Decreased platelet alpha-2 adrenoceptor density in major depression: effects of tricyclic antidepressants and fluoxetine.

BACKGROUND: It has been suggested that major depression is accompanied by a subsensitivity of central alpha 2-adrenoceptors (alpha 2-ARs) and, consequently, by an impaired negative feedback on the presynaptic catecholaminergic neuron, which, in turn, may induce a disinhibition of noradrenergic output and norepinephrine release in response to any activation. METHODS: The maximum number of platelet binding sites (Bmax) and their affinity for [3H]-rauwolscine, a selective alpha 2-AR antagonist, were measured in unmedicated and medicated major depressed patients and in normal volunteers. Specific binding was defined as that inhibited by idazoxan, another alpha 2-AR antagonist. RESULTS: Unmedicated major depressed patients had significantly decreased platelet [3H]-rauwolscine binding Bmax values compared to normal volunteers. [3H]-rauwolscine binding Kd values did not differ significantly between unmedicated major depressed patients and normal controls. [3H]-rauwolscine binding Kd values were significantly higher in depressed patients treated with tricyclic antidepressants than in unmedicated patients. Subchronic treatment with fluoxetine did not significantly alter either [3H]-rauwolscine binding Bmax or Kd values. [3H]-rauwolscine binding Bmax values were significantly greater in men than in women. CONCLUSIONS: The results suggest that i) major depression is accompanied by decreased platelet alpha 2-AR density; and that ii) subchronic treatment with tricyclic antidepressants, but not fluoxetine, results in a decreased affinity of rauwolscine for platelet alpha 2-ARs.

Elevated serum interleukin-6 (IL-6) and IL-6 receptor concentrations in posttraumatic stress disorder following accidental man-made traumatic events.

BACKGROUND: Recently, it has been reported that serum interleukin-1 beta (IL-1 beta), but not soluble IL-2 receptor (sIL-2R), concentrations were significantly higher in patients with posttraumatic stress disorder (PTSD) than in normal volunteers, and that psychological stress in humans is associated with increased secretion of proinflammatory cytokines, such as IL-6. METHODS: The aim of the present study was to examine the inflammatory response system in patients with PTSD through measurements of serum IL-6, sIL-6R, sgp130 (the IL-6 signal transducing protein), sIL-1R antagonist (sIL-1RA; an endogenous IL-1 receptor antagonist), CC16 (an endogenous anticytokine), and sCD8 (the T suppressor-cytotoxic antigen). RESULTS: Serum IL-6 and sIL-6R, but not sgp130, sIL-RA, CC16, or sCD8, concentrations were significantly higher in PTSD patients than in normal volunteers. Serum sIL-6R concentrations were significantly higher in PTSD patients with concurrent major depression than in PTSD patients without major depression and normal volunteers. There were no significant relationships between serum IL-6 or sIL-6R and severity measures of PTSD. CONCLUSIONS: The results suggest that PTSD is associated with increased IL-6 signaling. It is hypothesized that stress-induced secretion of proinflammatory cytokines is involved in the catecholaminergic modulation of anxiety reactions.

Peripheral markers of serotonergic and noradrenergic function in post-pubertal, caucasian males with autistic disorder.

Some studies have suggested that disorders in the peripheral and central metabolism of serotonin (5-HT) and noradrenaline may play a role in the pathophysiology of autistic disorder. This study examines serotonergic and noradrenergic markers in a study group of 13 male, post-pubertal, caucasian autistic patients (age 12-18 y; I.Q. > 55) and 13 matched volunteers. [3H]-paroxetine binding Kd values were significantly higher in patients with autism than in healthy volunteers. Plasma concentrations of tryptophan, the precursor of 5-HT, were significantly lower in autistic patients than in healthy volunteers. There were no significant differences between autistic and normal children in the serum concentrations of 5-HT, or the 24-hr urinary excretion of 5-hydroxy-indoleacetic acid (5-HIAA), adrenaline, noradrenaline, and dopamine. There were no significant differences in [3H]-rauwolscine binding Bmax or Kd values, or in the serum concentrations of tyrosine, the precursor of noradrenaline, between both study groups. There were highly significant positive correlations between age and 24-hr urinary excretion of 5-HIAA and serum tryptophan. The results suggest that: 1) serotonergic disturbances, such as defects in the 5-HT transporter system and lowered plasma tryptophan, may play a role in the pathophysiology of autism; 2) autism is not associated with alterations in the noradrenergic system; and 3) the metabolism of serotonin in humans undergoes significant changes between the ages of 12 and 18 years.

