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Psychosomatic Medicine 66:23-28 (2004)
© 2004 American Psychosomatic Society

ORIGINAL ARTICLES

Hyperleptinemia in Subjects With Persistent Partial Posttraumatic Stress Disorder After a Major Earthquake

Shih-Cheng Liao, MD, Ming-Been Lee, MD, Yue-Joe Lee, MD and Tien-Shang Huang, MD

From the Department of Psychiatry (S.-C.L., M.-B.L., Y.-J.L.) and Department of Internal Medicine (T.-S.H.), National Taiwan University Hospital and National Taiwan University College of Medicine, and Department of Social Medicine, National Taiwan University College of Medicine (M.-B.L., T.-S.H.), and Graduate Institute of Epidemiology, College of Public Health, National Taiwan University (S.-C.L.), Taipei, Taiwan.

Address correspondence and reprint requests to Prof. Tien-Shang Huang, Department of Internal Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, 7 Chung-Shan South Road, Taipei, Taiwan. E-mail: huang{at}ntumc.org


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
 CONCLUSION
 REFERENCES
 
OBJECTIVE: Leptin, a peptide hormone derived from adipose tissue, regulates food intake and controls weight. Serum leptin levels may be elevated in critically ill patients and in cases of physical stress. Our aim was to examine the relationship between postdisaster psychiatric symptoms and serum leptin levels.

METHODS: We recruited 92 subjects who visited emergency medical stations immediately after the giant earthquake seized middle Taiwan on September 21, 1999. Of these cases, 43 met the criteria for subsyndromal acute stress disorder. Eighteen months later, we measured serum leptin levels and performed in-depth psychiatric assessments using the posttraumatic stress disorder subset in the Mini International Neuropsychiatric Instrument and the Brief Symptom Rating Scale short form.

RESULTS: After we adjusted for age, gender, and body mass index, serum leptin levels were significantly higher in the persistent subsyndromal group (N = 15; estimated marginal mean, 9.641; 95% confidence interval, 7.673–11.610) than in others (estimated marginal means, 4.775–6.368). A hyperaroused state predicted a higher adjusted leptin level. On the Brief Symptom Rating Scale, general severity index, paranoid tendency, anxiety symptoms, and depressive symptoms were positively correlated with adjusted leptin levels.

CONCLUSIONS: We found a direct relationship between stress-related psychopathologic symptoms and serum leptin levels. Subjects with persistent subsyndromal posttraumatic stress disorder and hyperarousal had significantly higher serum leptin levels. Therefore, leptin may be a valid neuroendocrinologic marker for the hypervigilant state of vulnerable people who have faced tremendous danger and uncertainty. Further studies are needed to examine the correlation between leptin levels and hypothalamic-pituitary-adrenal axis function, particularly the inverted diurnal serum leptin levels in hyperaroused subjects.

Key Words: leptin, • partial PTSD, • stress-related psychopathology, • natural disaster.

Abbreviations: BMI = body mass index;; BSRS = Brief Symptom Rating Scale;; GLM = general linear model;; HPA = hypothalamic-pituitary-adrenal;; MINI = Mini International Neuropsychiatric Instrument;; PTSD = posttraumatic stress disorder;; SCL-90-R = Symptom Check List-90-Revised.


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
 CONCLUSION
 REFERENCES
 
Leptin is the product of the obese (ob) gene and is secreted by adipocytes (1). It was initially described as a signaling factor that, after interacting with its receptor, induced a complex response, including control of food intake, energy expenditure, and body weight (2). Leptin receptors are abundant in brain areas such as the hypothalamus, cortex, dorsal Raphe nucleus, and cerebellum. Evidence supporting the claim that leptin is an adipostat was provided by the decreased body weight and improved metabolic control in rodents with genetic or diet-induced obesity that were injected with leptin (2).

Some psychiatric disorders and their pharmacologic treatments are associated with appetite and weight changes. Therefore, the pathophysiologic role of leptin in these psychiatric disorders was examined in several studies. However, the results were controversial. For example, normal (3), nocturnally elevated (4), and decreased (5) serum leptin levels were found in patients with major depression. This variability may be caused by the heterogeneous nature of current psychiatric diagnostic categories, the timing of blood sample collection, or different disease stages.

