Integrated genome-wide methylation and expression analyses provide predictors of diagnosis and early response to antidepressant in panic disorder.

BACKGROUND: We investigated differentially methylated and expressed genes between panic disorder (PD) and healthy controls (HCs) to determine whether DNA methylation and expression level of candidate genes can be used as biomarkers for diagnosis and early response. METHODS: Illumina infiniun Methylation EPIC (850 k) Beadchip for genome-wide methylation screening and mRNA sequencing was conducted in a discovery set (30 patients with PD and 30 matched HCs). The candidate gene loci methylation and expression were verified in an independent validation sample (101 PD patients and 107 HCs). RESULTS: In the discovery set, there were 3613 differentially methylated cytosine phosphate guanosine sites and these differential methylation positions were located within 1938 unique genes, including 1758 hypermethylated genes, 150 hypomethylated genes, and the coexistence of hypermethylation and hypomethylation sites were found in 30 genes. There were 1111 differential transcripts in PD compared to normal controls (850 down-regulated and 261 up-regulated). Further, 212 differentially expressed genes were screened (40 up-regulated and 172 down-regulated). In the validation set, compared with HCs, there was no significant difference in DNA methylation level of Casitas B-lineage lymphoma (CBL) gene loci (cg07123846). The expression level of CBL gene in PD patients was lower (vs. HCs). After four weeks' treatment, the baseline expression level of CBL gene in the responders was higher than nonresponders. LIMITATIONS: The sample size was limited. We only chose CBL as a candidate gene. Follow-up periods were short. CONCLUSIONS: There are differences in genome-wide DNA methylation and mRNA expression between PD patients and HCs. The changes in expression level of CBL gene may be an important molecular marker for PD diagnosis and early response.

Onset and temporal sequencing patterns of comorbidity between lifetime major depression, panic disorder and fibromyalgia.

OBJECTIVES: Fibromyalgia (FM) is a syndrome of unknown aetiology characterised by chronic widespread musculoskeletal pain and associated with high rates of psychiatric comorbidities, mainly mood and anxiety disorders.This study aims to determine the age at onset (AAO) and temporal sequencing patterns of FM and its frequent and distinguishable psychiatric comorbidities, the major depressive episode/s (MDE), and panic disorder (PD). METHODS: Diagnosis of MDE and PD were assigned using the Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders fourth edition (DSM-IV). The AAO of FM, MDE, and PD was defined using the event history calendar. All patients completed a sociodemographic data form, self-report questionnaires measuring FM-related symptoms and function, and the Childhood Trauma Questionnaire-28 (CTQ-28). RESULTS: 98 (83%) of the 118 recruited patients with FM had at least one psychiatric comorbidity. Two main temporal patterns were identified among the 83 patients (70.3 %) who could reliably report the age at onset of FM and psychiatric comorbidities. In the concurrent comorbidity pattern (CCP), MDE and/or PD co-occurred with the onset of FM. In the sequential pattern (SP), the patients first developed PD, then MDE, and finally FM. FM patients with SP are overweight and younger than those with a CCP (FM concurrent with MDE and PD) and reported more childhood adversities, mainly sexual abuse. AAO of psychiatric comorbidities significantly differed between the two patterns. CONCLUSIONS: The presence of different temporal comorbidity patterns may suggest prevention/early treatment interventions, especially in patients with childhood adversities and early-onset PD.

Asthma and early smoking associated with high risk of panic disorder in adolescents and young adults.

PURPOSE: Studies have reported a strong link between asthma and panic disorder. We conducted a 17-year community-based large cohort study to examine the relationship between asthma, early smoking initiation, and panic disorder during adolescence and early adulthood. METHODS: A total of 162,766 participants aged 11-16 years were categorized into asthma and nonasthma groups at baseline and compared within the observation period. Covariates during late childhood or adolescence included parental education, cigarette smoking by family members of participants, and participant's gender, age, alcohol consumption, smoking, and exercise habits. Data for urbanicity, prednisone use, allergic comorbidity, and Charlson comorbidity index were acquired from the National Health Insurance Research Database. The Cox proportional-hazards model was used to evaluate the association between asthma and panic disorder. RESULTS: Our findings revealed that asthma increased the risk of panic disorder after adjustment for key confounders in the Cox proportional hazard regression model (adjusted HR: 1.70, 95% CI 1.28-2.26). Hospitalizations or visits to the emergency department for asthma exhibited a dose-response effect on the panic disorder (adjusted HR: 2.07, 95% CI 1.30-3.29). Patients with asthma with onset before 20 years of age who smoked during late childhood or adolescence had the greatest risk for panic disorder (adjusted HR: 4.95, 95% CI 1.23-19.90). CONCLUSIONS: Patients newly diagnosed with asthma had a 1.7-times higher risk of developing panic disorder. Smoking during late childhood or adolescence increased the risk for developing the panic disorder in patients with asthma.

