Thomas W. Uhde

Psychiatric Characteristics of Children with Selective Mutism: A Pilot Study

OBJECTIVE To ascertain characteristics of children with selective mutism. METHOD Subjects with selective mutism were evaluated by means of parent and teacher rating scales and structured diagnostic interviews. RESULTS Thirty children were evaluated. Mutism severity varied markedly in different environmental settings. Ninety-seven percent of the subjects were diagnosed with social phobia or avoidant disorder of childhood or adolescence or both and 30% with simple phobia. No other psychiatric disorders were common. Parent and teacher rating scales showed high levels of anxiety symptoms, especially social anxiety, and low levels of all other psychiatric symptoms. Anxiety and social anxiety severity correlated with mutism severity. First-degree family history of social phobia and of selective mutism, obtained by family history method, was present in 70% and 37% of families, respectively. There was no evidence of a causal relationship between psychologically or physically traumatic experiences and development of selective mutism. CONCLUSIONS Selective mutism may be a symptom of social anxiety, rather than a distinct diagnostic syndrome. Further study of the characteristics of children with selective mutism and their families is warranted.

Nonlinear measures of respiration: Respiratory irregularity and increased chaos of respiration in patients with panic disorder

Background: Respiratory irregularity has been previously reported in patients with panic disorder using time domain measures. However, the respiratory signal is not entirely linear and a few previous studies used approximate entropy (APEN), a measure of regularity of time series. We have been studying APEN and other nonlinear measures including a measure of chaos, the largest Lyapunov exponent (LLE) of heart rate time series, in some detail. In this study, we used these measures of respiration to compare normal controls (n = 18) and patients with panic disorder (n = 22) in addition to the traditional time domain measures of respiratory rate and tidal volume. Methods: Respiratory signal was obtained by the Respitrace system using a thoracic and an abdominal belt, which was digitized at 500 Hz. Later, the time series were constructed at 4 Hz, as the highest frequency in this signal is limited to 0.5 Hz. We used 256 s of data (1,024 points) during supine and standing postures under normal breathing and controlled breathing at 12 breaths/min. Results: APEN was significantly higher in patients in standing posture during normal as well as controlled breathing (p = 0.002 and 0.02, respectively). LLE was also significantly higher in standing posture during normal breathing (p = 0.009). Similarly, the time domain measures of standard deviations and the coefficient of variation (COV) of tidal volume (TV) were significantly higher in the patient group (p = 0.02 and 0.004, respectively). The frequency of sighs was also higher in the patient group in standing posture (p = 0.02). In standing posture, LLE (p < 0.05) as well as APEN (p < 0.01) contributed significantly toward the separation of the two groups over and beyond the linear measure, i.e. the COV of TV. Conclusion: These findings support the previously described respiratory irregularity in patients with panic disorder and also illustrate the utility of nonlinear measures such as APEN and LLE as additional measures toward a better understanding of the abnormalities of respiratory physiology in similar patient populations as the correlation between LLE, APEN and some of the time domain measures only explained up to 50–60% of the variation.

A comparison of the effects of intravenous pentagastrin on patients with social phobia, panic disorder and healthy controls

The present study sought to determine whether social phobics, like patients with panic disorder, have increased sensitivity to the panicogenic effects of pentagastrin. Intravenous pentagastrin and placebo were administered in a double-blind fashion to 19 social phobics, 11 patients with panic disorder, and 19 healthy controls while they participated in a structured social interaction task. Behavioral, cardiovascular, and neuroendocrine responses were obtained. Pentagastrin led to panic attacks in 47% of the social phobics, 64% of the panic disorder patients, and 11% of the healthy controls. The social interaction itself increased anxiety, blood pressure, and pulse in all three groups. These findings suggest that the panicogenic effects of pentagastrin are not limited to patients with panic disorder and provide further evidence for shared neurobiology in social phobia and panic disorder.

Regional cerebral metabolic asymmetries replicated in an independent group of patients with panic disorder

BACKGROUND Abnormal left/right (L/R) hemispheric ratios of regional cerebral glucose metabolic rates (rCMRglc) (hippocampus and inferior prefrontal cortex) have been noted in unmedicated panic disorder patients. METHODS An independent group of panic disorder patients placed on imipramine was studied with positron-emission tomography, testing for evidence of normalization versus persistence of the abnormal rCMRglc ratios. Differences in orbital frontal rCMRglc values between the imipramine-treated and the previously reported unmedicated panic disorder patients were tested examining for evidence that the differences would resemble those noted in obsessive-compulsive disorder (OCD) patients treated with clomipramine. RESULTS We found the same abnormally low L/R hippocampal and posterior inferior prefrontal rCMRglc ratios in the imipramine-treated panic disorder patients. In addition, we found posterior orbital frontal rCMRglc decreases in the imipramine-treated panic disorder patients compared with the unmedicated panic disorder patients. CONCLUSIONS These abnormal asymmetries found in unmedicated panic disorder patients and now in imipramine-treated panic disorder patients may reflect a trait abnormality. The orbital frontal rCMRglc differences between the imipramine-treated and unmedicated patients are similar to changes noted in OCD patients treated with clomipramine and may reflect direct or indirect effects of imipramine treatment in panic disorder patients.

