart rate, blood pressure, respiratory rate and “anxiety” measured in the social interaction test. Next, they were pretreated with either vehicle, LY354740 (0.3 and 0.6 mg/kg) or alprazolam (0.5 and 1.0 mg/kg) and re-challenged with lactate infusions. LY354740 treatment was equally efficacious as alprazolam in preventing lactate-induced panic attacks in this model. These data suggest that LY354740 could be a novel anti-panic drug, as effective as alprazolam in acute treatment.

Cerebral glucose metabolism in women with panic disorder.

This study was undertaken to clarify earlier inconsistent findings in brain metabolic topography in panic disorder patients at rest. Positron emission tomography (PET) with [18F]fluorodeoxyglucose was used to determine cerebral metabolic activity in six female patients with a DSM-III-R diagnosis of panic disorder and in six healthy female volunteers. All patients with panic disorder were medication free and were sensitive to lactate infusion. A significant increase in glucose metabolism was found in the left hippocampus and parahippocampal area of the panic disorder subjects in comparison with that found in the healthy subjects. In addition, a significant decrease in metabolism was found in the right inferior parietal and right superior temporal brain regions of the panic disorder subjects in comparison with that of the normal subjects. There was no significant correlation between scores for the severity of panic disorder or for the severity of lactate-induced panic attack and the quantified PET abnormality. These data provide further support for the hypothesis of an abnormal brain metabolism in the hippocampal and parahippocampal area in individuals with panic disorder and also suggest other areas of aberrant brain metabolism in this disorder.

Atrial natriuretic hormone in lactate-induced panic attacks: mode of release and endocrine and pathophysiological consequences

Previous studies have shown unequivocally a lack of pituitary-adrenocortical stress hormone activation during lactate-induced panic attacks despite considerable psychopathological alterations, signs of arousal and several vegetative symptoms regularly occurring during stressful conditions. To study the possible inhibitory action of atrial natriuretic hormone (ANH) on adrenocorticotrophic hormone (ACTH) and cortisol release in humans, 10 patients with panic disorder (DSM-III-R) received sodium lactate and placebo (0.9% saline) infusions and ten healthy comparison subjects additionally received a 2.5% saline infusion and the response of ANH, vasopressin, ACTH, cortisol, and several biochemical and physiological cardiovascular parameters were measured. In comparison to placebo, lactate infusion led to enhanced ANH levels in both non-panicking comparison subjects and panickers. Importantly, panickers showed significantly lower baseline levels of ANH than comparison subjects followed by a faster release. No significant concomitant changes in vasopressin, ACTH, and cortisol were observed. During lactate infusion, heart rate was accelerated considerably in the two groups; in contrast, the reduction of pCO 2 indicated an enhanced ventilation only in panickers. The pattern of ANH release cannot be attributed simply to either the volume load administered, the cardiac activation or an osmotic effect since neither 0.9 nor 2.5% saline resulted in comparable effects. Additional central nervous mechanisms must be considered for the increased ANH concentrations in lactate-induced panic attacks. We propose that the release of ANH is an intrinsic mechanism contributing to the apparent unresponsiveness of the pituitary-adrenocortical system in lactate-induced panic attacks. In addition, we surmise that ANH may also play a role in the yet unknown mechanisms for termination of panic attacks e.g. either by inhibitory actions on the locus coeruleus or by bronchiorelaxation and consecutive decatastrophization.

Effect of Alcoholism on the Incidence of Lactate-Induced Panic Attacks

Background: Chronic alcohol use is associated with higher than expected rates of panic disorder. Methods: To study the relationship between alcoholism and panic disorder, we administered the panicogenic agent, sodium lactate, to 26 alcoholics with either panic disorder or frequent panic attacks (ALCPAN), 20 nonalcoholics with panic disorder (PAN), 14 alcoholics without a history of panic attacks, and 14 healthy volunteers. Results: PAN were significantly more likely to have a lactate-induced panic attack (65%) than ALCPAN (23%). ALCPAN who had the onset of panic attacks prior to alcoholism also had a reduced frequency of lactate-induced panic attacks (26.7%) compared to PAN. Conclusions: There is a reduced incidence of lactate-induced panic attacks in ALCPAN. This reduction does not appear to be explained by the relative onset of panic attacks to alcoholism. The role of excessive alcohol consumption in the decreased frequency of lactate-induced panic attacks seen in ALCPAN needs further study.