Panic disorder respiratory subtype: psychopathology and challenge tests - an update

Panic disorder (PD) pathophysiology is very heterogeneous, and the discrimination of distinct subtypes could be very useful. A subtype based on respiratory symptoms is known to constitute a specific subgroup. However, evidence to support the respiratory subtype (RS) as a distinct subgroup of PD with a well-defined phenotype remains controversial. Studies have focused on characterization of the RS based on symptoms and response to CO2. In this line, we described clinical and biological aspects focused on symptomatology and CO2 challenge tests in PD RS. The main symptoms that characterize RS are dyspnea (shortness of breath) and a choking sensation. Moreover, patients with the RS tended to be more responsive to CO2 challenge tests, which triggered more panic attacks in this subgroup. Future studies should focus on discriminating respiratory-related clusters and exploring psychophysiological and neuroimaging outcomes in order to provide robust evidence to confirm RS as a distinct subtype of PD.

Pre-treatment peripheral biomarkers associated with treatment response in panic symptoms in patients with major depressive disorder and panic disorder: A 12-week follow-up study.

OBJECTIVE: Peripheral biomarkers have been studied to predict treatment response of panic symptoms. We hypothesized that depressive disorder (MDD) vs. panic disorder (PD) would exhibit different peripheral biomarkers, and their correlation with severity of panic attacks (PA) would also differ. METHODS: Forty-one MDD patients, 52 PD patients, and 59 healthy controls were followed for 12 weeks. We measured peripheral biomarkers along with the Panic Disorder Severity Scale (PDSS) at each visit-pre-treatment, 2, 4, 8, and 12 weeks on a regular schedule. Peripheral biomarkers including serum cytokines, plasma and serum brain-derived neurotrophic factor (BDNF), leptin, adiponectin, and C-reactive protein (CRP) were quantified using enzyme-linked immunosorbent assay (ELISA). RESULTS: Patients with MDD and PD demonstrated significantly higher levels of pre-treatment IL-6 compared to controls, but no differences were seen in plasma and serum BDNF, leptin, adiponectin, and CRP. Pre-treatment leptin showed a significant clinical correlation with reduction of panic symptoms in MDD patients at visit 5 (p=0.011), whereas pre-treatment IL-6 showed a negative correlation with panic symptom reduction in PD patients (p=0.022). An improvement in three panic-related items was observed to be positively correlated with pre-treatment leptin in MDD patients: distress during PA, anticipatory anxiety, and occupational interference. CONCLUSION: Higher pre-treatment leptin was associated with better response to treatment regarding panic symptoms in patients with MDD, while higher IL-6 was associated with worse response regarding panic symptoms in PD patients. Different predictive peripheral biomarkers observed in MDD and PD suggest the need for establishing individualized predictive biomarkers, even in cases of similar symptoms observed in different disorders.

Pseudopheochromocytoma.

Pseudopheochromocytoma manifests as severe, symptomatic paroxysmal hypertension without significant elevation in catecholamine and metanephrine levels and lack of evidence of tumor in the adrenal gland. The clinical manifestations are similar but not identical to those in excess circulating catecholamines. The underlying symptomatic mechanism includes augmented cardiovascular responsiveness to catecholamines alongside heightened sympathetic nervous stimulation. The psychological characteristics are probably attributed to the component of repressed emotions related to a past traumatic episode or repressive coping style. Successful management can be achieved by strong collaboration between a hypertension specialist and a psychiatrist or psychologist with expertise in cognitive-behavioral panic management.

Development of a very brief scale for detecting and measuring panic disorder using two items from the Panic Disorder Severity Scale-Self Report.