In addition to its function in metabolic control, leptin has important roles in regulating the hypothalamic-pituitary-adrenal (HPA) axis and the immune response (2,6–9). Leptin also correlates with sleep and locomotion (10,11). Leptin produces its behavioral effects by modulating brain reward circuitry (12) and possibly by inhibiting hypothalamic neuropeptide Y, corticotropin-releasing factor, and the adrenal axis (11,13,14). The leptin-HPA axis interaction may be of clinical importance, and recent findings have led to the suggestion that leptin is an acute-phase stress hormone (6). However, these studies were confined mostly to animal models, human volunteers, perioperative subjects, or critically ill patients (6,15–19). Data about people suffering from persistent, stress-related psychopathologic symptoms caused by a natural disaster are not available.

The purpose of this study was to investigate serum leptin levels in relation to stress-related psychopathology. Because partial posttraumatic stress disorder (PTSD) often accompanies postdisaster mental illness (20,21), we examined the correlation between leptin levels and the severity of psychological distress using structured psychiatric measurements. We used categorical and dimensional approaches of psychopathology to determine the specific relationship between serum leptin levels and psychometric data.


   SUBJECTS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 SUBJECTS AND METHODS
RESULTS
 DISCUSSION
 CONCLUSION
 REFERENCES
 
Subjects
For this study, 92 of the people who visited an emergency medical station after a major earthquake were recruited. They had no major systemic diseases or psychiatric disorders. The earthquake, measuring 7.2 on the Richter scale, struck central Taiwan at 1:47 AM on September 21, 1999 (921 Earthquake), and caused severe property damage in several counties near the epicenter; more than 2300 people were killed. All of the study subjects resided within 10 miles of the epicenter during the entire follow-up period. Few visitors to our emergency medical station met the criteria for full syndromal PTSD. Because of their psychiatric comorbidity (eg, alcohol abuse, major depression, and personality disorders), visitors with full syndromal PTSD were excluded from this neuroendocrinologic study (21). Most of our subjects had been terrified by the earthquake and were therefore referred to us by other physicians for psychosomatic complaints. We did not recruit visitors with severe physical injuries or major systemic diseases.

Measurement Schedules
We performed two waves of assessments. We conducted the first wave in an emergency medical service station during the second and third weeks after the earthquake. Because of ethical considerations and the complexity of the rescue work, we merely gathered gross medical history and structured screening data for PTSD (21). At that time, 43 subjects met the criteria for subsyndromal acute stress disorder. The other 49 subjects had demographic features comparable with those of the disease group but no subsyndromal acute stress disorder; they served as the comparison group. We conducted the second wave of the study 18 months after the earthquake. In addition to in-depth psychiatric measurements, we obtained a thorough medical history, physical examination, and serum leptin and cortisol levels.

We applied the PTSD subschedule of the Chinese version of the Mini International Neuropsychological Interview (MINI) as the diagnostic schedule in both waves of assessments. Senior psychiatric residents and attending doctors who received structured training in applying MINI performed this diagnostic schedule. The reliability and validity of MINI were previously examined (22). The validity of the PTSD subschedule of MINI (Chinese version) was proven in other disaster psychiatric studies in Taiwan (21,23). Using this subschedule, we recorded in categorical form (positive or negative) three symptomatic dimensions of PTSD: re-experiencing, numbness/avoidance, and hyperarousal. We defined partial PTSD subjects as those with a subsyndromal presentation of PTSD; they were positive for more than one but fewer than three symptoms (21).

