sodium-lactate and Panic-Disorder

Sodium lactate (NaL) infusion and carbon dioxide (CO. Odds ratios were calculated for each of the original studies and were pooled using the random-effects model.. The evidence for the efficacy of the two panic provocation tests is very strong. Yet, the results support the superiority of NaL infusion over CO

Topics: Brain; Carbon Dioxide; Humans; Panic; Panic Disorder; Sodium Lactate

Laboratory measures have played an integral role in diagnosing pathology; however, compared to traditional medicine, psychiatric medicine has lagged behind in using such measures. A growing body of literature has begun to examine the viability and development of different laboratory measures in order to diagnose psychopathologies. The present review examines the current state of development of both sodium lactate infusion and CO2-35% inhalation as potential ancillary measures to diagnose panic disorder (PD). A previously established 3-step approach to identifying laboratory-based diagnostic tests was applied to available literature assessing the ability of both sodium lactate infusion or CO2-35% inhalation to induce panic attacks in PD patients, healthy controls, and individuals with other psychiatric conditions. Results suggest that across the literature reviewed, individuals with PD were more likely to exhibit panic attacks following administration of sodium lactate or CO2-35% compared to control participants. The majority of the studies examined only compared individuals with PD to healthy controls, suggesting that these ancillary measures are underdeveloped. In order to further determine the utility of these ancillary measures, research is needed to determine if panic attacks following administration of these chemical agents are unique to PD, or if individuals with related pathologies also respond, which may be indicative of transdiagnostic characteristics found across disorders.

Topics: Administration, Inhalation; Carbon Dioxide; Humans; Infusions, Intravenous; Panic Disorder; Predictive Value of Tests; Sodium Lactate

Idiopathic environmental intolerance (IEI), also known as multiple chemical sensitivity, is a clinical description for a cluster of symptoms of unknown etiology that have been attributed by patients to multiple environmental exposures when other medical explanations have been excluded. Because allergy has not been clearly demonstrated and current toxicological paradigms for exposure-symptom relationships do not readily accommodate IEI, psychogenic theories have been the focus of a number of investigations. A significantly higher lifetime prevalence of major depression, mood disorders, anxiety disorders, and somatization disorder has been reported among patients with environmental illness compared with that in controls. Symptoms often include anxiety, lightheadedness, impaired mentation, poor coordination, breathlessness (without wheezing), tremor, and abdominal discomfort. Responses to intravenous sodium lactate challenge or single-breath inhalation of 35% carbon dioxide versus a similar breath inhalation of clean air have shown a greater frequency of panic responses in subjects with IEI than in control subjects, although such responses did not occur in all subjects. Preliminary genetic findings suggest an increased frequency of a common genotype with panic disorder patients. The panic responses in a significant proportion of IEI patients opens a therapeutic window of opportunity. Patients in whom panic responses may at least be a contributing factor to their symptoms might be responsive to intervention with psychotherapy to enable their desensitization or deconditioning of responses to odors and other triggers, and/or may be helped by anxiolytic medications, relaxation training, and counseling for stress management.

Topics: Administration, Inhalation; Anti-Anxiety Agents; Carbon Dioxide; Counseling; Genetic Predisposition to Disease; Genotype; Humans; Infusions, Intravenous; Multiple Chemical Sensitivity; Odorants; Panic Disorder; Psychotherapy; Relaxation Therapy; Sodium Lactate; Stress, Psychological

Various provocative agents, including sodium lactate, carbon dioxide (CO2), caffeine, yohimbine, serotoninergic agents, and cholecystokinin (CCK), have been utilized as panicogenics in studies on healthy volunteers as well as in panic disorder patients. An overview of the utilization of these agents to study the neurobiology of panic disorder is presented. The possible roles of several neurotransmitters and neuromodulators in the etiology of panic disorder and in the actions of drugs used in its treatment are also discussed.

Topics: Caffeine; Carbon Dioxide; Cholecystokinin; Humans; Neurotransmitter Agents; Panic Disorder; Piperazines; Serotonin Receptor Agonists; Sodium Lactate; Synaptic Transmission; Yohimbine

Topics: Anxiety Disorders; Comorbidity; Disease Susceptibility; Female; Humans; Infusions, Intravenous; Panic Disorder; Premenstrual Syndrome; Sodium Lactate; Stress, Psychological

Despite the considerable revisions to diagnostic criteria, recent data indicate that generalized anxiety disorder (GAD) is one of the most common anxiety disorders. Growing evidence also indicates that GAD is a serious illness, which frequently causes moderate impairment and often requires prolonged treatment. Thus, investigation of the biological correlates of GAD may be helpful in the development of effective treatments for this disorder. Recent data suggest possible abnormalities in the regulatory mechanisms of several important biological components in GAD patients. Maladaptive responses to stressful stimuli have been observed in the locus-ceruleus-norepinephrine-sympathetic nervous system, the hypothalamic-pituitary-adrenocortical axis, and the cholecystotin system. Abnormalities in other important CNS modulators, such as 5-HT and gamma-aminobutyric acid, may also be involved in the biology of GAD. In the following article, the authors will review the existing information regarding these potential biological abnormalities in GAD.

