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Background: Abnormalities in ventilatory physiology have been noted in adults with panic disorder. We tested the hypothesis that abnormalities in ventilatory physiology differentiate children and adolescents with anxiety disorders from psychiatrically healthy children., Methods: Ventilatory physiology was monitored with a canopy apparatus during room-air breathing and 15 minutes of carbon dioxide exposure in 33 children and adolescents comprising 18 probands with an anxiety disorder and 15 psychiatrically healthy children., Results: During room-air breathing, probands had significantly larger minute ventilation, larger tidal volumes, and more variable breathing patterns than healthy comparisons, but the groups did not differ in end-tidal carbon dioxide or respiratory rate. During carbon dioxide challenge, probands exhibited larger minute ventilation and respiratory rate responses relative to comparisons., Conclusion: These findings on the association between ventilatory physiology and anxiety disorders in children and adolescents are consistent with results from studies of adults with panic disorder.

Background: We evaluated the role of plasma cortisol levels in determining sodium lactate-induced panic by reporting psychological, physiological, and biochemical data collected from an extended sample of 214 subjects during the "placebo" infusion (isotonic saline solution) immediately preceding the lactate infusion procedure., Methods: One hundred seventy patients with panic disorder, 101 (59%) of whom were assessed to have panicked (P group), and 69 (41%) who were assessed not to have panicked (NP group) with lactate infusion; and 44 normal healthy volunteer controls (1 of whom panicked with lactate infusion) were studied., Results: Before the lactate infusion, the P group exhibited hypothalamic-pituitary-adrenal (HPA) axis activation (high plasma cortisol levels) and evidence of hyperventilation (low PCO2 levels) in comparison with NP and control groups. Self-reported fear, dyspnea, and diastolic blood pressure were highest in the P group, intermediate in the NP group, and lowest in the control group. Within the P group, baseline fear scores correlated inversely with PCO2 levels and positively with cortisol levels while PCO2 levels correlated negatively with cortisol levels. Significant predictors of lactate-induced panic were prelactate infusion fear and the interaction of high cortisol levels and low PCO2 levels., Conclusion: Combined data suggest that synchronized elevations of HPA axis activity, self-reported fear, and hyperventilation during the period before lactate infusion predisposes to lactate-induced panic.

Venlafaxine, a structurally novel antidepressant that combines mechanisms of action of both the cyclic antidepressants and SSRIs, may be effective in the treatment of panic disorder. Thirteen patients with DSM-IV panic disorder with or without agoraphobia participated in an open-label, fixed-flexible dose treatment study with venlafaxine. All patients who completed the 10-week trial exhibited statistically significant decreases in scores on anxiety symptoms as well as complete cessation of panic attacks at an effective mean daily dose of 47 mg per day. Venlafaxine was well tolerated in all completers. Venlafaxine may be an effective antipanic agent, even at lower than typical antidepressant dosages.

This study compares the hemodynamic response to panic disorder subjects with that of normal controls during respiratory challenges. Panic patients meeting DSM-IIIR criteria for panic disorder and normal controls were challenged with room air hyperventilation, 5% CO2 breathing, and 7% CO2 breathing. Measurements of pulse and blood pressure were taken at resting baseline and before and at the end of each respiratory challenge. Panic attack to each challenge was determined by using raters blinded to subject diagnosis and each subject's self-rating of panic. Significantly larger systolic and diastolic blood pressure increases were found in patients who panicked with room air hyperventilation than nonpanicking patients or normal controls. No significant blood pressure differences were found with 7% or 5% CO2 challenges, but higher pulse rates were found in the patient group. It may be possible that panic with room air hyperventilation causes a significant increase in systolic and diastolic blood pressure, or that a subgroup of panic disorder patients has a hyperactive vascular response to hypocapnia. These patients panic with room air hyperventilation and develop greater vasoconstriction and/or increased blood pressure response.