At the 18-month follow-up, we assessed the syndromal presentation of PTSD and measured the frequency and severity of general psychiatric symptoms using the Brief Symptom Rating Scale (BSRS) (24). The BSRS is a self-report measure with 30 items rated from 0 to 4 on the basis of the degree of distress caused over the past week. Each item was scored 0, not at all; 1, a little bit; 2, moderately; 3, quite a bit; or 4, extremely. The BSRS has been shown to be a reliable and valid psychiatric self-rating scale for use in disaster psychiatry (23,25) and psychosomatic research in Taiwan (26–28). The BSRS was modified from the widely used Derogatis Symptom Check List-90-Revised (SCL-90-R) (29,30) and was designed to be used as a shorter form. Like SCL-90-R, the BSRS covers nine dimensions of psychopathology: somatization, obsessive-compulsive, interpersonal sensitivity, depression, anxiety, hostility, phobic-anxiety, and paranoid ideation, and additional symptoms including vegetative signs and suicidal ideation. The General Symptom Index is essentially a mean score of all BSRS categories. The BSRS had an excellent split-half reliability in various populations and a good internal structure according to factor analysis (24). In addition, BSRS scores are highly correlated with the parental form SCL-90-R among the medical population for each symptom dimension (24).

Leptin and Cortisol Assays
During the second wave of the study, we assessed serum leptin and cortisol by collecting venous blood samples between 8:00 AM and 9:00 AM. We instructed subjects to fast after midnight. We determined cortisol levels using the Amersham radioimmunoassay kit (Buckinghamshire, UK) and leptin levels using the Linco radioimmunoassay kit (St. Louis, MO). The interassay and intra-assay variation was less than 10%.

Data Analysis
Data were analyzed with SPSS for Windows (Version 8.0, SPSS Inc., Chicago, IL). To determine the statistical significance in continuous variables between groups, we used Student’s t test. A value of p < .05 was considered significant. We calculated the body mass index (BMI) by dividing the weight (kg) by the squared height (m2). To investigate the relationship between partial PTSD and serum leptin levels, we divided the subjects into four groups: in group A, subjects did not meet subsyndromal PTSD criteria during either wave of assessment; in group B, subjects met the criteria only during the first wave; in group C, subjects met the criteria only during the second wave; and in group D, subjects met the criteria during both waves of assessments. The logistic regression model with the Enter method and Wald test was applied to examine the predictors of partial PTSD diagnosis during the second wave of the study. Age, sex, educational level, and partial PTSD diagnosis at the first wave of study were the independent variables. Furthermore, the general linear model (GLM) with the general factorial procedure was applied to investigate the correlation between the two waves of diagnosis of partial PTSD and the serum leptin and cortisol levels. This procedure provides regression analysis and analysis of variance for one dependent variable by one or more factors or independent variables, or both.

Gender, age, and BMI may influence leptin levels (31). These three variables were used as covariates in this general linear model. Estimated marginal means of the leptin levels of each group were also obtained. The GLM with the general factorial procedure was also used to determine the predictive power of the PTSD symptom dimensions and their interaction for leptin and cortisol levels. The partial correlation between dimensional scores of symptoms in the BSRS, anorexic symptoms, and the leptin/cortisol level, which controlled for the effects of sex, age, and BMI, were also tested.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 SUBJECTS AND METHODS
 RESULTS
DISCUSSION
 CONCLUSION
 REFERENCES
 
The study population was predominantly female and relatively aged; these characteristics reflected the population characteristics we observed in the emergency medical service station (21). The mean body height was 155.85 ± 8.10 cm, mean body weight was 58.96 ± 9.13 kg, and mean BMI was 24.23 ± 2.90 kg/m2 (Table 1). The BMIs of most subjects were within normal limits based on the community survey in Taiwan. We found no significant demographic differences in the initial group of subjects defined in the first wave (Table 2). During the second wave of the study, 20 subjects fulfilled the criteria for partial PTSD. The unadjusted serum leptin levels were not significantly different between these two groups (Table 2). The logistic regression model showed that a diagnosis of partial PTSD at the first wave of the study (second to third week after the major earthquake) significantly predicted the diagnosis of partial PTSD in the second wave of the study (18-month follow-up; OR = 5.654, Wald = 8.148, 95% confidence interval for OR = 1.721–18.576, p = .0043). Other independent variables including sex, age, and education level failed to predict the diagnosis of partial PTSD in the second wave of the study. In the GLM of serum leptin, sex and BMI had significant effects on the serum leptin level (sex: F = 15.891, df = 1, p < .001; BMI: F = 17.522, df = 1, p < .001). A wave 1 diagnosis of partial PTSD (F = 5.306, df = 1, p = .024) and the interaction between wave 1 and wave 2 diagnoses of partial PTSD (F = 4.605, df = 1, p = .035) also had significant effects on the serum leptin level (Table 3). In the GLM of serum cortisol, sex (F = 9.827, df = 1, p = .002) was the only independent variable that had a significant effect on the serum cortisol level (Table 3). For the estimated marginal means of serum leptin levels in the wave 1 and wave 2 interactive grouping, subjects with persistent partial PTSD (group D; estimated mean, 9.641; 95% confidence interval, 7.673–11.610) were significantly higher than those in other groups (estimated means of group A = 6.204, B = 6.368, C = 4.775; Table 4).