Topics: Anxiety Disorders; Carbon Dioxide; Humans; Hypothalamo-Hypophyseal System; Models, Biological; Models, Neurological; Neurotransmitter Agents; Norepinephrine; Panic Disorder; Pituitary-Adrenal System; Psychiatric Status Rating Scales; Sodium Lactate; Terminology as Topic

Premenstrual symptoms are common among young menstruating women, but the psychiatric disorder premenstrual dysphoric disorder (PMDD) is seen only in approximately 3% of this group. The symptom profile of PMDD has been empirically derived from a number of investigations including a large data base from five university centers. The most commonly reported symptoms are depression and mood swings, but a substantial number of women report tension and anxiety. Lifetime psychiatric illness is also common in women with PMDD, and although mood disorders predominate, past histories of anxiety disorders are also common, further suggesting an association between PMDD and anxiety disorders. The strongest data supporting such an association lie with challenge studies that have been used to provoke panic in panic patients and are effective in precipitating panic attacks in women with PMDD. Finally, treatments that are effective for anxiety disorders are also useful in the treatment of PMDD. In this paper, the above outlined relationship between anxiety disorders and PMDD is reviewed.

Topics: 1-Naphthylamine; Adult; Age of Onset; Anxiety; Anxiety Disorders; Buspirone; Carbon Dioxide; Comorbidity; Depressive Disorder; Diagnosis, Differential; Female; Humans; Mental Disorders; Panic Disorder; Piperazines; Premenstrual Syndrome; Psychotherapy; Risk Factors; Sertraline; Sodium Lactate; Triazoles

The validity of experimentally induced panic attacks as a model to study the pathophysiology of panic disorder has been questioned. Unspecific, unpleasant and aversive effects as well as specific patterns of psychovegetative symptoms pointing to different subtypes of panic disorder patients have been observed. These findings raise the question of challenge paradigms as a valuable tool to identify different vulnerabilities in patients with panic disorder.. We compared the two most widely studied panicogenic drugs sodium lactate and cholecystokinine tetrapeptide (CCK-4) with placebo in 25 patients with panic disorder and matched healthy control subjects. Psychophysiological changes were measured using the Acute Panic Inventory (API) and visual analogue scales for anxiety and arousal.. In patients with panic disorder 18 out of 25 experienced a sodium lactate- or a CCK-4 induced panic attack. Lactate or CCK-4 induced symptoms and induced panic attacks were only correlated in healthy controls, but not in patients with panic disorder.. The mechanisms of lactate and CCK-4 induced panic attacks are distinct in panic disorder patients but not in healthy controls. Different neurobiological vulnerabilities may be uncovered by different challenges.

Topics: Adult; Case-Control Studies; Double-Blind Method; Female; Humans; Male; Middle Aged; Panic Disorder; Sodium Lactate; Tetragastrin

Patients with postural tachycardia syndrome (POTS) might be misdiagnosed with panic disorder due to shared clinical features. The first aim of our study was to investigate the relationship between symptoms of POTS and panic disorder. The second aim was to delineate clinical features distinguishing symptoms of POTS from panic disorder. A total of 11 patients with POTS and 11 control subjects participated in an IRB-approved, prospective, placebo-controlled study. The experimentally induced panic-like symptoms of POTS were systematically studied using the Acute Panic Inventory (API) questionnaire. The participants answered the questionnaire after each placebo infusion and after each of the three provoking stimuli: head-up tilt test (HUT), isoproterenol infusion (ISI), and sodium lactate infusion (SLI). API responses were summed for each subject at each time point of administration. Individual API symptoms and summed responses were analyzed for statistical significance. All patients with POTS developed symptoms of orthostatic intolerance during HUT. Pharmacologically induced symptoms subjectively mimicked spontaneous symptoms in 5 of 11 patients during ISI and in none of 11 patients during SLI. In contrast, API scores in these patients reached panic threshold in 0 of 11 following HUT, in 4 of 11 following ISI and in 4 of 11 following SLI. Individual symptoms analysis revealed that significant increase in scores was limited to the somatic symptoms of palpitations, dyspnea, and twitching or trembling. In conclusion, the symptoms of POTS are phenomenologically different and clinically distinguishable from panic disorder symptoms.

Topics: Adult; Cardiotonic Agents; Diagnosis, Differential; Female; Humans; Hypotension, Orthostatic; Isoproterenol; Middle Aged; Panic Disorder; Posture; Prospective Studies; Sodium Lactate; Surveys and Questionnaires; Tachycardia; Tilt-Table Test

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.