Serotonergic and noradrenergic markers of post-traumatic stress disorder with and without major depression.

Some studies have suggested that disorders in the peripheral and central metabolism of serotonin (5-HT) and noradrenaline (NE) may play roles in the pathophysiology of post-traumatic stress disorder (PTSD). This study examines (1) the availability of plasma total tryptophan, the precursor of 5-HT, and tyrosine, the precursor of NE; and (2) the platelet 5-HT transporter and alpha 2-adrenoceptor (alpha 2-AR) binding sites in patients with PTSD and healthy volunteers. High-performance liquid chromatography (HPLC) was employed to measure plasma tryptophan and tyrosine as well as amino acids known to compete with the same cerebral transport system; that is, valine, leucine, phenylalanine, and isoleucine. The maximum number of binding sites (Bmax) and their affinity (Kd) for binding to [3H]-paroxetine and [3H]-rauwolscine, a selective alpha 2-AR antagonist, were determined. [3H]-paroxetine and [3H]-rauwolscine binding Kd values were significantly higher in patients with PTSD than in healthy volunteers. [3H]-rauwolscine binding Kd values were significantly higher in patients with PTSD and concurrent major depression (MD) than in PTSD patients without MD and healthy volunteers. Plasma tyrosine concentrations and the ratio of tyrosine/valine + leucine + isoleucine + phenylalanine + tryptophan were significantly higher in PTSD patients with MD than in those without MD and healthy volunteers. The results show that PTSD is accompanied by lower affinity of paroxetine binding sites and that PTSD with concurrent MD is accompanied by lower affinity of alpha 2-ARs and increased plasma tyrosine availability to the brain. The results suggest that (1) serotonergic mechanisms, such as defects in the 5-HT transporter system, may play a role in the pathophysiology of PTSD; and (2) that catecholaminergic mechanisms, such as increased precursor availability and lowered affinity of alpha 2-ARs, may play a role in the pathophysiology of PTSD with concurrent MD.

Risk and preventive factors of post-traumatic stress disorder (PTSD): alcohol consumption and intoxication prior to a traumatic event diminishes the relative risk to develop PTSD in response to that trauma.

BACKGROUND: Previous reports examined the effects of selected pre- (e.g. female gender, previous trauma), peri- (e.g. the horror of the trauma, threatened death) or post-exposure (e.g. the physical injury caused by the trauma) risk factors on the development of post-traumatic stress disorder (PTSD), an anxiety disorder associated with a traumatic event outside the range of usual human experience. We hypothesized that alcohol consumption prior to traumatic events may reduce the incidence rate of PTSD. The aim of this study was to examine the effects of the above risk factors and preventive factors, such as alcohol consumption, on the development of PTSD. METHODS: An epidemiological cohort study was carried out on 127 victims trapped in a ballroom fire. Data were collected, 7-9 months after the traumatic event, by means of the Composite International Diagnostic Interview (CIDI) and structured interviews, aimed to assess the above pre-, peri- and post-exposure factors. Logistic regression analysis was used to examine the association of PTSD with the etiologic factors and to delineate those risk factors which contribute most to the development of PTSD. RESULTS: Female gender, the number of previous trauma, a past history of simple phobia, threatened death, trauma exposure, hospitalization for trauma-induced injuries and the presence of burns increased the odds of PTSD, whereas a sense of control during the trauma, and alcohol consumption and intoxication decreased the odds of PTSD. Six factors made independent contributions to the prediction of PTSD, i.e. the number of previous trauma, a past history of simple phobia, loss of control (increase the odds), a sense of control, alcohol consumption and alcohol intoxication (decrease the odds). CONCLUSIONS: The results of this study show that the development of PTSD is determined by the effects of pre-, peri- and post-exposure risk factors and may be prevented by the effects of peri-traumatic factors, such as sense of control, alcohol consumption and intoxication.