OBJECTIVE: To minimize the burden in detecting and monitoring Panic Disorder and Agoraphobia by developing a very brief scale with selected items from the Panic Disorder Severity Scale-Self Report (PDSS-SR), and to investigate the proposed scale's psychometric properties in a comorbid sample. METHODS: A sample of 5103 patients from the Internet Psychiatry Clinic in Sweden, diagnosed and treated with Internet-based cognitive behavioral therapy for panic disorder (n = 1390), social anxiety disorder (n = 1313) or depression (n = 2400), responded to the PDSS-SR. Six criteria related to factor structure, sensitivity to change and clinical representativeness were used to select items. Psychometric analyses for the selected very brief scale were performed. RESULTS: Items 2 (distress during panic attacks) and 4 (agoraphobic avoidance), were selected to create the very brief PDSS-SR version. Correlations with the full scale were high at screening, pre and post, and for change (0.87-0.93). Categorical Omega was ⍵C = 0.74. With a cut-off of 3 points, the scale could detect panic disorder in a psychiatric sample with a sensitivity of 85% and a specificity of 66%. LIMITATIONS: Limitations include lack of healthy controls and lack of blinding on secondary outcome measures. CONCLUSION: The proposed 2-item PDSS-SR version is a good candidate for a very brief panic disorder questionnaire, both for detecting cases and for measuring change. This is especially useful in clinical settings when measuring more than one condition at a time.

A clinical TRIAD for early suspicion of autoimmune encephalitis as a possibility in patients presenting with progressive cognitive decline.

Patients with progressive cognitive decline mostly suffer from degenerative disease and carry a relatively poor prognosis. But small groups among these patients have a potentially treatable cause of illness and therefore every patient with dementia needs to be considered treatable unless proved otherwise. This group can be identified only by high degree of suspicion based on clinical clues. We have evaluated the validity of some simple clinical clues which we noticed in our patients with immune mediated dementias. The Panic score, Epsworth sleepiness score, catatonic symptoms and history of seizures were compared between 23 and 11 patients with serologically confirmed anti-NMDA antibody and anti-VGKC antibody associated encephalitis respectively. They were compared with 20 patients with probable behavioral variant of Frontotemporal dementia (bvFTD) and 20 patients with probable Alzheimer's disease (AD). Chi-square test was used to compare across the groups and there was significant difference (P < 0.05) across the 4 groups comprising anti NMDA encephalitis, anti VGKC encephalitis, FTD and AD among the four variables (Panic scores, Catatonic symptoms, Epsworth sleepiness score and seizures) studied. Our study revealed that panic and sleepiness is highly significant when tested across all groups and catatonia showed a trend towards NMDA and when compared with degenerative dementia versus immune mediated syndromes all the 4 parameters were highly significant This simple bedside TRIAD of panic, sleepiness with either of catatonia or seizures if found in patients it is appropriate to order antibody assessment before anything else is planned. This needs to be evaluated in a larger sample.

Flushing Disorders Associated with Gastrointestinal Symptoms: Part 2, Systemic Miscellaneous Conditions.

Flushing disorders with involvement of the gastrointestinal tract represent a heterogeneous group of conditions. In part 1 of this review series, neuroendocrine tumors (NET), mast cell activation disorders (MCAD), and hyperbasophilia were discussed. In this section we discuss the remaining flushing disorders which primarily or secondarily involve the gastrointestinal tract. This includes dumping syndrome, mesenteric traction syndrome, rosacea, hyperthyroidism and thyroid storm, anaphylaxis, panic disorders, paroxysmal extreme pain disorder, and food, alcohol and medications. With the exception of paroxysmal pain disorders, panic disorders and some medications, these disorders presents with dry flushing. A detailed and comprehensive family, social, medical and surgical history, as well as recognizing the presence of other systemic symptoms are important in distinguishing the different disease that cause flushing with gastrointestinal symptoms.

Body Image Dissatisfaction and Anxiety Trajectories During Adolescence.

The primary goal of this study was to examine the associations between baseline body image dissatisfaction (BID) and subsequent anxiety trajectories in a diverse, community sample of adolescent girls and boys. Participants were 581 adolescents (baseline age: M = 16.1, SD = 0.7; 58% female; 65% non-Hispanic White) from U.S. public high schools. Self-report questionnaires were administered during school at 3 annual assessment waves. Latent growth curve modeling examined the association between baseline BID and growth factors of anxiety disorder symptom trajectories. Covariates included baseline gender, age, race/ethnicity, parental education attainment, body mass index standard scores, and depressive symptoms. Higher BID at baseline was significantly associated with higher initial symptoms of generalized anxiety disorder (GAD), panic disorder (PD), social anxiety disorder (SAD), and significant school avoidance (SSA; ps = .001-.04) but was unrelated to initial separation anxiety disorder (SEP) symptoms (p = .27). Higher baseline BID also was associated with attenuated decreases in SAD symptoms across time (p = .001). Among adolescents with low baseline anxiety symptoms only, higher BID was associated with more attenuated decreases in SAD symptoms (p = .01) and greater increases in PD symptoms (p = .02). BID was unrelated to changes in GAD, SEP, and SSA symptoms (ps = .11-.94). Findings suggest that BID is associated with concurrent symptoms of multiple anxiety disorders and may have a prospective link to SAD and PD symptoms during adolescence. As such, assessing body image issues may be important to assess when identifying adolescents at risk for exacerbated SAD and PD symptoms.