Background: Disordered breathing among patients with panic disorder, including hyperventilation during attacks and increased anxiogenic response to carbon dioxide (CO2) inhalation, is well established. We wished to assess whether there is a change in the physiological response to CO2 after patients have undergone antipanic therapy with either tricyclic antidepressants or cognitive behavioral therapy (CBT)., Methods: Twenty-nine patients with panic disorder underwent baseline CO2 sensitivity testing using the traditional Read rebreathing method and then received either antidepressant treatment (n = 21) or CBT (n = 8). After completing treatment, CO2 testing was repeated. A comparison sample of 14 normal volunteers also had two CO2 sensitivity tests, separated by an average of 21.6 (SD = 8.8) weeks., Results: Using a liberal standard, in which all CO2 sensitivity tests whose correlations between minute ventilation and end-tidal CO2 were at least .75 were used, patients, but not controls, demonstrated a significant reduction in CO2 sensitivity between the first and second test. Using a more conservative .90 correlation standard reduced the sample size available and resulted in trend reduction in patients but no significant change in controls. There was a suggestion that the change was most pronounced in treatment responders, although the number of patient nonresponders is extremely small in this sample., Conclusions: These data indicate that treatment reduces CO2 sensitivity in patients with panic disorder. We speculate that manipulation of the serotonergic and noradrenergic neurotransmission systems, both known to play a role in the control of respiration, may have a specific effect in reducing respiratory hyperactivity in panic disorder.

Objective: Respiratory abnormalities may play a central role in the pathophysiology of panic disorder. The current study was undertaken to examine the respiratory response in the largest series of subjects to date during three respiratory challenges that used improved methodology., Method: Fifty-nine patients with DSM-III-R panic disorder and 39 normal volunteers were challenged with 5% and 7% CO2 inhalation and room air hyperventilation separated by room air breathing with continuous spirometry., Results: Patients with panic disorder were more sensitive to the anxiogenic effects of CO2 than were normal subjects, and CO2 was a more potent stimulus to panic than hyperventilation. Patients increased their respiratory rate more quickly during CO2 inhalation than did comparison subjects, and this increase preceded the panic attacks. Patients who panicked in response to 5% CO2 demonstrated continued rise in end-tidal CO2, while the end-tidal CO2 of the comparison groups stabilized. Low end-tidal CO2 and high variance in minute ventilation at baseline predicted panic attacks during CO2 inhalation. Following CO2 or hyperventilation challenges, respiratory rate dropped sharply, while tidal volume remained elevated longer in patients than in comparison subjects., Conclusions: The findings confirm the greater behavioral and physiological sensitivity of patients with panic disorder to CO2 inhalation and identify a series of respiratory abnormalities. Panic attacks in panic disorder may be explained by inefficient compensatory mechanisms, primarily of respiratory rate.

Background: Controlled trials suggest that clomipramine may be a highly effective antipanic drug. Lowering the starting dose may alleviate troublesome initial side effects and increase acceptability and compliance., Method: Fifty-eight patients with DSM-III-R panic disorder with or without agoraphobia underwent 13 weeks of clomipramine treatment. Starting at 10 mg/day, the dose was gradually increased to a mean dose of 97 mg/day., Results: While completers showed highly significant improvement, the benefits were severely limited by a high dropout rate due to adverse reactions occurring mostly during the first 2 weeks of treatment., Conclusion: Given the alternatives, clomipramine should not be used as a first-line antipanic medication.

Background: There is evidence of relationships among serotonin, aggressive behavior, and a childhood history of socially adverse-rearing conditions. This study examines the prolactin response to fenfluramine hydrochloride challenge in young boys who show clinically significant aggressive behavior or who are raised in a social environment that is conducive to the development of chronic aggression., Methods: A series of 34 younger brothers of convicted delinquents underwent standardized psychiatric and observation-based assessments of their social-rearing environments that were conducted during home visits. Approximately 2 years later, these boys underwent a reassessment of psychiatric status and an assessment of central serotonergic activity using the fenfluramine challenge procedure., Results: Increasing degrees of aggressive behavior at either assessment were positively correlated with the prolactin response to fenfluramine challenge. Furthermore, adverse-rearing circumstances that were conducive to the development of aggressive behavior also exhibited positive correlations with the prolactin response. This association between adverse rearing and the prolactin response was statistically independent of that between aggression and the prolactin response., Conclusion: In young boys, aggressive behavior and social circumstances that are conducive to the development of aggressive behavior are positively correlated with a marker of central serotonergic activity.