Topics: Adrenocorticotropic Hormone; Adult; Arousal; Double-Blind Method; Female; Humans; Hypothalamo-Hypophyseal System; Male; Panic; Panic Disorder; Pituitary-Adrenal System; Prolactin; Sodium Lactate

Flumazenil is a benzodiazepine receptor antagonist that has been reported to provoke panic attacks in patients with panic disorder. This study was undertaken to compare the effects of flumazenil and sodium lactate, the most widely studied panic provocation agent.. Ten patients with panic disorder were given infusions of saline, sodium lactate, and flumazenil in randomized order. Panic attacks, psychopathological changes, heart rate, and cortisol and ACTH secretion were recorded.. Eight of the 10 patients experienced a panic attack after sodium lactate, but none did after flumazenil or saline. Cortisol and ACTH secretion were not enhanced by any of the treatments. Sodium lactate increased heart rate, whereas flumazenil had the opposite effect.. These findings do not lend support to the view that the benzodiazepine receptors of lactate-susceptible patients with panic disorder are hypersensitive and that flumazenil can therefore act as an inverse agonist.

Topics: Adrenocorticotropic Hormone; Adult; Double-Blind Method; Female; Flumazenil; Heart Rate; Humans; Hydrocortisone; Infusions, Intravenous; Male; Panic Disorder; Receptors, GABA-A; Sodium Chloride; Sodium Lactate

Rats with chronic inhibition of GABA synthesis by infusion of l-allyglycine, a glutamic acid decarboxylase inhibitor, into their dorsomedial/perifornical hypothalamus are anxious and exhibit panic-like cardio-respiratory responses to treatment with intravenous (i.v.) sodium lactate (NaLac) infusions, in a manner similar to what occurs in patients with panic disorder. We previously showed that either NMDA receptor antagonists or metabotropic glutamate receptor type 2/3 receptor agonists can block such a NaLac response, suggesting that a glutamate mechanism is contributing to this panic-like state. Using this animal model of panic, we tested the efficacy of CBiPES and THIIC, which are selective group II metabotropic glutamate type 2 receptor allosteric potentiators (at 10-30 mg/kg i.p.), in preventing NaLac-induced panic-like behavioral and cardiovascular responses. The positive control was alprazolam (3mg/kg i.p.), a clinically effective anti-panic benzodiazepine. As predicted, panic-prone rats given a NaLac challenge displayed NaLac-induced panic-like cardiovascular (i.e. tachycardia and hypertensive) responses and "anxiety" (i.e. decreased social interaction time) and "flight" (i.e. increased locomotion) -associated behaviors; however, systemic injection of the panic-prone rats with CBiPES, THIIC or alprazolam prior to the NaLac dose blocked all NaLac-induced panic-like behaviors and cardiovascular responses. These data suggested that in a rat animal model, selective group II metabotropic glutamate type 2 receptor allosteric potentiators show an anti-panic efficacy similar to alprazolam.

Topics: Alprazolam; Animals; Anti-Anxiety Agents; Anxiety; Behavior, Animal; Cardiovascular System; gamma-Aminobutyric Acid; Glutamic Acid; Male; Panic; Panic Disorder; Rats; Rats, Sprague-Dawley; Receptors, Metabotropic Glutamate; Sodium Lactate

Corticotropin releasing factor (CRF) is implicated in a variety of stress-related disorders such as depression and anxiety, and blocking CRF receptors is a putative strategy for treating such disorders. Using a well-studied animal model of panic, we tested the efficacy of JNJ19567470/CRA5626, a selective, non-peptidergic CRF type 1 receptor (CRF1) antagonist (3, 10 and 40 mg/kg intraperitoneal injection), in preventing the sodium lactate (NaLac)-induced panic-like behavioural and cardiovascular responses. Adult male rats with chronic reduction of GABA levels (by inhibition of GABA synthesis with l-allyglycine, a glutamic acid decarboxylase inhibitor) in the dorsomedial/perifornical hypothalamus are highly anxious and exhibit physiological and behavioural responses to intravenous NaLac infusions similar to patients with panic disorder. These 'panic-prone' rats pre-treated with vehicle injections displayed NaLac-induced increases in autonomic responses (i.e. tachycardia and hypertensive responses), anxiety-like behaviour in the social interaction test, and flight-like increases in locomotor activity. However, systemically injecting such panic-prone rats with the highest dose of CRF1 receptor antagonist prior to NaLac infusions blocked all NaLac-induced behaviour and cardiovascular responses. These data suggest that selective CRF1 receptor antagonists could be a novel target for developing anti-panic drugs that are as effective as benzodiazepines in acute treatment of a panic attack without the deleterious side-effects (e.g. sedation and cognitive impairment) associated with benzodiazepines.