Effect of the cholecystokinin-B receptor antagonist L-365,260 on lactate-induced panic attacks in panic disorder patients

Panic attacks are characterized by a rapid crescendo of fear or apprehension associated with the endorsement of physical symptoms. In panic disorder (PD) patients these panic attacks occur usually spontaneously (American Psychiatric Association 1989). Panic attacks can also be provoked by a number of pharmacologic agents (Westenberg and den Boer 1994). Among the different panic-provoking substances, one of the most widely studied is sodium lactate (Liebowitz et al 1984; den Boer and Westenberg 1989). Although the exact mechanism by which sodium lactate induces panic remains unclear, it appears to be a valid model for panic attacks, and clinically effective antipanic agents have been found to be able to antagonize sodium-lactateinduced panic attacks (Rifkin et al 1981; Cowley et al 1991; Coplan et al 1992). An intriguing new development is the discovery that cholecystokinin-B (CCK-B) receptor agonists possess panic-inducing properties. Panic attacks elicited by CCK-B receptor agonists like CCK-4 and pentagastrin have been found to be similar to naturally occurring panic attacks (van Megen et al 1994). Recently, we have investigated the effect of the CCK-B receptor antagonist L-365,260 on CCK-4-induced panic attacks (Bradwejn et al 1994). L-365,260 was able to block CCK-4-induced panic attacks in a dose-dependent fashion. This raises the question whether this effect of L-365,260 can be

Symptoms essential to the experience of sodium lactate-induced panic

We report on subjective ratings and symptoms experienced before and during sodium lactate infusion by patients with panic disorder or agoraphobics with panic attack (DMS-III-R criteria). Symptoms were assessed using the Acute Panic Inventory (API). During the lactate infusion 59% of the patients were rated by an attending psychiatrist as having experienced lactate-induced panic attacks. Patients experiencing lactate-induced panic attacks overwhelmingly rated this experience as very similar to their typical naturally occurring attacks. Among the individual API symptoms items at baseline (prelactate) only Afraid in general (r = 0.26) was significantly, but not strongly, correlated with the panic response. Controlling for baseline symptom levels, the most robust partial correlations of symptomatic increment with panic were Desire to flee (0.70), Fear of losing control (0.57), Afraid in general (0.49), and Dyspnea (0.48). Using a dichotomized symptom increment greater than 1, 13 of 29 API items indicated a panic response to lactate infusion; the best were Dyspnea, Feeling confused, Afraid in general, Difficulty speaking, Difficulty concentrating, Desire to flee, and Fear of losing control. A logistic regression analysis showed that among baseline measures, Afraid in general and Feeling confused significantly predicted panic. For dichotomized change scores, Afraid in general, Dyspnea, and Dizziness/lightheadedness significantly indicated panic. In these analyses three symptom items stand out as the most predictive and revealing of panic to lactate infusion: Afraid in general, Dyspnea, and Desire to flee. These results are discussed in the context of Klein's (1993) suffocation false alarm theory of panic.

Consistencies between recalled panic and lactate-induced panic.

This study investigated the frequency and severity of symptoms during naturally occurring panic attacks recollected as "usual" and during sodium lactate-induced attacks. Seventy-six male and 126 female patients with panic disorder or agoraphobics with panic attack (DSM-III criteria) underwent lactate infusion studies and were serially administered the Acute Panic Inventory (API). Fifty-nine percent of the subjects were rated by an attending psychiatrist to have experienced lactate-induced panic attacks. Patients were also asked to API symptom rate their "usual" panic attacks. For panic recollected as usual, the most frequently reported symptoms (> or = 75%) at the moderate to severe levels included: afraid in general, difficulty concentrating, difficulty performing a job, desire to flee, afraid of losing control, palpitations, feeling hot or cold or both, dyspnea, dizzy-lightheaded. During lactate infusion, 25 of 29 API symptoms increased significantly from prelactate to point of panic; however, particularly robust effect sizes were exhibited for the desire to flee, dyspnea, tingling, twitching/trembling and difficulty doing a job. Comparison of panic recollected as usual and lactate-induced panic showed that more than half of the symptoms did not differ after Bonferroni correction; however, the most notable were fear in general, dyspnea, chest pain/discomfort, difficulty swallowing, feeling weak, desire to flee, and feeling hot/cold or both. These data point to a very distinctive role during both recollected and lactate-induced panic attacks for fearfulness the desire to flee (by definition), and for dyspnea, difficulty performing a job and fear of losing control. During lactate-induced panic, dyspnea exhibited the most robust effect size of all physical symptoms.

Panic attacks during placebo procedures in the laboratory. Physiology and symptomatology.