Objectives: This study examined the longitudinal relationship between psychopathology and obesity in young adulthood., Methods: More than 700 youth in a population-based sample were psychiatrically assessed in 1983 (mean age = 14 years) and 1992 (mean age = 22 years). Self-reported body mass index (BMI) in 1992 was regressed on measures of depression and conduct disorder as well as a set of covariates including indices of physical health, social class, intelligence, and cigarette and alcohol use. Associations were examined with BMI treated as a continuous variable and with a binary index of obesity derived from the BMI distribution in each gender., Results: BMI in young adults was positively related to a number of covariates. With all covariates controlled, BMI was inversely related to adult depressive symptoms in males but not females. BMI was positively related to adolescent symptoms of conduct disorder in both sexes. Similar associations were found between psychiatric symptoms and obesity., Conclusions: Conduct disorder symptoms in adolescence predicted BMI and obesity in early adulthood. These associations remained after controlling for factors that can affect the association between psychopathology and obesity.

Background: Central noradrenergic (NA) dysregulation has provided a major theoretical framework for understanding the pathogenesis of panic disorder (PD). Using clonidine, an alpha 2-adrenergic receptor agonist, as a probe of NA function, we investigated the hypothesis that the antipanic efficacy of the selective serotonin reuptake inhibitors may be associated with normalization of a putatively dysregulated NA system., Methods: We report further analyses on data from 17 subjects with PD and 16 healthy volunteers who underwent measurement of the plasma NA metabolite 3-methoxy-4-hydroxyphenylglycol (MHPG) immediately before and after oral clonidine administration. Thirteen patients with PD were rechallenged after 12 weeks during open fluoxetine hydrochloride treatment using the same clonidine paradigm; 13 healthy volunteers were rechallenged at 12 weeks, not having received treatment between challenges., Results: Patients with PD, compared with healthy volunteers, have markedly elevated plasma MHPG volatility during the first clonidine challenge. Volatility describes the magnitude of within-subject plasma MHPG oscillatory activity as assessed by the root of the mean square successive difference. A greater degree of clinical global improvement was predicted by a greater magnitude of basal MHPG reduction with fluoxetine treatment. Antipanic response to fluoxetine was accompanied by a significant decrease of MHPG volatility to volunteer levels. Volunteer MHPG volatility remained unchanged from the first to second clonidine challenge., Conclusions: Further evidence is provided for the hypothesis of NA dysregulation in PD as reflected by elevations of within-subjects plasma MHPG volatility during clonidine challenge. Effective selective serotonin reuptake inhibitor-antipanic treatment in this clinical sample was paralleled by normalization of dysregulated NA function.

The advent of highly effective antipanic medications with specific serotonin reuptake inhibition as a mechanism of action has prompted the need for new pathophysiological models of panic disorder. The authors attempt an integration of the emerging basic science literature regarding the neuro-anatomy and physiology of the mammalian central serotonin nervous system, its influence on neural substrates that underlie fear and defense responses, and the clinical literature pertaining to serotonin-related abnormalities in panic disorder. A neuro-anatomical model for the potential sites of action of the specific serotonin reuptake inhibitors in panic disorder is proposed.

On the basis of preclinical studies, we hypothesized that deficient serotonin neurotransmission may be associated with the respiratory hyperactivity and carbon dioxide sensitivity seen in panic disorder. We used the tryptophan depletion method to investigate the effects of transient reductions in serotonin on respiration in five patients with panic disorder and seven normal control subjects. During room air breathing, the patients showed significantly increased ventilation when tryptophan-depleted, while the normal subjects showed no significant changes in respiration. These preliminary data suggest that serotonergic manipulation may affect ventilatory indices, with panic disorder patients being particularly sensitive to the effect of tryptophan depletion.