Normal urinary free cortisol and postdexamethasone cortisol in social phobia: comparison to normal volunteers

In primates, social stress is associated with activation of the hypothalamic-pituitary-adrenal (HPA) axis. Social phobia is a common, often disabling, form of pathological anxiety characterized by marked distress in situations involving possible scrutiny or evaluation. Little is known about HPA function in patients with social phobia. We examined 24-hour excretion of urinary free cortisol (UFC) in 54 patients with social phobia and post-dexamethasone cortisol levels in 64 patients with social phobia and found no evidence of HPA-axis overactivity compared to normal controls, despite pathological levels of anxiety.

Effects of intravenous caffeine administered to healthy males during sleep.

Pharmacological challenge paradigms have been useful for elucidating the phenomenology and neurobiology of panic attacks. A drawback of the pharmacological challenge method is that individual differences in baseline arousal and outcome expectancy can lead to different subjective and physiological drug responses. One method for eliminating differences in baseline arousal and expectancy is to perform pharmacological challenges during non‐rapid eye movement (non‐REM) sleep. In the present study, fourteen healthy male volunteers received caffeine (5 mg/kg) and placebo (normal saline) during non‐REM sleep on two successive nights, in a single‐blind manner. Caffeine, compared to placebo, was associated with increased arousal, sleep disruption, and elevations in adrenocorticotropic hormone (ACTH) and cortisol. In one subject, caffeine infusion during sleep induced a panic attack. These findings indicate that caffeine leads to increased arousal and hypothalamic‐pituitary‐adrenal axis (HPA) axis activation in the absence of high baseline anxiety and expectancy bias. Further, they suggest that similar techniques can be employed in patient populations to elucidate the neurobiology of sleep panic attacks. Depression and Anxiety 5:21–28, 1997.

Heart rate and QT interval variability: abnormal alpha-2 adrenergic function in patients with panic disorder

Anxiety disorders are associated with an increase in cardiovascular mortality. Studies using heart rate (HR) and QT interval variability measures suggest a decreased cardiac vagal function and a relatively increased sympathetic function in anxiety. This is important, as increased sympathovagal balance is associated with life-threatening arrhythmias. Several studies have shown that panic disorder is associated with an increased sensitivity to yohimbine and a blunted growth hormone response to clonidine, which are alpha-2 adrenoceptor antagonist and agonist, respectively. This study investigated the changes in QTvi (QT variance corrected for mean QT interval squared/HR variance corrected for mean HR squared) during placebo, oral clonidine (150 mg) and oral yohimbine (20 mg) in a double-blind design in 12 normal controls and 19 patients with panic disorder. HR and QT variability measures, especially QTvi, were obtained before and after the administration of these drugs to patients in supine and standing postures. As expected, patients with panic disorder became more anxious after yohimbine. In addition, the patients had a significant increase in QTvi after yohimbine and a significant decrease in QTvi after clonidine, which was not seen in the control group. The decreased anxiety after placebo was associated with decreased QTvi in patients. This study supports the previous reports of an abnormal sensitivity of alpha-2 adrenergic receptors in patients with panic disorder compared to controls and partly explains the association of increased cardiovascular mortality with conditions of anxiety. QTvi, a non-invasive indicator of cardiac repolarization lability, appears to be a useful tool to study cardiac sympathetic function.

Paroxetine decreases respiratory irregularity of linear and nonlinear measures of respiration in patients with panic disorder: A preliminary report

Previous studies indicate that serotonin reuptake inhibitors do not appear to have serious cardiac side effects. However, the effects of these agents on respiratory measures have not been studied in detail. Several studies indicate that patients with anxiety exhibit irregular breathing patterns as measured by tidal volume and respiratory rate. In this study, we evaluated the effects of a serotonin reuptake inhibitor, paroxetine, on respiratory variability in patients with panic disorder (n = 13), using linear and nonlinear measures of regularity, approximate entropy (APEN) and a measure of chaos, the largest Lyapunov exponent (LLE), with pre- and posttreatment lung volume time series (256 s long sampled at 4 Hz). Our results show that paroxetine significantly decreases some of the linear measures of variability and supine APEN and standing LLE of lung volume series after successful treatment. The implications of these findings on respiratory and cardiovascular function have been discussed.

Significant difference in beat-to-beat QT interval variability among different leads.