Heart rate, respiratory measurements, and Acute Panic Inventory symptoms of 17 patients with panic disorder who experienced panic attacks during a placebo infusion (situationally provoked panic) were analyzed and compared with similar data from a group of 19 patients with panic disorder who panicked during lactate infusion. Previously, it was shown that the group with lactate-induced panic attacks exhibited increased minute ventilation compared with normal control subjects and nonpanicking patients with panic disorder during lactate infusion. The group with situationally provoked panic attacks exhibited significant increases in both heart rate and minute ventilation immediately preceding the onset of the panic attack. The increase in minute ventilation appeared to be caused more by increase in tidal volume than in respiratory frequency. The increase in heart rate in the group with situationally provoked panic attacks was very similar to that seen in the group with lactate-induced panic attacks, but the group with situationally provoked panic attacks appeared to have somewhat greater increase in minute ventilation than the group with lactate-induced panic attacks. This suggests that the metabolic alkalosis produced by lactate infusion might actually blunt the full expression of panic-associated respiratory stimulation. These data validate the belief that significant cardiorespiratory stimulation occurring during panic attacks in the laboratory is not simply secondary to the intrinsic physiologic effects of panic-inducing substances such as lactate, yohimbine, and carbon dioxide.

Valproate treatment of panic disorder and lactate-induced panic attacks

Several lines of evidence suggest that the anticonvulsant drug valproate may have antipanic properties: (1) It enhances γ-aminobutyric acid activity in the brain; (2) it has anxiolytic effects in animal models of anxiety; and (3) it has been reported to be effective in panic disorder in several preliminary studies; however, valproate has not been studied in the prevention of lactate-induced panic attacks. Sixteen patients with panic disorder underwent a lactate infusion followed by a 28-day treatment period with valproate and subsequent rechallenge with lactate. Response was measured by change in panic attack frequency and Hamilton Anxiety Scale (HAS) scores and by the ability of valproate to block lactate-induced panic on rechallenge. Of the 14 patients completing the 28-day trial, 10 (71%) experienced a greater than 50% reduction in the weekly frequency of panic attacks. Six (43%) had complete remission. HAS scores dropped significantly from a baseline mean of 30.8 ± 9.4 (SD) to 12.6 ± 7 after 4 weeks of treatment. Valproate blocked reinduction of panic symptoms on lactate rechallenge in 10 (83%) of 12 patients who had initially experienced panic symptoms on initial infusion. The significant reduction in spontaneous panic attacks and the blockade of lactate-induced panic symptoms by valproate support earlier studies suggesting that the drug may be an effective treatment for panic disorder.

Lactate sensitivity in sleeping panic disorder patients and healthy controls

In spite of a series of careful physiological and neuroendocrine studies of sodium lactate-induced panic attacks in Panic Disorder (PD) patients, the mechanism of panic induction remains poorly understood. To further explore this mechanism, we administered sodium lactate infusions to PD patients and normal controls during sleep, taking advantage of the opportunity that sleep provides for closely monitoring shifts in state of arousal. In previous work (Koenigsberg et al 1987) we reported that sodium lactate but not dextrose-saline infusions, administered during stage 3-4 sleep, induced prompt awakenings in panic disorder (PD) patients.

Lactate-induced panic attacks in alcoholics with panic disorder: Teresa Lindquist, David T. George and Markku Linnoila. National Institute on Alcohol Abuse and Alcoholism, Bethesda, MD

Lactate-induced panic attacks in alcoholics with panic disorder: Teresa Lindquist, David T. George and Markku Linnoila. National Institute on Alcohol Abuse and Alcoholism, Bethesda, MD

Imipramine dose effects on lactate-induced panic attacks : Alfonso Ontiveros, Guadalupe Leija Monterrey, Mexico 64461

Imipramine dose effects on lactate-induced panic attacks : Alfonso Ontiveros, Guadalupe Leija Monterrey, Mexico 64461

Effects of NaCl and D 5W on lactate-induced panic attacks : David T. George, Teresa Lindquist, Markku Linnoila Laboratory of Clinical Studies, National Institute on Alcohol Abuse and Alcoholism, Bethesda, MD 20892

Effects of NaCl and D 5W on lactate-induced panic attacks : David T. George, Teresa Lindquist, Markku Linnoila Laboratory of Clinical Studies, National Institute on Alcohol Abuse and Alcoholism, Bethesda, MD 20892

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.

Biological correlates of lactate sensitivity in panic disorder

In this pilot study, 9 9 patients with panic disorder experienced a lactate-induced panic attack as compared with 0 9 controls. Baseline measurements were significant for higher anxiety self-ratings, higher heart and respiratory rates, elevated potassium, and lower lymphocyte 3H-dihydroalprenolol (DHA) binding in the patient group. Spielberger State anxiety scores correlated with baseline mean heart rate, and Spielberger Trait anxiety scores with lymphocyte DHA binding. The lactate infusion was not found to differentially affect any physiological or biochemical measures in the two groups, though heart rate surges occurred in most patients. Intravenous propranolol reduced the panic to a negligible degree, whereas intravenous diazepam was quite effective. Neurobiological implications are discussed, and the contradictory biological findings in the lactate literature are reviewed.