Topics: Animals; Anxiety; Behavior, Animal; Cardiovascular Physiological Phenomena; Dorsomedial Hypothalamic Nucleus; gamma-Aminobutyric Acid; Glycine; Interpersonal Relations; Male; Panic; Panic Disorder; Peptides; Rats; Rats, Sprague-Dawley; Receptors, Corticotropin-Releasing Hormone; Sodium Lactate

Panic disorder is a severe anxiety disorder with recurrent, debilitating panic attacks. In individuals with panic disorder there is evidence of decreased central gamma-aminobutyric acid (GABA) activity as well as marked increases in autonomic and respiratory responses after intravenous infusions of hypertonic sodium lactate. In a rat model of panic disorder, chronic inhibition of GABA synthesis in the dorsomedial-perifornical hypothalamus of rats produces anxiety-like states and a similar vulnerability to sodium lactate-induced cardioexcitatory responses. The dorsomedial-perifornical hypothalamus is enriched in neurons containing orexin (ORX, also known as hypocretin), which have a crucial role in arousal, vigilance and central autonomic mobilization, all of which are key components of panic. Here we show that activation of ORX-synthesizing neurons is necessary for developing a panic-prone state in the rat panic model, and either silencing of the hypothalamic gene encoding ORX (Hcrt) with RNAi or systemic ORX-1 receptor antagonists blocks the panic responses. Moreover, we show that human subjects with panic anxiety have elevated levels of ORX in the cerebrospinal fluid compared to subjects without panic anxiety. Taken together, our results suggest that the ORX system may be involved in the pathophysiology of panic anxiety and that ORX antagonists constitute a potential new treatment strategy for panic disorder.

Topics: Adult; Alprazolam; Animals; Anxiety; Disease Models, Animal; Female; Humans; Hypothalamus; Intracellular Signaling Peptides and Proteins; Male; Middle Aged; Neurons; Neuropeptides; Neurotransmitter Agents; Orexin Receptors; Orexins; Panic Disorder; Rats; Receptors, G-Protein-Coupled; Receptors, Neuropeptide; Sodium Lactate

Panic disorder is a severe anxiety disorder characterized by recurrent panic attacks that can be consistently provoked with intravenous (i.v.) infusions of hypertonic (0.5 M) sodium lactate (NaLac), yet the mechanism/CNS site by which this stimulus triggers panic attacks is unclear. Chronic inhibition of GABAergic synthesis in the dorsomedial hypothalamus/perifornical region (DMH/PeF) of rats induces a vulnerability to panic-like responses after i.v. infusion of 0.5 M NaLac, providing an animal model of panic disorder. Using this panic model, we previously showed that inhibiting the anterior third ventricle region (A3Vr; containing the organum vasculosum lamina terminalis, the median preoptic nucleus, and anteroventral periventricular nucleus) attenuates cardiorespiratory and behavioral responses elicited by i.v. infusions of NaLac. In this study, we show that i.v. infusions of 0.5 M NaLac or sodium chloride, but not iso-osmolar D-mannitol, increased 'anxiety' (decreased social interaction) behaviors, heart rate, and blood pressure responses. Using whole-cell patch-clamp preparations, we also show that bath applications of NaLac (positive control), but not lactic acid (lactate stimulus) or D-mannitol (osmolar stimulus), increases the firing rates of neurons in the A3Vr, which are retrogradely labeled from the DMH/PeF and which are most likely glutamatergic based on a separate study using retrograde tracing from the DMH/PeF in combination with in situ hybridization for vesicular glutamate transporter 2. These data show that hypertonic sodium, but not hyper-osmolarity or changes in lactate, is the key stimulus that provokes panic attacks in panic disorder, and is consistent with human studies.

Topics: Action Potentials; Animals; Cardiovascular Physiological Phenomena; Disease Models, Animal; Dorsomedial Hypothalamic Nucleus; gamma-Aminobutyric Acid; Hypothalamus; Male; Neurons; Organ Culture Techniques; Osmolar Concentration; Panic Disorder; Patch-Clamp Techniques; Preoptic Area; Rats; Rats, Sprague-Dawley; Saline Solution, Hypertonic; Sodium Chloride; Sodium Lactate; Third Ventricle