QT interval on the surface electrocardiogram (ECG) reflects the time for repolarization of myocardium, and QTc prolongation is strongly associated with sudden cardiac death. Findings of studies that have examined the dispersion of QT interval in 12-lead ECGs strongly suggest that an increased QT dispersion between different leads is associated with an increased risk of cardiac mortality. Recent studies using novel techniques on beat-to-beat QT interval variability have also shown that the interval is both influenced by the autonomic nervous system and a predictor of sudden cardiac death. However, in these studies the variability of QT was quantified in a single lead, and thus is different from QT dispersion. The present study examined whether there was a significant difference between QT variability (detrended QT variance [QTv]) and Qtvi (index of QT interval variability corrected for mean QT squared divided by heart rate variability corrected for mean heart rate squared) in 17 data sets of continuous ECGs recorded in three channels (leads V(5), V(1), and V(3)) during ambulatory monitoring of ECG digitized at 1,000 Hz. The results showed a highly significant difference between QT variability measures (QTv and QTvi) (P < 0.0001) in two of three lead configurations that were used (V(5) and V(1) versus V(3)). This finding underscores the importance of using the same lead while recording ECG for the calculation of QT variability, though further investigations are clearly warranted before any definitive conclusion can be made. These findings should be evaluated in relation to the issue of local versus global cardiac repolarization of ventricular myocardium.

Genetics and brain function: implications for the treatment of anxiety

In March 2000, the Anxiety Disorders Association of America (ADAA), jointly with the National Institute of Mental Health (NIMH), sponsored a conference entitled “Genetics and Brain Function: Implications for the Treatment of Anxiety.” With a focus on genetic implications for the understanding of anxiety and development of new treatments for the anxiety disorders, leading researchers presented advances on a spectrum of topics, with perspectives from basic science and clinical research. This meeting, as reflected in the compendium of articles in this issue (Bakshi and Kalin 2000; Caldji et al 2000; Goldsmith and Lemery 2000; Gross et al 2000; Rosenberg and Hanna 2000; Watson et al 2000), underscored two compelling realities regarding the field of anxiety (i.e., behavioral neuroscience) research. On the one hand, the human genome project, combined with emerging tools such as DNA microassays (Watson et al 2000), opens heretofore incomprehensible pathways of discovery into the role of genes in the important biological functions of anxiety, startle, fearful temperament, alarm, and arousal. On the other hand, the notion that the pathophysiology of any DMS-IV anxiety disorder might be exclusively linked to a single gene seems implausible. Nonetheless, the intellectual attractiveness of single gene hypotheses underlying pathologic anxiety is reminiscent of earlier single-neurotransmitter or single-receptor or receptor subtype theories of the anxiety disorders (Uhde et al 1990). With the advent of any new research tool (e.g., the “chip” [Watson et al 2000]; functional magnetic resonance imaging [fMRI] [Rosenberg and Hanna 2000]; gene targeting and tissue specific receptor manipulations [Bakshi and Kalin 2000; Gross et al 2000]), the evolution of scientific inquiry predictably moves from reductionist to integrative models of pathophysiology. Thus, though the biological targets of our research have become more discreet (organ to neurotransmitter, to receptor, to cellular, to molecular, etc.), the discovery of a final common pathway has so far eluded detection. It is probable that fear and anxiety are inevitably mediated by an interplay of factors. Using different terminology, the age-old question of “nature versus nurture” in the mediation of the anxiety disorders may not be elucidated by candidate gene or related methodologies. In fact, asking the nature versus nurture question itself may have delayed more relevant investigations into the relationships among mind, brain, and behavior. Several lines of evidence, as collectively represented in this issue (Bakshi and Kalin 2000; Caldji et al 2000; Goldsmith and Lemery 2000; Moldin 2000) and elsewhere, highlight that it is increasingly difficult to separate “Chicken–egg” types of causation when it comes to gene–environment interactions, perhaps especially in relation to complex emotions such as anxiety and behavioral inhibition. Genes present at birth shape later life experiences (e.g., trauma), behavioral traits (e.g., risk taking), environmental context (e.g., socioeconomic status, food consumption), and interpersonal dynamics (e.g., maternal bonding), factors that themselves collectively and separately affect gene expression. That genes and environment determine who we are as individuals is self-evident; more interestingly, perhaps, is how these same forces at one point in time may affect individuals across generations. A provocative and emerging area of study might be coined genomic sociology(i.e., how the impact of gene–environmental factors influences emotions and behavior across generations). This has a familiar ring, albeit using a distinctly different construct, similar to Carl Jung’s notions of archetypes and the collective unconscious (Jung 1968). How do genetic–environmental interactions influnce human behavior at a single time point and over time (within individuals) as well as across generations and divergent cultures? How do both genomic and nongenomic factors influence the risks for the emergence of anxiety disorders across generations (Francis et al 1999; Yehuda et al 1998)? It appears that we have the tools to begin to unravel such mysteries. Although the data presented at the ADAA/NIMH meeting do not exclude the importance of single genes in regulating some “seminal” feature(s) of any anxiety disorder, there is striking evidence to suggest that the functions of alarm, stress, and arousal in humans and animals are the result of multiple genes working in concert with environmental factors. Nonetheless, even a single susceptibility gene, which influences a key feature of a “polygenetic” anxiety disorder, may serve as a useful target for drug discovery and the development of therapeutic agents that improve a subset of symptoms and/or course of illness (Anderson and Cook 2000; Gray et al 2000; Kola 1999). The major reason for investigating the etiology of the anxiety disorders is to improve treatment. Tomorrow’s physician theoretically will have knowledge about anxiety susceptibility genes and, together with other infor-