Lesional Temporal Lobe Epilepsy: Beware the Deceitful "Panic Attack".

BACKGROUND: Ganglioglioma is a rare, benign, intraaxial glioneuronal tumor but a relatively common cause of pharmacoresistant temporal lobe epilepsy (TLE). Given its often nonspecific neuropsychiatric manifestations and frequently negative electroencephalographic workup, TLE can be easily misdiagnosed as a psychiatric disorder, particularly panic attacks. CASE DESCRIPTION: We present a case of a 17-year-old boy who was found to have lesional TLE secondary to a left temporal ganglioglioma, 5 years after having been misdiagnosed with panic disorder and having undergone ineffective and unnecessary psychotherapy. He was successfully cured by surgery. Although a few similar cases of TLE masquerading as a panic disorder have been previously reported in the literature, this is the youngest and only pediatric patient described to date. CONCLUSION: This report underscores the challenges in making an accurate clinical diagnosis of TLE and the importance of timely brain imaging whenever an atypical or medically refractory panic disorder is encountered.

Drug-induced panic attacks: Analysis of cases registered in the French pharmacovigilance database.

BACKGROUND: The potential role of drugs in the onset of panic attacks (PAs) is poorly understood. AIM: The objective of our study was to characterize drug-induced PAs. METHOD: We performed an analysis of PAs registered in the French pharmacovigilance database between 01/01/1985 and 05/11/2014. RESULTS: Among the 163 recorded cases, 136 (83.4%) were directly related to drugs, mainly antidepressants (11.3%, mainly serotonin reuptake inhibitors), mefloquine (7.2%), isotretinoin (5.2%), rimonabant (3.6%) and corticosteroids (4.7%). PAs are labelled in the Summary of Product Characteristics (SmPC) for a minority (8.6%) of these drugs. In 31.4% of these cases, withdrawal of the suspected drug was performed more than a week after the onset of PAs. PAs could also be secondary to another adverse drug reaction (ADR; n = 14, 8.6%), mainly an allergy to antineoplastic or immunomodulating agents. In 13 cases (8.0%), PAs occurred during a drug-withdrawal syndrome, mainly after benzodiazepines or opioids. Most cases (73%) involved patients without any previous psychiatric disorder. CONCLUSION: This is the first pharmacoepidemiological study about iatrogenic PAs. Beside antidepressants, the most often encountered drugs are not indicated for psychiatric diseases. This study also reveals that iatrogenic PAs mostly occur in patients without any psychiatric medical history and that PAs can be triggered by another ADR. Lastly, the many cases with delayed management underline the need to raise awareness of this relatively unknown ADR among physicians, especially since PAs are generally not labelled in SmPCs of the suspected drugs.

Características básicas do transtorno do pânico / Basic features of panic disorder

O objetivo é caracterizar o Transtorno do Pânico (TP) com ênfase em seu diagnóstico e tratamento. O TP é um dos transtornos de ansiedade, caracterizado por ataques de pânico recorrentes acompanhados por uma persistente preocupação com ataques adicionais e alterações mal adaptativas do comportamento (Associação Americana de Psiquiatria - DSM-V). Sua etiologia ainda não é conhecida, mas deve envolver uma interação de fatores genéticos, de desenvolvimento e ambientais que resultam em altera- ções no funcionamento de algumas áreas cerebrais. O tratamento farmacológico de primeira escolha é com o uso de antidepressivos inibidores seletivos da recaptação de serotonina, os quais apresentam uma latência de 20 a 30 dias para o início do efeito. (AU)

The aim of this paper is to characterize the Panic Disorder (PD) with an emphasis on diagnosis and treatment. PD is one of the anxiety disorders, characterized by recurrent panic attacks accompanied by a persistent preoccupation with additional attacks and maladaptive behavioral changes (American Psychiatric Association ­ DSM-V). Its etiology is not known, but should involve an interaction of genetic, developmental and environmental factors that result in changes in the functioning of some brain areas. The pharmacological treatment of choice is with the use of selective serotonin reuptake inhibitors, which has a latency of 20 for 30 days for the beginning of the therapeutic effect. (AU)

Cardiac sarcoidosis resembling panic disorder: a case report.