Higher serum prolyl endopeptidase activity in patients with post-traumatic stress disorder.

BACKGROUND: It is reported that psychiatric disorders, such as depression and schizophrenia, are associated with changes in serum activity of prolyl endopeptidase (EC 3.4.21.26), a cytosolic endopeptidase, which cleaves peptide bonds on the carboxylside of proline in proteins of relatively small molecular mass. AIMS AND METHODS: The aims of the present study were to examine serum PEP activity in patients with post-traumatic stress disorder (PTSD) versus healthy volunteers. PEP activity has been determined by a fluorimetric assay. RESULTS: Serum PEP activity was significantly higher in patients with PTSD than in normal volunteers. Serum PEP activity was significantly higher in patients with PTSD and concurrent major depression than in patients with PTSD without major depression. In PTSD patients, there were no significant correlations between serum PEP activity and severity of PTSD symptoms. CONCLUSIONS: The results show that PTSD and, in particular, PTSD with concurrent major depression is associated with increased activity of PEP. RELEVANCE: these results may be of importance for the (i) neuroendocrine pathophysiology of PTSD since PEP degrades neuropeptides, such as arginine vasopressin (AVP) and thyrotropin releasing hormone (TRH); and (ii) etiology of PTSD, since PEP degrades behaviorally active neuropeptides, such as AVP, TRH, oxytocin, neurotensin and substance P, which play a key role in positive reinforcement, social interactions, emotions and stress responsivity.

Pre- and post-disaster negative life events in relation to the incidence and severity of post-traumatic stress disorder.

There is evidence suggesting that stressful life events may precede major psychiatric illness, such as major depression, and that the severity of a traumatic event outside the range of usual human experience may provoke post-traumatic stress disorder (PTSD). The present study was carried out to examine the effects of pre- and post-disaster stressful life events on the incidence rate of PTSD following two man-made traumatic events. An epidemiological study examining 127 victims of a flash fire in a ballroom and 55 motor vehicle accident (MVA) victims was undertaken. PTSD symptoms were assessed by means of the Composite International Diagnostic Interview and the pre- and post-disaster stressful life events by means of the Diagnostic Interview Schedule, Disaster Supplement. Binary logistic and multiple linear regression analyses were employed to examine the relationships between PTSD and pre- and post-disaster life events. There were no significant relationships between stressful life events the year prior to the traumatic event and the incidence or severity of PTSD. There were highly significant relationships between the cumulative number and event severity of post-disaster negative life events and the incidence rate and severity of PTSD. The post-disaster life events were significantly more related to the avoidance-depression dimension than to the anxiety-arousal dimension of PTSD. The most significant life events were: loss of job or income, broken relationships, serious illnesses or injuries in the victims and death or illness in close acquaintances. The results of this study show that the number and severity of additional stressful life events signal a higher risk to develop PTSD and a higher severity of the avoidance-depression dimension of PTSD symptomatology.

Serotonergic markers and lowered plasma branched-chain-amino acid concentrations in fibromyalgia.