Lactate uses an unknown mechanism to induce panic attacks in people and panic-like symptoms in rodents. We tested whether intraperitoneal (IP) lactate injections act peripherally or centrally to induce panic-like symptoms in rats by examining whether IP lactate directly affects the CNS. In Long-Evans rats, IP lactate (2 mmol/kg) injection increased lactate levels in the plasma and the cerebrospinal fluid. IP lactate also induced tachycardia and behavioral freezing suggesting the production of panic-like behavior. To enter intermediate metabolism, lactate is oxidized by lactate dehydrogenase (LDH) to pyruvate with co-reduction of NAD(+) to NADH. Therefore, we measured the ratio of NADH/NAD(+) to test whether IP lactate altered lactate metabolism in the CNS. Lactate metabolism was studied in the hippocampus, a brain region believed to contribute to panic-like symptoms. IP lactate injection lowered the ratio of NADH/NAD(+) without altering the total amount of NADH and NAD(+) suggesting oxidation of hippocampal redox state. Lactate oxidized hippocampal redox since intrahippocampal injection of the LDH inhibitor, oxamate (50mM) prevented the oxidation of NADH/NAD(+) by IP lactate. In addition to oxidizing hippocampal redox, IP lactate rapidly increased the firing rate of hippocampal neurons. Similar IP pyruvate injections had no effect. Neural discharge also increased following intrahippocampal lactate injection suggesting that increased discharge was a direct action of lactate on the hippocampus. These studies show that oxidation of brain redox and increased hippocampal firing are direct actions of lactate on the CNS that may contribute to the production of lactate-induced panic.

Topics: Action Potentials; Animals; Hippocampus; Injections; Lactates; NAD; Neurons; Oxidation-Reduction; Panic Disorder; Pyruvic Acid; Rats; Rats, Long-Evans; Sodium Lactate

The paper here presented was motivated by a case study involving high-dimensional and high-frequency tidal volume traces measured during induced panic attacks. The focus was to develop a procedure to determine the significance of whether a mean curve dominates another one. The key idea of the suggested method relies on preserving the order in mean while reducing the dimension of the data. The observed data matrix is projected onto a set of lower rank matrices with a positive constraint. A multivariate testing procedure is then applied in the lower dimension. We use simulated data to illustrate the statistical properties of the proposed testing procedure. Results on the case study confirm the preliminary hypothesis of the investigators and provide critical support to their overall goal of creating an experimental model of the clinical panic attack in normal subjects.

Topics: Adult; Algorithms; Biometry; Female; Humans; Male; Models, Statistical; Multivariate Analysis; Panic Disorder; Sodium Lactate; Tidal Volume

Panic patients are vulnerable to induction of panic attacks by sub-threshold interoceptive stimuli such as intravenous (i.v.) sodium lactate infusions. Facilitation of serotonergic signaling with selective serotonin reuptake inhibitors can suppress anxiety and panic-like responses, but the mechanisms involved are not clearly defined. We investigated the effects of i.v. 0.5 M sodium lactate or saline, in control and panic-prone rats on c-Fos expression in serotonergic neurons within subdivisions of the midbrain/pontine raphe nuclei. Rats were chronically infused with either the GABA synthesis inhibitor l-allylglycine into the dorsomedial hypo thalamus to make them panic-prone, or the enantiomer d-allylglycine (d-AG) in controls. Lactate increased c-Fos expression in serotonergic neurons located in the ventrolateral part of the dorsal raphe nucleus (DRVL) and ventrolateral periaqueductal gray (VLPAG) of control, but not panic-prone, rats. The distribution of lactate-sensitive serotonergic neurons in d-AG-treated rats is virtually identical to previously defined pre-sympathomotor serotonergic neurons with multisynaptic projections to peripheral organs mediating 'fight-or-flight'-related autonomic and motor responses. We hypothesized that serotonergic neurons within the DRVL/VLPAG region represent a 'sympathomotor control system' that normally limits autonomic/behavioral responses to innocuous interoceptive and exteroceptive stimuli, and that dysfunction of this serotonergic system contributes to an anxiety-like state and increases vulnerability to panic in animals and humans.

Topics: Allylglycine; Animals; Anxiety Disorders; gamma-Aminobutyric Acid; Male; Neurons; Panic Disorder; Proto-Oncogene Proteins c-fos; Rats; Rats, Sprague-Dawley; Serotonin; Sodium Lactate

It was suspected that the delusional convictions of bewitchment and devil persecution of two female patients (41 and 40-years-old) could be the consequence of an erroneous interpretation of the sensations induced by panic attacks, as several authors have previously suggested. The interest of this case report stems from the manner in which we tested our clinical hypothesis. The patients agreed to the use of a lactate provocation test in double-blind, placebo-controlled conditions during four randomized sessions on consecutive days (two with lactate and two with placebo). The results for patient A strongly supported our hypothesis: patient A developed two full-blown panic attacks during the active lactate sessions, whereas patient B developed one subthreshold and one moderate panic attack during the active lactate sessions. The results of these investigations led to a more specific psychotherapeutic approach for patient A.