BACKGROUND: Sarcoidosis is a systemic disease of unknown etiology, in which granulomas develop in various organs, including the skin, lungs, eyes, or heart. It has been reported that patients with sarcoidosis are more likely to develop panic disorder than members of the general population. However, there are many unknown factors concerning the causal relationship between these conditions. CASE PRESENTATION: We present the case of a 57-year-old woman who appeared to have panic disorder, as she experienced repeated panic attacks induced by transient complete atrioventricular block, associated with cardiac sarcoidosis. Psychotherapy and pharmacotherapy were not effective in the treatment of her panic attacks. However, when we implanted a permanent pacemaker and initiated steroid treatment for cardiac sarcoidosis, panic attacks were ameliorated. Based on these findings, we diagnosed the patient's symptoms as an anxiety disorder associated with cardiac sarcoidosis, rather than panic disorder. CONCLUSIONS: This report highlights the importance of considering cardiac sarcoidosis in the differential diagnosis of panic disorder. This cardiac disease should be considered especially in patients have a history of cardiac disease (e.g., arrhythmia) and atypical presentations of panic symptoms. Panic disorder is a psychiatric condition that is typically diagnosed after other medical conditions have been excluded. Because the diagnosis of sarcoidosis is difficult in some patients, caution is required. The palpitations and symptoms of heart failure associated with cardiac sarcoidosis can be misdiagnosed as psychiatric symptoms of panic disorder. The condition described in the current case study appears to constitute a physical disease, the diagnosis of which requires significant consideration and caution.

Establishing Clinically Relevant Severity Levels for the Central Sensitization Inventory.

OBJECTIVES: The aim of this study was to create and validate severity levels for the central sensitization inventory (CSI), a valid and reliable patient-reported outcome instrument designed to identify patients whose presenting symptoms may be related to a central sensitivity syndrome (CSS; eg, fibromyalgia, chronic fatigue syndrome, irritable bowel syndrome), with a proposed common etiology of central sensitization (CS). METHODS: Based on CSI score means and standard deviations from previously published subject samples, the following CSI severity levels were established: subclinical = 0 to 29; mild = 30 to 39; moderate = 40 to 49; severe = 50 to 59; and extreme = 60 to 100. The concurrent validity of the CSI severity levels was then confirmed in a separate chronic pain patient sample (58% with a CSS diagnosis and 42% without) by demonstrating associations between CSI scores and (1) the number of physician-diagnosed CSSs; (2) CSI score distributions in both CSS and non-CSS patient samples; (3) patient-reported history of CSSs; and (4) patient-reported psychosocial measures, which are known to be associated with CSSs. RESULTS: Compared to the non-CSS patient subsample, the score distribution of the CSS patient subsample was skewed toward the higher severity ranges. CSI mean scores moved into higher severity levels as the number of individual CSS diagnoses increased. Patients who scored in the extreme CSI severity level were more likely to report previous diagnoses of fibromyalgia, chronic fatigue syndrome, temporomandibular joint disorder, tension/migraine headaches, and anxiety or panic attacks (P < 0.01). CSI severity levels were also associated with patient-reported depressive symptoms, perceived disability, sleep disturbance, and pain intensity (P ≤ 0.02). CONCLUSION: This study provides support for these CSI severity levels as a guideline for healthcare providers and researchers in interpreting CSI scores and evaluating treatment responsiveness.

The PHQ-PD as a Screening Tool for Panic Disorder in the Primary Care Setting in Spain.