The aims of the present study were to examine serotonergic markers, i.e. [3H]paroxetine binding characteristics and the availability of plasma tryptophan, the precursor of serotonin (5-HT), and the plasma concentrations of the branched chain amino acids (BCAAs), valine, leucine and isoleucine, in fibromyalgia. The [3H]paroxetine binding characteristics, B(max) and K(d) values, and tryptophan and the competing amino acids (CAA), known to compete for the same cerebral uptake mechanism (i.e. valine, leucine, isoleucine, phenylalanine and tyrosine), were determined in fibromyalgia patients and normal controls. There were no significant differences in the [3H]paroxetine binding characteristics (B(max) and K(d)) between fibromyalgia and control subjects. There were no significant differences in plasma tryptophan or the tryptophan/CAA ratio between fibromyalgia patients and normal controls. In the fibromyalgia patients, there were no significant correlations between [3H]paroxetine binding characteristics or the availability of tryptophan and myalgic or depressive symptoms. Patients with fibromyalgia had significantly lower plasma concentrations of the three BCAAs (valine, leucine and isoleucine) and phenylalanine than normal controls. It is hypothesized that the relative deficiency in the BCAAs may play a role in the pathophysiology of fibromyalgia, since the BCAAs supply energy to the muscle and regulate protein synthesis in the muscles. A supplemental trial with BCAAs in fibromyalgia appears to be justified.

The two-factorial symptom structure of post-traumatic stress disorder: depression-avoidance and arousal-anxiety.

UNLABELLED: The first part of this study showed that the DSM-III-R symptom structure of post-traumatic stress disorder (PTSD), i.e. criteria B (reexperience), C (avoidance-numbing), and D (arousal), and, consequently the diagnosis of PTSD, could not be validated in fire and car-accident victims. The aims of this study were to: (i) determine the factors as well as their structure in the symptoms of PTSD; and (ii) develop a new classification or typology of PTSD. Exploratory and confirmatory factor analyses and cluster analyses were employed to: (i) examine the factors in PTSD symptomatology; and (ii) find and validate adequate diagnostic criteria for PTSD. The Composite International Diagnostic Interview (CIDI), PTSD Module, was used between 7 and 9 months after the traumatic event in a study group of 185 victims of two different traumatic events, i.e. 130 fire and 55 car-accident victims. Our findings support the existence of two factors, i.e. a first labeled 'depression-avoidance (DAV) dimension', as it contains items reminiscent of depression and avoidance, and a second labeled 'the anxiety-arousal (AA) dimension', as it contains symptoms reminiscent of anxiety and increased arousal. Cluster analysis yielded two clusters, i.e. a cluster of subjects with PTSD cases and another with non-cases. Our PTSD algorithm was significantly less restrictive than the DSM-III-R diagnosis of PTSD. There are only quantitative, but no qualitative, differences between the cluster analytically derived classes. IN CONCLUSION: PTSD is not a well-delineated clinical entity, as there is a clinical continuum from PTSD non-cases to cases with less and more severe DAV and AA symptoms. It is more appropriate to express PTSD in terms of general severity of PTSD and severity of the DAV and AA dimensions.

Epidemiologic and phenomenological aspects of post-traumatic stress disorder: DSM-III-R diagnosis and diagnostic criteria not validated.

The aim of this cohort study was: (i) to validate the diagnostic criteria for post-traumatic stress disorder (PTSD) of the DSM-III-R; and (ii) to examine the incidence rate of PTSD in a study population exposed to two different traumatic events, i.e. a fire in a hotel ball-room and a multiple collision car-crash on a Belgian highway. One hundred and eighty-five victims (130 fire and 55 car accident victims) were assessed between 7 and 9 months after the traumatic event using the Composite International Diagnostic Interview (CIDI), PTSD Module, a fully structured diagnostic interview for the assessment of PTSD according to DSM-III-R criteria. Twenty-three percent of the study population met DSM-III-R criteria for PTSD. By means of unsupervised and supervised multivariate statistical analyses we were unable to validate the three-factorial structure, i.e. criteria B, C and D, of the DSM-III-R PTSD diagnosis. The latter relies heavily on the C diagnostic criteria, which appear to be too restrictive. Women were more likely to develop symptoms of reexperience (B) and arousal (D) than men. There was a significantly higher incidence of criteria B, C and D, but not of PTSD, in fire than in car-accident victims. Between 42 and 57% of the victims developed the first PTSD symptoms on the day of the trauma; within the next week these incidence rates increased to 77.1, 57.8 and 73.5% for criteria B, C and D, respectively. In conclusion, this study was unable to demonstrate the validity of the diagnostic criteria for PTSD according to DSM-III-R. The present cohort study has defined a number of factors that may predict new occurrences of PTSD symptoms after a traumatic event, i.e. gender, type of trauma and time delay between the trauma and the assessment of the diagnostic criteria.