There is increasing evidence for an important role of adverse early experience on the development of major psychiatric disorders in adulthood. Corticotropin-releasing factor (CRF), an endogenous neuropeptide, is the primary physiological regulator of the mammalian stress response. Grown nonhuman primates who were exposed as infants to adverse early rearing conditions were studied to determine if long-term alterations of CRF neuronal systems had occurred following the early stressor. In comparison to monkeys reared by mothers foraging under predictable conditions, infant monkeys raised by mothers foraging under unpredictable conditions exhibited persistently elevated cerebrospinal fluid (CSF) concentrations of CRF. Because hyperactivity of CRF-releasing neurons has been implicated in the pathophysiology of certain human affective and anxiety disorders, the present finding provides a potential neurobiological mechanism by which early-life stressors may contribute to adult psychopathology.

An ambulatory monitor, body suit, and calibration procedure were developed to compare the respiration of seven patients with panic disorder and twelve normal volunteers. Subjects wore a body suit with Respitrace bands, connected to a portable respiratory monitor for a period of 24 hours. Breath by breath values for respiratory rate and tidal volume were computed every two minutes. There was a significant difference between patients and controls in their patterns of minute ventilation during sleep. Tidal volume, rather that respiratory rate increases characterized the periods of anxiety and limited symptom attacks.

The high comorbidity of panic disorder and depression might be anticipated on epidemiologic grounds alone. Both are common disorders with a characteristically chronic course, increasing the probability that a given patient with one disorder will develop the other. Symptoms of anxiety are highly prevalent among depressed patients; however, not all such symptoms represent an actual comorbid anxiety disorder. Conversely, about 50% of patients with panic disorder ultimately experience an episode of major depression. The comorbidity of panic disorder and depression has significant and potentially ominous prognostic implications; the high rate of suicide attempts observed in panic disorder are further exacerbated by the presence of a comorbid depression. Panic disorder and depression share well-defined disturbances in hypothalamic-pituitary-adrenal axis function, serotonergic neurotransmission, and growth hormone response to pharmacologic challenge. In addition, most of the available medications used to treat depression are also first-line therapy for panic disorder. Although initial studies suggested that patients with comorbid panic disorder and depression have a poorer treatment outcome, recent data show similar outcomes for patients with both disorders and those with panic disorder uncomplicated by depression.

In summary, VFD subjects appear to have sustained long-term behavioral and biologic sequelae following disruption of normative maternal-infant attachment patterns. The sequelae are primarily manifest as stable anxiety or affective traits and, from a biologic perspective, are most analogous to recent data that have emerged from studies of patients with PTSD. Multiple abnormalities are observed of systems directly involved in affect regulation. Further studies are required to clarify the pathologic ontogeny of the VFD condition and its potential relevance to human psychopathology.

The psychological and physiological effects of acute low-potency benzodiazepine administration on lactate-induced panic were examined in 10 patients with panic disorder (PD). The patients, who had panicked during a standard sodium-lactate infusion, underwent a repeat infusion modified by pretreatment with intravenous diazepam (5 mg). Acute Panic Inventory (API) scores preceding the second lactate infusion, which were associated with diazepam pretreatment, were significantly reduced in compared with those measured before the first lactate infusion. However, the second visit "fear of doom" item of the API was significantly reduced relative to the same time point of the first visit 35 min before lactate infusion, when diazepam had not yet been administered. Thus, the reduction of prelactate anxiety preceding the second infusion appeared to reflect both pharmacological and nonpharmacological contributions. The diazepam pretreatment condition was associated with a significantly increased infusion duration and a significant attenuation of rate of API symptom increase in response to lactate. Despite significant attenuation of lactate infusion effects associated with the diazepam pretreatment condition, 7 of 10 patients experienced a second panic attack. This pilot study suggests that diazepam pretreatment is associated with a marked reduction of symptomatic response during a second lactate infusion, although the magnitude of attenuation observed was insufficient to block lactate-induced panic in a majority of lactate-vulnerable PD patients.

In order to compare the ventilatory response of panic patients and normal controls, 21 panic disorder patients with agoraphobia and 21 normal controls underwent the Read rebreathing test. Panic patients panicked significantly more during the test, responded with more respiratory rate and less tidal volume, but showed no hypersensitivity to inhaled carbon dioxide compared to normal controls.