Topics: Adult; Diagnosis, Differential; Female; Humans; Panic Disorder; Patient Education as Topic; Psychoses, Substance-Induced; Relaxation; Sodium Lactate

Sensitivity to pharmacological challenges has been reported in patients with panic disorder. We have previously validated transgenic mice overexpressing the neurotrophin-3 (NT-3) receptor, TrkC (TgNTRK3), as an engineered murine model of panic disorder. We could determine that TgNTRK3 mice presented increased cellularity in brain regions, such as the locus ceruleus, that are important neural substrates for the expression of anxiety in severe anxiety states. Here, we investigated the sensitivity to induce anxiety and panic-related symptoms by sodium lactate and the effects of various drugs (the alpha2-adrenoceptor antagonist, yohimbine and the adenosine antagonist, caffeine), in TgNTRK3 mice. We found enhanced panicogenic sensitivity to sodium lactate and an increased intensity and a differential pattern of Fos expression after the administration of yohimbine or caffeine in TgNTRK3. Our findings validate the relevance of the NT-3/TrkC system to pathological anxiety and raise the possibility that a specific set of fear-related pathways involved in the processing of anxiety-related information may be differentially activated in panic disorder.

Topics: Animals; Anxiety; Brain; Caffeine; Disease Models, Animal; Fear; Male; Mice; Mice, Transgenic; Oncogene Proteins v-fos; Panic Disorder; Random Allocation; Sodium Lactate; Yohimbine

Certain metabolites of progesterone such as 3alpha,5alpha-tetrahydroprogesterone (3alpha,5alpha-THP; allopregnanolone) and 3alpha,5beta-THP (pregnanolone) are potent, positive allosteric modulators of gamma-aminobutyric acid type A receptors. Although animal studies suggest anxiolytic properties of these endogenous modulators of central nervous excitability, no clinical data indicate whether they are also involved in the pathophysiology of anxiety disorders and panic attacks.. We quantified the concentrations of 3alpha,5alpha-THP, 3alpha,5beta-THP, the isomer 3beta,5alpha-THP, and their precursors in the plasma of 10 patients with panic disorder and matched control subjects during panic attacks induced by means of sodium lactate and cholecystokinin tetrapeptide administration, using a highly sensitive gas chromatography-mass spectrometry analysis.. Panic attacks induced by sodium lactate and cholecystokinin tetrapeptide in patients with panic disorder were accompanied by pronounced decreases in the concentrations of 3alpha,5alpha-THP and 3alpha,5beta-THP and a concomitant increase in the concentrations of the functional antagonistic isomer 3beta,5alpha-THP, findings that are compatible with a decreased gamma-aminobutyric acid-ergic tone. No changes in neuroactive steroid concentrations were observed after placebo administration in patients with panic disorder or after placebo, sodium lactate, or cholecystokinin tetrapeptide administration in controls.. The association between changes in plasma neuroactive steroid concentrations and experimentally induced panic attacks and the well-documented pharmacological properties of these compounds as gamma-aminobutyric acid type A receptor modulators suggest that neuroactive steroids may play a role in the pathophysiology of panic attacks in patients with panic disorder.

Topics: Adult; Female; Gas Chromatography-Mass Spectrometry; Gonadal Steroid Hormones; Humans; Male; Middle Aged; Panic Disorder; Placebos; Pregnanolone; Receptors, GABA-A; Sodium Lactate; Tetragastrin

This unit describes a putative animal model for panic disorder. The basic premise is that pharmacological disruption of critical brain regions implicated in the circuitry of anxiety will lead to a condition similar to that of the human disorder. A clinically relevant test, the sodium lactate challenge, is utilized to assess parallels between the human condition and this rat model.

Topics: Amygdala; Animals; Anxiety Disorders; Biomedical Research; Disease Models, Animal; Disease Susceptibility; Infusions, Intravenous; Male; Neurosciences; Panic Disorder; Rats; Rats, Wistar; Sodium Lactate; Urocortins

Increased fighting is an effect of desynchronized sleep deprivation (DSD) in rats, and recently this behavior has been suggested to be spontaneous panic and equivalent to panic disorder. In the present study we tested this hypothesis by evaluating the effect of sodium lactate on this aggressiveness, because this substance is recognized to induce spontaneous panic attacks in patients. A total of 186 male albino Wistar rats, 250-350 g, 90-120 days of age, were submitted to DSD (multiple platform method) for 0, 4, or 5 days. At the end of the deprivation period the rats were divided into subgroups respectively injected intraperitoneally with 1.86, 2.98 and 3.72 g/kg of 1 M sodium lactate, or 1.86 and 3.72 g/kg of 2 M sodium lactate. The control animals were submitted to the same procedures but received equivalent injections of sodium chloride. Regardless of DSD time, sleep-deprived animals that received sodium lactate presented a significantly higher mean number of fights (0.13 +/- 0.02 fights/min) and a longer mean time spent in confrontation (2.43 +/- 0.66 s/min) than the controls (0.01 +/- 0.006 fights/min and 0.12 +/- 0.07 s/min, respectively; P<0.01, Student t-test). For the sodium lactate group, concentration of the solution and time of deprivation increased the number of fights, with the mean number of fights and mean duration of fighting episodes being greater with the 2.98 g/kg dose using 1 M lactate concentration. These results support the hypothesis that fighting induced by DSD is probably a spontaneous panic manifestation. However, additional investigations are necessary in order to accept this as a promising animal model for studies on panic disorder.

