BACKGROUND: Amygdala plays an important role in the neurobiological basis of panic disorder (PD), and the amygdala contains different subregions, which may play different roles in PD. The aim of the present study was to examine whether there are common or distinct patterns of functional connectivity of the amygdala subregions in PD using resting-state functional magnetic resonance imaging and to explore the relationship between the abnormal spontaneous functional connectivity patterns of the regions of interest (ROIs) and the clinical symptoms of PD patients. METHODS: Fifty-three drug-naïve, non-comorbid PD patients and 70 healthy controls (HCs) were recruited. Seed-based resting-state functional connectivity (rsFC) analyses were conducted using the bilateral amygdalae and its subregions as the ROI seed. Two samples t test was performed for the seed-based Fisher's z -transformed correlation maps. The relationship between the abnormal spontaneous functional connectivity patterns of the ROIs and the clinical symptoms of PD patients was investigated by Pearson correlation analysis. RESULTS: PD patients showed increased rsFC of the bilateral amygdalae and almost all the amygdala subregions with the precuneus/posterior cingulate gyrus compared with the HC group (left amygdala [lAMY]: t  = 4.84, P  <0.001; right amygdala [rAMY]: t  = 4.55, P  <0.001; left centromedial amygdala [lCMA]: t  = 3.87, P  <0.001; right centromedial amygdala [rCMA]: t  = 3.82, P  = 0.002; left laterobasal amygdala [lBLA]: t  = 4.33, P  <0.001; right laterobasal amygdala [rBLA]: t  = 4.97, P  <0.001; left superficial amygdala [lSFA]: t  = 3.26, P  = 0.006). The rsFC of the lBLA with the left angular gyrus/inferior parietal lobule remarkably increased in the PD group ( t  = 3.70, P  = 0.003). And most of the altered rsFCs were located in the default mode network (DMN). A significant positive correlation was observed between the severity of anxiety and the rsFC between the lSFA and the left precuneus in PD patients ( r  = 0.285, P  = 0.039). CONCLUSIONS Our research suggested that the increased rsFC of amygdala subregions with DMN plays an important role in the pathogenesis of PD. Future studies may further explore whether the rsFC of amygdala subregions, especially with the regions in DMN, can be used as a biological marker of PD.
Humans ; Panic Disorder ; Magnetic Resonance Imaging/methods* ; Amygdala ; Gyrus Cinguli ; Comorbidity

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Acupuncture ; Acupuncture Points ; Acupuncture Therapy ; Catgut ; Humans ; Panic Disorder/therapy* ; Perimenopause

OBJECTIVES: The objective of this study is to investigate differences in clinical characteristics between female panic disorder (PD) patients with abortion history (PD+A) and without abortion history (PD−A).METHODS: We examined data from 341 female patients diagnosed with PD. We divided the patients with PD into PD+A (82 patients) and PD−A (259 patients) to compare demographic and clinical characteristics. The following instruments were applied : stress coping strategies, NEO-neuroticism, the Anxiety Sensitivity Index-Revised (ASI-R), the Albany Panic and Phobia Questionnaire (APPQ), the Beck Depression Inventory, the Beck Anxiety Inventory (BAI) and the Sheehan Disability Scale.RESULTS: Compared to the PD−A, the PD+A group showed no significant difference in coping strategies. However, significantly higher scores in neuroticism, the ASI-R, the APPQ and the BAI were observed. In terms of health-related disability, the PD+A group did not show significant difference.CONCLUSIONS: Our results suggest that the PD+A group may differ from the PD−A group in trait markers such as neuroticism and anxiety sensitivity, and abortion history may be associated with panic-related symptom severity. Our study suggests that further consideration is needed on such clinical characteristics in PD patients with abortion history.
Abortion, Induced ; Anxiety ; Depression ; Female ; Humans ; Panic Disorder ; Panic ; Phobic Disorders

“Comfort women” are survivors of sexual slavery by the Imperial Japanese Army during World War II, who endured extensive trauma including massive rape and physical torture. While previous studies have been focused on the trauma of the survivors themselves, the effects of the trauma on the offspring has never been evaluated before. In this article, we reviewed the first study on the offspring of former “comfort women” and aimed to detect the evidence of transgenerational transmission of trauma. In-depth psychiatric interviews and the Structured Clinical Interview for DSM-5 Axis I Disorders were conducted with six offspring of former “comfort women.” Among the six participants, five suffered from at least one psychiatric disorder including major depressive disorder, panic disorder, posttraumatic stress disorder, adjustment disorder, insomnia disorder, somatic symptom disorder, and alcohol use disorder. Participants showed similar shame and hyperarousal symptoms as their mothers regarding stimuli related to the “comfort woman” issue. Increased irritability, problems with aggression control, negative worldview, and low self-esteem were evident in the children of mothers with posttraumatic stress disorder. Finding evidence of transgenerational transmission of trauma in offspring of “comfort women” is important. Future studies should include more samples and adopt a more objective method.
Adjustment Disorders ; Aggression ; Asian Continental Ancestry Group ; Child ; Depressive Disorder, Major ; Humans ; Methods ; Military Personnel ; Mothers ; Panic Disorder ; Rape ; Shame ; Slavery ; Sleep Initiation and Maintenance Disorders ; Stress Disorders, Post-Traumatic ; Survivors ; Torture ; World War II