In this paper the authors examine the interrelationship of both the noradrenergic (NA) system and the hypothalamic-pituitary-adrenal (HPA) axis and its implications for panic disorder (PD). Seventeen PD patients and 16 healthy volunteers were challenged orally 12 weeks apart with the alpha 2-agonist clonidine (13 healthy volunteers and 12 patients repeated the challenge). Between challenges, PD patients were treated with fluoxetine, with 10 of 12 improving at least moderately. Both during the acute phase of the illness and during the phase of pharmacological improvement, patients demonstrated a greater percentage of reductions of plasma 3-methoxy-4-hydroxyphenylglycol (MHPG) and plasma cortisol during clonidine challenge. We used correlational matrices to examine the relationship between the NA system, as reflected by plasma MHPG, and the HPA axis, as reflected by plasma cortisol measures. Healthy volunteers exhibited multiple significant "couplings" between either baseline or maximal decrease (delta max) of plasma MHPG, with either baseline or delta max plasma cortisol measures both within the first and second challenges and between the first and second challenges. In contrast, PD patients demonstrated "uncoupling" of the NA system and the HPA axis, with no significant correlations observed between either baseline and/or maximal decrease (delta max) measures of MHPG with the same cortisol measures for either the first or second challenge. The same uncoupling was observed for NA/HPA correlations between the first and second challenges. These data suggest that the hyperresponsivity to clonidine in PD patients persists during fluoxetine treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

Objective: The authors determined the effects of antipanic treatment with fluoxetine on human growth hormone (GH) response to the alpha 2 agonist clonidine., Method: Seventeen patients with panic disorder and 15 healthy volunteers were challenged with clonidine. Thirteen of the patients and 12 of the volunteers were given a second challenge with clonidine 12 weeks later. The patients received open fluoxetine and the healthy subjects received no treatment between challenges. Subjects with high baseline human GH levels (greater than 2 ng/ml) at the first and second challenges were excluded from further analysis., Results: The patients with panic disorder (N = 13 for the first challenge and N = 9 for the second) had significantly lower human GH responses to clonidine than the healthy subjects (N = 14 during the first challenge and N = 9 for the second) during both challenges, despite clinical improvement in eight of the nine patients at the time of the second challenge., Conclusions: Blunted secretion of human GH in response to clonidine in patients with panic disorder persists despite clinical recovery.

Objective: Previous studies have indicated that patients with panic disorder are more likely than normal subjects to have acute panic attacks during inhalation of CO2, but methodological objections have been raised. In this study the authors attempted to address three of these methodological problems by ensuring that raters who assessed whether panic attacks occurred were blind to subjects' diagnoses, by randomizing the order of administration of 5% CO2 and hyperventilation, and by challenging a greater number of subjects with 7% CO2., Method: Patients with panic disorder and normal subjects underwent 20-minute inhalations of 5% CO2 and 7% CO2 and 15 minutes of room-air hyperventilation. Ratings of panic/no panic during each condition were made separately by an assessor blind to diagnosis and by the subject. Scores on four panic rating scales were also recorded before and after each intervention., Results: Room-air hyperventilation caused panic attacks in a small number of patients; the difference in panic rate between patients and comparison subjects was statistically significant by the subjects' but not by the raters' assessment. Panic rates during 5% CO2 and 7% CO2 were significantly greater among the patients by both assessments; the panic rate was greatest during 7% CO2. Order of administration did not significantly affect panic rates for hyperventilation and 5% CO2., Conclusions: Panic patients were clearly more sensitive to the anxiogenic effects of CO2 than comparison subjects, and CO2 was a more potent anxiogenic stimulus than room-air hyperventilation. Seven percent CO2 discriminated best between patients and comparison subjects and should be the focus of further research.

It has been proposed that certain adverse early experiences may play a role in determining subsequent susceptibility to adult anxiety and affective disorders and this relationship may be the result of altered neurodevelopment of the noradrenergic and/or serotonergic systems. In this study of nonhuman primates, the predictability of foraging requirements for mothers during an early period of their infants' lives was manipulated. When the offspring were young adults, these early manipulations were related to differences in behavioral response to acute administration of two putative anxiety-provoking agents: the noradrenergic probe, yohimbine, and the serotonergic probe, mCPP. These long-term effects of the developmental environment on subsequent pharmacological responsivity suggest that both neuronal systems may be permanently altered by early experiential factors.