Topics: Aggression; Animals; Behavior, Animal; Male; Panic Disorder; Rats; Rats, Wistar; Sleep Deprivation; Sodium Lactate; Statistics, Nonparametric

A fast, proton echo-planar spectroscopic imaging (PEPSI) technique, capable of simultaneously measuring metabolites from multiple brain regions, was used to investigate the anatomical distribution and magnitude of brain lactate responses to intravenous lactate infusion among subjects with panic disorder and control subjects.. Fifteen subjects with panic disorder and 10 control subjects were studied. All subjects were medication free and met DSM-IV criteria for panic disorder, or, for controls, no Axis I psychiatric disorder. Two-dimensional axial metabolite images having 1-cm3 spatial resolution were acquired at 61/2-minute intervals during 3 conditions: a 20-minute baseline, 20-minute 0.5-mol/L sodium lactate infusion, and 15-minute postinfusion period.. Intravenous lactate infusion increased brain lactate levels throughout the axial brain section studied in all subjects. Panic-disordered subjects had significantly greater global brain lactate increases in response to lactate infusion. Lateralization of brain lactate response did not occur, nor were discrete regional loci of elevated lactate observed. Cerebrospinal fluid lactate changes corresponded to lactate changes in brain tissue. Severity of symptoms provoked by lactate infusion did not directly correlate with brain lactate response.. Greater overall rises in brain lactate among subjects with panic disorder compared with controls occurred in response to lactate infusion. We were unable to detect a distinct regional pattern for magnitude differences in brain lactate rise by which to identify a specific neuroanatomical substrate underlying a lactate-induced panic response. The wide anatomical distribution of these brain lactate increases suggest metabolic and/or neurovascular mechanisms for the abnormal rise in subjects with panic disorder.

Topics: Adult; Brain; Brain Chemistry; Echo-Planar Imaging; Female; Humans; Infusions, Intravenous; Lactates; Magnetic Resonance Spectroscopy; Male; Panic Disorder; Protons; Regional Blood Flow; Severity of Illness Index; Sodium Lactate

The purpose of this study was to determine if nocturnal panic patients have greater autonomic dysregulation than patients with daytime panic.. Three groups were studied: patients who suffer from panic attacks during sleep (n = 12), those who suffer from daytime panic attacks only (n = 12), and control subjects (n = 12). Each subject underwent 24-hour holter monitoring for heart rate variability (HRV), an overnight sleep recording, and sodium lactate challenge during wakefulness.. There was a marked subjective response to the sodium lactate challenge in the panic disorder (PD) patients but not in control subjects. Each group showed changes in HRV in response to sodium lactate challenge. The decrease in HRV measures was more marked in PD patients as a whole than in control subjects. During non-rapid eye movement (REM) sleep the value for total power (TP) was significantly higher in the nocturnal panic patients. The PD patients as a whole had higher values for TP and low-frequency (LF) power during REM sleep than control subjects. There were no significant differences between the two PD groups in sleep architecture. The PD patients as a whole had lower sleep efficiency and less stage 4 sleep than control subjects.. These findings indicate that there are substantial differences between PD and control subjects in autonomic regulation and that there are small differences between patients with daytime panic attacks and those with sleep-related panic attacks.

Topics: Adult; Circadian Rhythm; Heart Rate; Humans; Infusions, Intravenous; Panic Disorder; Polysomnography; Sleep; Sleep Wake Disorders; Sodium Lactate

Topics: Amygdala; Animals; Bicuculline; Efferent Pathways; GABA-A Receptor Antagonists; Heart Rate; Infusions, Intravenous; Panic Disorder; Rats; Receptors, GABA-A; Sodium Lactate; Tetrodotoxin; Yohimbine

Topics: Adrenocorticotropic Hormone; Adult; Female; Humans; Hydrocortisone; Infusions, Intravenous; Male; Panic Disorder; Sodium Chloride; Sodium Lactate

Sodium lactate infusion has induced flashbacks accompanied by panic attacks in male combat veterans with posttraumatic stress disorder (PTSD) and concurrent panic disorder. This study addressed whether sodium lactate induces flashbacks or other intrusive PTSD symptoms in PTSD patients free of concurrent panic disorder.. Behavioral, cardiovascular, catecholamine, and cortisol responses to infusion of 0.5 M sodium lactate were compared among seven subjects with PTSD without panic disorder, seven subjects with panic disorder only, and seven healthy subjects.. Six of the seven PTSD subjects but no panic disorder or healthy subjects reported flashbacks or other intrusive PTSD symptoms during lactate infusion. Flashbacks were accompanied by substantial anxiety symptoms. Cortisol levels were low in the PTSD subjects.. Sodium lactate induces flashbacks in persons with PTSD without comorbid panic disorder. The relationship between anxiety responses accompanying a PTSD flashback and those in a panic attack remains unclear.