BACKGROUND: Panic disorder (PD) and major depressive disorder (MDD) can occur concurrently, despite different clinical manifestations. Because MDD and PD patients tend to have more complicated conditions, understanding the co-occurrence and pattern of these conditions is important. Here, we investigated the influence of PD and MDD on each other, with respect to time interval. METHODS: Data from three national representative surveys were pooled (total 18,807 respondents), and the age of onset (AOO) of PD and MDD was analyzed. We performed Kaplan-Meier analysis to estimate separate survival functions, using the AOO of MDD and PD as the outcome. To understand the temporal effect of other disorders, we used a Cox proportional hazard model to estimate the hazard ratios for the onset of MDD/PD with other comorbidities as time-dependent covariates. RESULTS: PD elevated the risk of subsequent MDD by 1.5-fold, whereas MDD elevated the risk of subsequent PD by 3.8-fold. The effect of such an elevation risk was significant for up to 2 years. CONCLUSION: The results revealed a bidirectional relationship between MDD and PD. Each disease represents a risk of a subsequent occurrence of the other, which lasts for a considerable duration.
Age of Onset ; Comorbidity ; Depressive Disorder, Major ; Humans ; Kaplan-Meier Estimate ; Korea ; Panic Disorder ; Panic ; Proportional Hazards Models

OBJECTIVE: Treatment for panic disorder (PD) have evolved, although there is still a strong unmet need for more effective and tolerable options. The present study summarizes and discusses recent evidence regarding the pharmacological and neuromodulatory treatment of PD. METHODS: MEDLINE, Cochrane Library, PsycINFO and Thomson Reuters’s Web of Science were searched for clinical trials published between 2010 and 2018. We included all prospective experimental studies including randomized controlled trials (RCT) and other clinical trials with more than 10 patients. RESULTS: Only 11 articles met the inclusion criteria, including 4 RCT, 3 open clinical trials and 5 comparative clinical trials. RCT demonstrated efficacy of transcranial magnetic stimulation (TMS) in only one of two trials. Neither pindolol nor d-fenfluramine were effective in blocking flumazenil-induced panic attacks. Augmentation with quetiapine was not superior to placebo. Open trials indicated that escitalopram, vortioxetine and TMS may be effective. Comparative trials did not demonstrate superiority from any drug, but confirmed tranylcypromine, paroxetine, clonazepam and alprazolam as effective options. CONCLUSION: The current study confirmed the efficacy of tranylcypromine, paroxetine, clonazepam, alprazolam and escitalopram. Vortioxetine and TMS, with duration of 4 or more weeks, also seems to be effective. Quetiapine, pindolol and d-fenfluramine were not considered effective compounds.
Alprazolam ; Citalopram ; Clonazepam ; Humans ; Panic Disorder ; Panic ; Paroxetine ; Pindolol ; Prospective Studies ; Quetiapine Fumarate ; Transcranial Magnetic Stimulation ; Tranylcypromine

BACKGROUND: Internet-delivered psychological treatments have been suggested as a chance to expand the access to professional help. However, little is known about the usefulness of different support formats and approaches of digital treatments for panic disorder among clinicians. OBJECTIVE: This narrative review aimed to explore the recent evidence base on the efficacy and acceptability of different internet-delivered treatments for adults with panic disorder. METHODS: A systematic search in electronic databases (Pubmed/Medline, PSYNDEX) and a hand search were performed to identify articles on randomized controlled trials published within the past five years (2012/12/10–2017/12/12) in English peer-reviewed journals. RESULTS: Eight studies (1,013 participants) involving 10 interventions met the inclusion criteria. Nine interventions were primarly based on Cognitive Behavioral Therapy principles. Most interventions were effective, when compared to a control condition (6 of 8 comparisons). Minimal guidance was associated with improved outcomes in one study and adherence in two studies (3 comparisons). Furthermore, no differences were found based on treatment approach (2 comparisons). Regarding acceptability, the attrition rates were moderate to high, ranging from 9.8% to 42.1% of randomized participants. Adherence rates also varied largely (7.8–75%), whereas participant satisfaction of program completers was assessed overall high (5 studies). CONCLUSION: Diverse effective internet-delivered treatments are available for the self-management of panic symptoms. Especially selfguided and transdiagnostic Cognitive Behavioral Therapy approaches appear being efficient options for the dissemination in routine care. However, due to the limited evidence base, further efforts are required to improve the actual uptake of internet-delivered treatments and identify moderators of outcomes.
Adult ; Anxiety Disorders ; Cognitive Therapy ; Hand ; Humans ; Internet ; Panic Disorder ; Panic ; Self Care ; Telemedicine