Background: Although panic disorder is generally responsive to single antidepressant pharmacotherapy, a substantial percentage of patients fail either to respond adequately or to maintain a therapeutic response., Method: The authors report on seven consecutive openly treated patients with panic disorder who showed inadequate antipanic responses to treatment regimens including either a tricyclic (TCA) or fluoxetine. Those patients taking a TCA had fluoxetine added and those patients taking fluoxetine had a TCA added., Results: All seven patients showed an improvement in antipanic response to the combination treatment., Conclusion: The current case series is the first, to our knowledge, to suggest that the combination of a TCA and fluoxetine may provide a viable pharmacotherapeutic option for panic disorder patients who have failed to respond to an adequate trial of either a TCA or fluoxetine. Appropriate controlled studies are recommended.

Outcome of anxiety disorder treatment with psychotherapy and medication is generally as good as or better than that of other psychiatric illnesses. Nevertheless, refractory cases occur. The first step in approaching the treatment-resistant patient with an anxiety disorder is to be certain that the treatment has been adequate. Failure to provide an adequate dose of medication for adequate periods of time may be the most common cause of "treatment resistance." The second step is to reconsider the diagnosis and/or determine if new diagnoses have emerged since the original consultation. Depression and substance abuse are especially likely to complicate anxiety disorders. Several studies have shown that concomitant personality disorders (axis II) increase the occurrence of resistance to standard treatment and must be addressed through psychotherapy. Last, a variety of possible underlying medical conditions, including thyroid disorder, arrhythmia, and complex partial seizure, should be considered. Then, the clinician should consider a variety of pharmacologic approaches that are specific to each anxiety disorder. Panic disorder patients who are refractory to imipramine frequently respond to high-potency benzodiazepines, monoamine oxidase (MAO) inhibitors, serotonin reuptake inhibitors, or various combinations. Generalized anxiety disorder, if unresponsive to benzodiazepines, may respond to buspirone or a tricyclic antidepressant. Patients with obsessive compulsive disorder who have failed to respond to clomipramine or fluoxetine and other serotonin reuptake blockers may benefit from augmentation strategies using combination therapies including buspirone, fenfluramine, and neuroleptics. Social phobia refractory to beta-blockers and MAO inhibitors may benefit from buspirone, fenfluramine, and neuroleptics. Social phobia refractory to beta-blockers and MAO inhibitors may benefit from buspirone, fluoxetine, or alprazolam.

Twenty panic disorder patients with mitral valve prolapse showed amelioration of prolapse on repeat echocardiogram after treatment for panic disorder. This effect was significant when compared to repeat echocardiograms in eight psychiatrically normal control subjects with mitral valve prolapse.

Objective: To further the understanding of lactate-induced panic in patients with panic disorder, the authors examined cisternal lactate and carbon dioxide levels in nonhuman primates after infusions of sodium lactate comparable to those used in studies of human beings., Method: CSF and venous blood lactate, pH, PCO2, PO2, and bicarbonate were measured in five ketamine-anesthetized nonhuman primates, without mechanical ventilation, before and after they underwent infusions of sodium lactate. In addition, the same measurements were made for three of the five subjects who were given saline infusions., Results: Despite the development of the characteristic peripheral biochemical effects of infused sodium lactate--increased lactate and bicarbonate levels and metabolic alkalosis--no increases in central lactate or carbon dioxide levels were observed. Saline infusions produced no biochemical effects on venous and cisternal measures., Conclusions: The results of this study are in keeping with previous findings of nonpermeability of the blood-brain barrier to anionic compounds such as lactate. They therefore support theories of lactate panic based on cognitive and/or brainstem misevaluation of peripheral somatic sensations.