Topics: Adult; Blood Pressure; Comorbidity; Epinephrine; Female; Heart Rate; Humans; Hydrocortisone; Infusions, Intravenous; Male; Memory; Middle Aged; Norepinephrine; Panic Disorder; Sodium Lactate; Stress Disorders, Post-Traumatic

Many patients who are first seen with what has been called multiple chemical sensitivity syndrome (MCS) experience symptoms suggestive of panic disorder including chest tightness, shortness of breath, palpitations, paresthesias, light-headedness, and mental confusion. Although such patients are often convinced that these symptoms reflect toxic effects of environmental "chemicals," direct evidence of this is lacking. To the contrary, a previous study has shown that some of these individuals exhibit hyperventilation responses on exposure to non-noxious stimuli, and it has been suggested that the resulting hypocarbia accounts for their symptoms. We postulated that some patients with self-identified MCS had an underlying condition similar to panic disorder and would therefore demonstrate similar responses to provocative challenges, such as sodium lactate infusion.. Patients referred to an allergy and clinical immunology service for evaluation of "chemical sensitivity" were investigated to rule out underlying medical conditions, including asthma, as a cause of their symptoms and were enrolled for study after giving informed consent. After a standardized psychiatric assessment was performed, patients underwent single-blind intravenous infusions of normal saline solution (placebo) and sodium lactate (which reproduces symptoms in individuals with underlying panic disorder). All patients were referred for independent psychiatric assessment.. The standardized psychiatric assessment identified four of five patients as meeting DSM III-R diagnostic criteria for panic disorder along with other depressive and/or anxiety-related disorders. All five patients with self-identified chemical sensitivity exhibited a positive symptomatic response to sodium lactate compared with placebo infusion. Independent psychiatric assessment confirmed the diagnosis of panic disorder on the basis of DSM III-R criteria in each of the five patients.. These results suggest that MCS may have a neurobiologic basis similar, if not identical, to that of panic disorder. We speculate that treatments with demonstrated efficacy in panic disorder may also be of benefit in MCS, and conversely, treatments that reinforce anticipatory anxiety and avoidance behavior in patients with MCS may be detrimental.

Topics: Adult; Female; Humans; Infusions, Intravenous; Male; Middle Aged; Multiple Chemical Sensitivity; Panic Disorder; Pilot Projects; Psychiatric Status Rating Scales; Single-Blind Method; Skin Tests; Sodium Lactate

Patients with panic disorder experience panic attacks after intravenous sodium lactate infusions by an as yet unexplained mechanism. Lactate elicits a panic-like response in rats with chronic dysfunction of GABA neurotransmission in the dorsomedial hypothalamus (DMH). The circumventricular organs, organum vasculosum lamina terminalis (OVLT) and subfornical organ (SFO), are potential sites that could detect increases in plasma lactate levels and activate the DMH. To test this, we obtained baseline heart rate (HR) and blood pressure (BP) responses to lactate infusions in rats fit with femoral arterial and venous catheters. Next, unilateral chronic injection cannulae connected to an Alzet infusion pump filled with the GABA synthesis inhibitor L-allylglycine (L-AG) were implanted into the DMH. Another chronic injection cannula was implanted into the region of the OVLT, SFO, or an adjacent control site, the median preoptic area (MePOA). These rats were tested once again with lactate infusions after injection of either artificial cerebrospinal fluid (ACSF) or tetrodotoxin (TTX) into the CVO sites. Injecting TTX into the OVLT completely blocked the lactate-induced response, whereas TTX injections into the SFO or MePOA did not. Also, direct injections of lactate (100 or 500 nl) into the OVLT elicited robust anxiety-like responses in these rats. These results suggest that the OVLT may be the primary site that detects lactate infusions, activating an anxiety-like response in a compromised DMH, and provide the first neuroanatomical basis for lactate response in panic disorder.

Topics: Allylglycine; Animals; Anxiety; Blood Pressure; Cerebrospinal Fluid; Heart Rate; Hypothalamus, Middle; Injections, Intravenous; Male; Microinjections; Neural Pathways; Panic Disorder; Preoptic Area; Rats; Rats, Sprague-Dawley; Social Behavior; Sodium Lactate; Subfornical Organ; Tetrodotoxin