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  		TABLE 1. Basic Demographic Data Obtained From 92 Subjects Who Visited an Emergency Medical Station After a Major Earthquake Struck Taiwan
 

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  		TABLE 2. Statistical Analysis of Basic Demographic Data Obtained From Subjects Who Visited an Emergency Medical Station After an Earthquake in Taiwan (N = 92)
 

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  		TABLE 3. General Linear Model Illustrating the Between-Subject Effects of Partial PTSD on Serum Leptin Levels During Both Waves of the Studya
 

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  		TABLE 4. Intergroup Differences of Estimated Marginal Means of Serum Leptin Levels Measured at the 18-Month Follow-Upa
 
We assessed the prevalence of each symptom dimension of PTSD at the second wave of the study: re-experiencing dimension occurred in 15.2% of the subjects, for the numbness/avoidance dimension in 3.3% and hyperarousal dimension in 19.6%. For these three symptom dimensions of PTSD measured in the second wave of study, in addition to the effects of sex and BMI, a positive hyperarousal symptom dimension was predictive of a higher leptin level (F = 9.322, df = 1, p = .003) (Table 5).


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  		TABLE 5. General Linear Model Illustrating the Between-Subject Effects of PTSD Symptom Dimensions on Serum Leptin Levelsa
 
The Cronbach {alpha} of BSRS was 0.8846; therefore, the reliability was acceptable. In the partial correlation between the scores of BSRS symptom dimensions and the leptin level, the general severity index (r = 0.294, p = .005), paranoid tendency (r = 0.287, p = .006), anxiety symptoms (r = 0.267, p = .011), phobic-anxiety (r = 0.259, p = .014), and depressive symptoms (r = 0.285, p = .006) were positively correlated with the adjusted leptin level (Table 6). The correlation between the serum leptin level and the single item in BSRS that measures anorexic symptoms was not significant (r = 0.142, p = .178). There was no significant correlation between serum cortisol and various symptom scores, except for phobic-anxiety (r = 0.216, p = .04).


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  		TABLE 6. Partial Correlation Between Serum Leptin and Cortisol Levels and Concurrent Psychiatric Symptom Dimensions Measured by the Short Form BSRS at the 18-Month Follow-Upa
 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
CONCLUSION
 REFERENCES
 
We found significant correlations between stress-related psychopathology and serum leptin levels in the victims of a major earthquake. The correlation was not dependent on gender, age, appetite, or BMI. Persistent partial PTSD significantly predicted higher serum leptin levels. Of the three symptom dimensions of PTSD, hyperarousal was positively correlated with leptin levels. Using the dimensional approach of psychopathology, we found that the severity of psychological distress, characterized by paranoid tendency, anxiety, and phobic tendency, was positively correlated with serum leptin level. These characteristics are indicative of hypervigilance. Hence, leptin may function as a satiety factor and as a valid neuroendocrinologic marker for the persistent hypervigilant state of vulnerable human beings who have faced tremendous danger and uncertainty.

Hyperaroused patients with partial PTSD have elevated serum leptin levels. In contrast, patients with narcolepsy, a disorder of dramatically reduced arousal, have profoundly reduced leptin levels. Schuld et al. (10) and Kok et al. (32) found that serum leptin levels were reduced by more than 50% in narcoleptic patients compared with the control groups. They suggested that low plasma leptin levels may predispose narcoleptic humans to weight gain and alter the complex regulation of food intake and metabolism. Therefore, leptin not only influences metabolic control in humans but also correlates with the level of vigilance, a specific psychic phenomenon.