The antipanic utility of imipramine and monoamine oxidase inhibitors has led to hypotheses of noradrenergic and/or serotonin (5-HT)-related abnormalities underlying panic disorder (PD) and its agoraphobic complications. Further data support significant antipanic effects for agents with acute 5-HT reuptake blockade effects. It is unlikely that ameliorative effects observed following chronic administration of 5-HT drugs remain 5-HT specific. Despite a range of recently discovered 5-HT receptor subtypes, evidence for a specific receptor abnormality in PD is lacking. Preclinical studies suggest an important role for 5-HT effects in several animal models of anxiety, including separation-induced infant protest responses and respiratory modulation. Induction of anxiety with putative 5-HT agents such as meth-chloro-phenylpiperazine and fenfluramine lend further support to 5-HT involvement in anxiety states. Critical behavioral, physiologic, and neuroendocrine differences between putative 5-HT anxiogens and "classic" panicogens, such as lactate and carbon dioxide are discussed. We propose that 5-HT agents mediate antipanic effects through amelioration of a deranged internal evaluative mechanism along cybernetic lines, rather than simple augmentation or reduction of 5-HT function.

To assess the role of noradrenergic stimulation during lactate-induced panic, ten patients with panic disorder who panicked during a standard sodium-lactate infusion underwent a repeat infusion following intravenous clonidine pretreatment. Although clonidine significantly lowered prelactate systolic blood pressure, the drug did not significantly lower prelactate anxiety levels, as reflected by the Acute Panic Inventory (API). Clonidine blocked lactate-induced panic in four of ten subjects, a significant effect. Clonidine treatment also significantly attenuated lactate-panic symptoms, as reflected by time to panic and API comparison between trials. Nevertheless, over half the subjects still panicked in response to lactate despite clonidine. This preliminary study suggests that reduction of central noradrenergic activity by clonidine, at least at the dosage levels employed in the current study, only partially attenuates panic response to lactate. Noradrenergic theories of panic may not therefore fully account for lactate panicogenesis.

Eight unrestrained macaques were observed for 2 hours following either two oral doses of yohimbine (0.2 mg/kg and 2.0 mg/kg) or placebo administration. Four of the subjects were normally reared and four subjects had early maternal and social deprivation. In the normal subjects, yohimbine, at both doses, produced increased tension and enervation and decreased species-typical "normal" behaviors. In deprivation-reared subjects, low-dose yohimbine produced reductions in tension and enervation, and increases in "normal" behaviors. High doses of yohimbine diminished behavioral score differences between groups. The prominent increases in enervation observed in normally reared subjects suggests that yohimbine is not unequivocally anxiogenic. Moreover, early social deprivation may alter the pattern of response to yohimbine, perhaps as a result of aberrant neurodevelopment. This study reflects the role of experiential factors in determining patterns of affective response to putative anxiogenic agents.

Six unrestrained bonnet macaques were each observed after oral administration of four dosages of yohimbine hydrochloride (0.10, 0.25, 0.50, and 0.75 mg/kg) and a placebo. Yohimbine significantly increased episodes of motoric activation and affective response interspersed with intervals of behavioral enervation. Yohimbine scores correlated closely with baseline levels; there was no dose-response relationship. Response to oral yohimbine differed in several ways from subcutaneous and intravenous sodium lactate infusions, including prominent enervative symptoms and the appearance of sexual arousal. In light of the appearance of cyclic enervative episodes, this study suggests limitations to primate models of panic disorder utilizing oral yohimbine.

Symptoms compatible with a diagnosis of anxiety disorder frequently complicate the course of affective illness. Patients with depression may have panic attacks, phobias, severe social anxiety, obsessions, compulsions, and generalized anxiety. If the affective disorder is the primary condition, its treatment should be sufficient in most instances to relieve the concomitant anxiety symptoms. Thus, judicious choice of antidepressant therapy for treatment of major and atypical depression will usually resolve associated panic attacks, generalized anxiety, phobias, and compulsions. It must be recalled, however, that antidepressant therapy usually takes between 4 and 6 weeks to have full clinical effect; in the interim, anxiety symptoms may be the most troubling and disabling aspect of the illness. Therefore, using antianxiety agents in treating depressed patients who also have anxiety symptoms is often recommended while waiting for the antidepressant to work. Benzodiazepines are extremely useful for short-term treatment of most anxiety symptoms in depressed patients. The dose should be kept to the lowest possible to relieve symptoms, and the medication should be tapered and then discontinued once the underlying affective disturbance is relieved. Buspirone is also very effective in treating generalized anxiety disorder and may be used in conjunction with antidepressants of most classes. A wide range of behavioral and cognitive techniques may also help relieve anxiety symptoms in the depressed patient.