OBJECTIVE: Classifying mental disorders on the basis of objective makers might clarify their aetiology, help in making the diagnosis, identify “at risk” individuals, determine the severity of mental illness, and predict the course of the disorder. This study aims to review biological and clinical markers of panic disorder (PD). METHODS: A computerized search was carried out in PubMed and Science Direct using the key words: “marker/biomarker/clinical marker/neurobiology/staging” combined using Boolean AND operator with “panic.” In addition, the reference lists from existing reviews and from the articles retrieved were inspected. Only English language papers published in peer-reviewed journals were included. RESULTS: Structural changes in the amygdala, hippocampus, cerebral blood level in the left occipital cortex, serotonin 5-TH and noradrenergic systems activation, aberrant respiratory regulation, hearth rate variability, blood cells and peripheral blood stem cells, hypothalamic–pituitary–adrenal axis dysregulation were identified as potential candidate biomarkers of PD. Staging was identified as clinical marker of PD. According to the staging model, PD is described as follows: prodromal phase (stage 1); acute phase (stage 2); panic attacks (stage 3); chronic phase (stage 4). CONCLUSION: The clinical utility, sensitivity, specificity, and the predictive value of biomarkers for PD is still questionable. The staging model of PD might be a valid susceptibility, diagnostic, prognostic, and predictive marker of PD. A possible longitudinal model of biological and clinical markers of PD is proposed.
Amygdala ; Biomarkers ; Blood Cells ; Diagnosis ; Hippocampus ; Mental Disorders ; Occipital Lobe ; Panic Disorder ; Panic ; Prodromal Symptoms ; Sensitivity and Specificity ; Serotonin ; Stem Cells

The core concept for pathophysiology in panic disorder (PD) is the fear network model (FNM). The alterations in FNM might be linked with disturbances in the autonomic nervous system (ANS), which is a common phenomenon in PD. The traditional FNM included the frontal and limbic regions, which were dysregulated in the feedback mechanism for cognitive control of frontal lobe over the primitive response of limbic system. The exaggerated responses of limbic system are also associated with dysregulation in the neurotransmitter system. The neuroimaging studies also corresponded to FNM concept. However, more extended areas of FNM have been discovered in recent imaging studies, such as sensory regions of occipital, parietal cortex and temporal cortex and insula. The insula might integrate the filtered sensory information via thalamus from the visuospatial and other sensory modalities related to occipital, parietal and temporal lobes. In this review article, the traditional and advanced FNM would be discussed. I would also focus on the current evidences of insula, temporal, parietal and occipital lobes in the pathophysiology. In addition, the white matter and functional connectome studies would be reviewed to support the concept of advanced FNM. An emerging dysregulation model of fronto-limbic-insula and temporooccipito-parietal areas might be revealed according to the combined results of recent neuroimaging studies. The future delineation of advanced FNM model can be beneficial from more extensive and advanced studies focusing on the additional sensory regions of occipital, parietal and temporal cortex to confirm the role of advanced FNM in the pathophysiology of PD.
Autonomic Nervous System ; Connectome ; Frontal Lobe ; Limbic System ; Neuroimaging ; Neurotransmitter Agents ; Occipital Lobe ; Panic Disorder ; Panic ; Parietal Lobe ; Rabeprazole ; Temporal Lobe ; Thalamus ; White Matter

To conceptualize a novel bio-psychosocial-behavioral treatment model of panic disorder (PD), it is necessary to completely integrate behavioral, psychophysiological, neurobiological, and genetic data. Molecular genetic research on PD is specifically focused on neurotransmitters, including serotonin, neuropeptides, glucocorticoids, and neurotrophins. Although pharmacological interventions for PD are currently available, the need for more effective, faster-acting, and more tolerable pharmacological interventions is unmet. Thus, glutamatergic receptor modulators, orexin receptor antagonists, corticotrophin-releasing factor 1 receptor antagonists, and other novel mechanism-based anti-panic therapeutics have been proposed. Research on the neural correlates of PD is focused on the dysfunctional “cross-talk” between emotional drive (limbic structure) and cognitive inhibition (prefrontal cortex) and the fear circuit, which includes the amygdala-hippocampus-prefrontal axis. The neural perspective regarding PD supports the idea that cognitive-behavioral therapy normalizes alterations in top-down cognitive processing, including increased threat expectancy and attention to threat. Consistent with the concept of “personalized medicine,” it is speculated that Research Domain Criteria can enlighten further treatments targeting dysfunctions underlying PD more precisely and provide us with better definitions of moderators used to identify subgroups according to different responses to treatment. Structuring of the “negative valence systems” domain, which includes fear/anxiety, is required to define PD. Therefore, targeting glutamate- and orexin-related molecular mechanisms associated with the fear circuit, which includes the amygdala-hippocampus-prefrontal cortex axis, is required to define a novel bio-psychosocial-behavioral treatment model of PD.
Glucocorticoids ; Molecular Biology ; Nerve Growth Factors ; Neuropeptides ; Neurotransmitter Agents ; Orexin Receptor Antagonists ; Panic Disorder ; Panic ; Serotonin