Psychiatric morbidity and comorbidity following accidental man-made traumatic events: incidence and risk factors.

UNLABELLED: The aims of this study were to examine the incidence and risk factors of major depression, bipolar disorder, psychoactive substance use, psychotic and anxiety disorders in relation to post-traumatic stress disorders (PTSD) in a study group exposed to two different traumatic events, i.e. 128 fire and 55 motor vehicle accident victims. Data have been collected 7-9 months after the traumatic event. The diagnosis of axis-I diagnoses, other than PTSD, was made according to DSM-III-R criteria using the Structured Interview according to the DSM-III-R. The incidence of new-onset major depression was 13.4%, generalised anxiety disorder (GAD) 12.6 %, agoraphobia 10.2% and psychoactive substance use disorders 6%. Simple phobia, panic disorder and obsessive compulsive disorder had a much lower incidence (< 2.0%). Fifty-one percent of the victims with PTSD had one or more additional axis-I diagnoses, major depression (26.2%), agoraphobia (21.0%) and generalised anxiety disorder (24.6 %) being the most common. Physical injury was the single best predictor for major depression. The best predictors for the development of new-onset anxiety disorders, other than PTSD, were: type and horror of the trauma, the extent of physical injury, the loss of control during the traumatic event, contextual stimuli, younger age and female sex. IN CONCLUSION: comorbid disorders, such as depression, GAD and agoraphobia, commonly occur within the first few months after man-made accidental traumata. Trauma variables, which are known to be related to the development of PTSD, are also related to the occurrence of these comorbid disorders.

Platelet alpha2-adrenoceptor density in humans: relationships to stress-induced anxiety, psychasthenic constitution, gender and stress-induced changes in the inflammatory response system.

BACKGROUND: This study examined the effects of psychological stress on platelet alpha2-adrenergic receptor (alpha2-AR) binding sites in relation to stress-induced anxiety and changes in the inflammatory response system (IRS). METHODS: The maximum number of binding sites (Bmax) and their affinity (Kd) for [3H]rauwolscine, a selective alpha2-AR antagonist, and the stimulated production of tumor necrosis factor-alpha (TNFalpha), the Th1-like cytokine, interferon-gamma (IFNgamma), and the Th2-like cytokines, interleukin-10 (IL-10) and IL-5, were measured in 35 university students a few weeks before (baseline) as well as on the day before a difficult, oral examination (stress condition). The State-Trait-Anxiety Inventory (STAI) was recorded during both conditions. The Minnesota Multiphase Personality Inventory (MMPI-2) was used to assess psychasthenia (Scale 7). RESULTS: Academic examination stress induced a significant increase in alpha2-AR density in students whose STAI scores increased in the stress period, in female students and in students who scored higher on psychasthenia. There were significant and positive correlations between stress-induced anxiety and changes in alpha2-AR density. Stress-induced anxiety was accompanied by a pro-inflammatory and Th1-like response, i.e. increased IFNgamma and TNFalpha production. The stress-induced changes in platelet alpha2-AR density were significantly and positively related to the production of TNFalpha, IL-10 and IL-5 and negatively to that of IFNgamma. CONCLUSIONS: Subchronic psychological stress in humans induces increased alpha2-AR density, which is related to stress-induced anxiety, an anxiety-prone constitution and female sex. Increased alpha2-AR density is accompanied by a Th2-like response and increased TNFalpha production. The results suggest that: (i) alpha2-AR density is sensitive to graded differences in stress-induced anxiety; and (ii) psychological stress is accompanied by intertwined responses in the catecholaminergic system, such as alpha2-ARs, and the IRS, such as Th1/Th2-like functions and the production of TNFalpha.