INTRODUCTION: Panic disorder is a common anxiety disorder and is highly prevalent in Spanish primary care centres. The use of validated tools can improve the detection of panic disorder in primary care populations, thus enabling referral for specialized treatment. The aim of this study is to determine the accuracy of the Patient Health Questionnaire-Panic Disorder (PHQ-PD) as a screening and diagnostic tool for panic disorder in Spanish primary care centres. METHOD: We compared the psychometric properties of the PHQ-PD to the reference standard, the Structured Clinical Interview for DSM-IV Axis I Disorders (SCID-I) interview. General practitioners referred 178 patients who completed the entire PHQ test, including the PHQ-PD, to undergo the SCID-I. The sensitivity, specificity, positive and negative predictive values and positive and negative likelihood ratios of the PHQ-PD were assessed. RESULTS: The operating characteristics of the PHQ-PD are moderate. The best cut-off score was 5 (sensitivity .77, specificity .72). Modifications to the questionnaire's algorithms improved test characteristics (sensitivity .77, specificity .72) compared to the original algorithm. The screening question alone yielded the highest sensitivity score (.83). CONCLUSION: Although the modified algorithm of the PHQ-PD only yielded moderate results as a diagnostic test for panic disorder, it was better than the original. Using only the first question of the PHQ-PD showed the best psychometric properties (sensitivity). Based on these findings, we suggest the use of the screening questions for screening purposes and the modified algorithm for diagnostic purposes.

Is panic disorder associated with clinical severity of fibromyalgia? A preliminary study in a tertiary-care centre.

OBJECTIVES: To investigate the influence of panic disorder (PD) with/without agoraphobia on the clinical severity of fibromyalgia (FM). METHODS: Eighty-one patients with FM, among those consecutively referring to a tertiary-care setting, were included in this cross-sectional study. Psychiatric diagnoses were made by the structured clinical interview in accordance with the 4th-TR version of the diagnostic and statistical manual of mental disorders. The clinical severity of FM was measured by means of the following self-administered scales: Fibromyalgia Impact Questionnaire (FIQ), Fibromyalgia Assessment Status (FAS), Health Assessment Questionnaire (HAQ). RESULTS: A final sample of 66 females with FM with or without past PD was included in the analyses. The two groups did not significantly differ in age, years of education, length of illness or medication distribution. We did not find significant differences between the two groups in the FIQ and FAS scale scores, whereas subjects with FM and past PD showed significantly higher HAQ scale scores than those without past PD (p<.001). CONCLUSIONS: A history of PD in patients with FM increases the severity of functional impairment in performing a wide range of daily-life activities, as measured by the HAQ scale, with no effects on the severity of other clinical dimensions of FM. Potential underlying mechanisms and clinical implications will be discussed.

Recognizing postural orthostatic tachycardia syndrome.

This article describes the pathophysiology, clinical presentation, differential diagnosis, diagnosis, and management of postural orthostatic tachycardia syndrome (POTS), a potentially debilitating autonomic disorder that can have many causes and presentations. POTS can be mistaken for panic disorder, inappropriate sinus tachycardia, and chronic fatigue syndrome. Clinician suspicion for the syndrome is key to prompt patient diagnosis and treatment.

The Association of Panic Disorder, Posttraumatic Stress Disorder, and Major Depression With Smoking in American Indians.

INTRODUCTION: Rates of cigarette smoking are disproportionately high among American Indian populations, although regional differences exist in smoking prevalence. Previous research has noted that anxiety and depression are associated with higher rates of cigarette use. We asked whether lifetime panic disorder, posttraumatic stress disorder, and major depression were related to lifetime cigarette smoking in two geographically distinct American Indian tribes. METHODS: Data were collected in 1997-1999 from 1506 Northern Plains and 1268 Southwest tribal members; data were analyzed in 2009. Regression analyses examined the association between lifetime anxiety and depressive disorders and odds of lifetime smoking status after controlling for sociodemographic variables and alcohol use disorders. Institutional and tribal approvals were obtained for all study procedures, and all participants provided informed consent. RESULTS: Odds of smoking were two times higher in Southwest participants with panic disorder and major depression, and 1.7 times higher in those with posttraumatic stress disorder, after controlling for sociodemographic variables. After accounting for alcohol use disorders, only major depression remained significantly associated with smoking. In the Northern Plains, psychiatric disorders were not associated with smoking. Increasing psychiatric comorbidity was significantly linked to increased smoking odds in both tribes, especially in the Southwest. CONCLUSIONS: This study is the first to examine the association between psychiatric conditions and lifetime smoking in two large, geographically diverse community samples of American Indians. While the direction of the relationship between nicotine use and psychiatric disorders cannot be determined, understanding unique social, environmental, and cultural differences that contribute to the tobacco-psychiatric disorder relationship may help guide tribe-specific commercial tobacco control strategies.