Yehuda et al. (33) suggested that major depression and PTSD may be accompanied by opposing changes in HPA activity. The pattern of cortisol secretion and regulation in PTSD patients may reflect an exaggerated sensitization; conversely, the chronobiological alterations associated with depression may reflect dysregulation of the HPA axis. Complicated interactions exist between leptin and the HPA axis (8,34). Generally, the HPA axis responds to acute stress quickly, and the system adapts to chronic stress so that further responsiveness of the axis is maintained (35). Leptin may provide a source of negative feedback inhibition to this axis that is crucial for adapting to chronic stress (8). Dysfunction of the HPA axis may be associated with low plasma and urinary free cortisol concentrations in PTSD (36–38). The HPA axis may be overregulated in PTSD (39), and the hypersensitization of the HPA axis may be associated with hyperleptinemia.

Kain et al. (15) characterized the dynamics of circulating leptin in relation to the acute activation of the HPA axis. They reported that during the postoperative period, leptin levels immediately fell, later increased, and finally normalized. The reverse was true for the changes in serum cortisol. When vulnerable people are faced with catastrophic stress, their leptin levels may not return to normal; in these cases, persistent hyperleptinemia will result. Our plasma sampling time occurred long after the moment of disaster, and we found that higher serum leptin levels in subjects with persistent partial PTSD were significantly correlated with hyperarousal symptoms. Abnormal leptin-HPA axis counterregulation may be the neuroendocrinologic basis for this prolonged hyperaroused state. Because we collected a single blood sample 18 months after the disaster, serum cortisol was not significantly different between the group that had persistent partial PTSD and the group that did not.

Licinio et al. (7) measured serum leptin repeatedly and described pulsatile leptin levels that fluctuated rapidly and varied diurnally. Kain et al. (15) also reported biphasic changes in leptin levels that decreased initially and increased 24 hours later in patients during acute perioperative stress. Our determining serum leptin from a single plasma sampling may appear to be a methodological pitfall. However, we collected all subjects’ plasma samples at the same time of day, and after we grouped the subjects into four categories, we found very few outliers and no extreme variation in the distribution of leptin levels. Furthermore, leptin is secreted in a circadian fashion with a nocturnal rise in normal lean or obese people (7,40). Critically ill patients under physical stress may have a reverse or blunted circadian variation (6,16,17); this situation also applies to patients with narcolepsy (32). With our single-sample method, the significant differences between subjects who had persistent partial PTSD and those who did not may be a result of different diurnal patterns in serum leptin levels. The pathophysiologic features underlying persistent partial PTSD may be responsible for this altered circadian pattern. Perioperative stress is transient and varies considerably from a persistent catastrophic reaction induced by disaster. Whole-day and multiple plasma sampling techniques will be necessary to examine stress-related psychopathologic changes.

A specific example of the correlation between trauma and psychopathology can be also observed in patients with bulimia nervosa, who tend to have high rates of childhood sexual abuse (41) and sexual or physical assault or both (42). Leptin has been well researched in feeding and eating disturbances in humans; for instance, Brewerton et al. (43) reported low leptin levels in patients with bulimia nervosa. The relationship between leptin, previous trauma, and bulimia nervosa needs to be explored in future neuroendocrinologic studies.


   CONCLUSION
TOP
 ABSTRACT
 INTRODUCTION
 SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
 CONCLUSION
REFERENCES
 
We discovered a direct relationship between serum leptin levels and human posttraumatic stress. In future studies, we will examine the correlation between leptin and the function of the HPA axis. Two focal points in our study of the physiologic role of leptin in the human stress response are the inverted diurnal changes in serum leptin levels and the possible inhibitory effect of cortisol in hyperaroused people.

Received for publication April 7, 2003.

Revision received July 26, 2003.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
 CONCLUSION
 REFERENCES
 

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