Changes in platelet alpha-2-adrenoceptors in fibromyalgia: effects of treatment with antidepressants.

The aim of this study was to determine platelet alpha(2)-adrenergic receptor (alpha(2)-AR) binding sites in fibromyalgia both before and after treatment with sertraline or placebo. The maximum number of binding sites (B(max)) and their affinity (K(d)) for [(3)H]rauwolscine, a selective alpha(2)-AR antagonist, were measured in 13 normal volunteers and 22 fibromyalgia patients. Severity of illness was evaluated by means of the Hamilton Depression Rating Scale (HDRS) and dolorimetric assessments of tenderness at tender points. Fibromyalgia patients had repeated measurements of [(3)H]rauwolscine binding characteristics both before and after subchronic treatment with sertraline or placebo for 12 weeks. [(3)H]rauwolscine binding K(d) values were significantly higher in fibromyalgia patients than in normal volunteers. There were significant inverse correlations between [(3)H]rauwolscine binding K(d) values and duration of illness, age and lower energy. Significantly higher [(3)H]rauwolscine binding K(d) values were found in fibromyalgia patients in an early phase of illness (<3 years) than in fibromyalgia patients with a protracted illness (>3 years). Repeated administration of sertraline had no significant effects on [(3)H]rauwolscine binding B(max) or K(d) values. The results suggest that fibromyalgia and, in particular, fibromyalgia in an early phase of illness, is accompanied by lowered affinity of platelet alpha(2)-ARs.

Increased 24-hour urinary cortisol excretion in patients with post-traumatic stress disorder and patients with major depression, but not in patients with fibromyalgia.

There is now firm evidence that major depression is accompanied by increased baseline activity of the hypothalamic-pituitary-adrenal (HPA) axis, as assessed by means of 24-h urinary cortisol (UC) excretion. Recently, there were some reports that fibromyalgia and post-traumatic stress disorder (PTSD), two disorders which show a significant amplitude of depressive symptoms, are associated with changes in the baseline activity of the HPA axis, such as low 24-h UC excretion. The aim of the present study was to examine 24-h UC excretion in fibromyalgia and PTSD patients compared to normal controls and patients with major depression. In the three patient groups, severity of depressive symptoms was measured by means of the Hamilton Depression Rating Scale (HDRS) score. Severity of fibromyalgia was measured using a dolorimetrically obtained myalgic score, and severity of PTSD was assessed by means of factor analytical scores computed on the items of the Composite International Diagnostic Interview (CIDI), PTSD Module. Patients with PTSD and major depression had significantly higher 24-h UC excretion than normal controls and fibromyalgia patients. At a threshold value of > or = 240 micrograms/24 h, 80% of PTSD patients and 80% of depressed patients had increased 24 h UC excretion with a specificity of 100%. There were no significant differences in 24-h UC excretion either between fibromyalgia patients and normal controls, or between patients with major depression and PTSD patients. In the three patient groups, no significant correlations were found between 24-h UC excretion and the HDRS score. In fibromyalgia, no significant correlations were found between 24-h UC excretion and the myalgic score. In PTSD, no significant correlations were found between 24-h UC excretion and severity of either depression-avoidance or anxiety-arousal symptoms. In conclusion, this study found increased 24-h UC excretion in patients with PTSD comparable to that in patients with major depression, whereas in fibromyalgia no significant changes in 24-h UC were found.