Effect of comorbid anxiety disorders on the hypothalamic-pituitary-adrenal axis response to a social stressor in major depression.

BACKGROUND: Major depressive disorder (MDD) is often complicated by anxiety symptoms, and anxiety disorders occur in approximately 30% of mood cases. This study examined the influence of anxiety comorbidity on the hypothalamic-pituitary-adrenal (HPA) axis response to stress in patients with MDD. METHODS: Untreated subjects with pure MDD (n = 15), MDD with comorbid anxiety disorders (n = 18), and pure anxiety disorders (n = 15) were recruited by advertising. Age- and gender-matched control subjects were recruited for each subject with a psychiatric diagnosis (n = 48). All subjects underwent a social stressor, the Trier Social Stress Test (TSST), and blood was collected for adrenocorticotropic hormone (ACTH) and cortisol assay. RESULTS: When all depressed patients (n = 33) were compared with their matched control subjects (n = 33), they showed a significantly greater ACTH response to the stressor; however, this exaggerated ACTH response was exclusively due to the depressed group with comorbid anxiety disorders. A similar but nonsignificant effect was observed in the cortisol response. Subjects with pure mood or pure anxiety disorders showed normal ACTH and cortisol responses to the TSST. All patient groups showed similar levels of TSST-induced anxiety. CONCLUSIONS: Comorbid anxiety disorders might play a role in the increased activation of the HPA axis observed in patients with major depression.     

Alterations in stress cortisol reactivity in depressed preschoolers relative to psychiatric and no-disorder comparison groups

BACKGROUND: Despite the robust and widely replicated finding of elevated hypothalamic-pituitary-adrenal (HPA) axis reactivity in depressed adults, studies of depressed children have yielded ambiguous findings. Animal models of early depression and studies of children experiencing early psychosocial deprivation have suggested that alterations in HPA axis reactivity are evident in early "depressive-like" conditions. The current study is, to our knowledge, the first investigation of HPA axis reactivity in very young children with a clinical depressive syndrome for which content validity has been established. METHODS: Depressed, psychiatric, and no-disorder comparison children aged 3 through 5.6 years were studied for HPA axis reactivity in response to experimental psychosocial stressors. The children were diagnosed using a developmentally appropriate, structured psychiatric interview. Salivary cortisol was obtained at 3 time points during a laboratory assessment before and after stressors involving separation from the parent and frustrating tasks. RESULTS: Repeated measures of multivariate analysis of variance revealed a significant interaction between the diagnostic group and 2 cortisol percent change scores. Depressed preschoolers displayed a pattern of increasing cortisol levels throughout the assessment in response to both separation and frustration stressors. In contrast, both comparison groups showed decreasing cortisol levels in response to the separation stressor. All groups displayed increasing cortisol levels in response to frustrating tasks. Preschoolers with a presumptive melancholic depressive subtype displayed these alterations at a greater magnitude relative to comparison groups. CONCLUSIONS: To our knowledge, these findings are the first to demonstrate altered HPA axis reactivity in depressed preschoolers. These alterations are consistent with those described in depressed adults and in animal models of early depression. These findings provide evidence for possible continuity of HPA axis alterations in depressive disorders across the lifespan and are discussed in the context of prior studies of HPA axis reactivity in clinically depressed children and adolescents, suggesting that younger age and inpatient status are features associated with altered HPA axis reactivity.     

Children suffering from separation anxiety disorder (SAD) show increased HPA axis activity compared to healthy controls

Research questions

Separation anxiety disorder (SAD) is one of the most common mental disorders in childhood, and one of the earliest emerging. Little is known about the association between SAD and the hypothalamic-pituitary-adrenocortical (HPA) axis activity. Therefore, the present study aimed at investigating this association in children suffering from separation anxiety compared to healthy controls.

Methods

A total of 31 children with diagnosed SAD (mean age: 8.45; 17 females, 14 males) and 25 healthy controls (HC; mean age: 9.74; 12 females, 13 males) took part in the study. All participants underwent psycho-physiological testing for HPA axis challenge. Testing consisted of a separation and a social exposure paradigm. Saliva samples to assess HPA axis-related cortisol secretion were gathered in parallel.

Results

Compared to healthy controls, children with SAD showed greatly increased HPA axis activity, as reflected by an increased cortisol secretion throughout the entire period of investigation. The rise of cortisol was already observed in anticipation of, but not following the separation paradigm. No gender-related differences of cortisol secretion were observed.

Conclusions

Separation anxiety disorder (SAD) in children is reflected in greatly increased HPA axis activity. Compared to healthy controls, children with SAD showed increased cortisol values from the beginning of, and throughout, the entire investigation. This pattern of results suggests that both the anticipation of a separation and a persistent hyperactivity of the HPA axis system leads to an increased cortisol secretion.     

Peri-sleep-onset cortisol levels in children and adolescents with affective disorders.

BACKGROUND: Changes in the hypothalamic-pituitary-adrenal (HPA) axis, as evidenced by patterns of cortisol secretion, have been of interest in understanding depression and anxiety disorders across the life span. Previous studies of pediatric depression have pointed to the period around sleep onset as a key time point for observing alterations in cortisol secretion associated with affective disorders. Evidence also indicates that pubertal development may influence the expression of HPA dysregulation. We hypothesized that adolescents with depression and youth with anxiety disorders exhibit elevated peri-sleep-onset cortisol. METHODS: Plasma cortisol was sampled every 20 min around sleep onset from children and adolescents with major depressive disorder (n = 116), anxiety disorders (n = 32), or no history of psychiatric disorder (control; n = 76). Sleep onset was determined by polysomnography. Classification of participants as children or adolescents was based on Tanner staging of pubertal maturation. RESULTS: Children with anxiety disorders had higher peri-sleep-onset cortisol than children with depression or control children. Adolescents with depression had marginally higher peri-sleep-onset cortisol than control adolescents and significantly higher peri-sleep-onset cortisol than children with depression. CONCLUSIONS: Depression and anxiety are associated with altered cortisol secretion around sleep onset, and these changes appear to be influenced by pubertal maturation.     

Cortisol response to clonidine in panic disorder: comparison with depressed patients and normal controls

Abnormalities in regulation of noradrenergic function have been proposed as part of the pathology of depressive and panic anxiety disorders. However, abnormalities in hypothalamic-pituitary-adrenal (HPA) axis function have largely been limited to patients with depressive disorders. Using the cortisol response to clonidine, an alpha 2-adrenergic receptor agonist, this study examined the relationship between the noradrenergic system and the HPA axis in 10 patients with major depression (4 unipolar, 6 bipolar), 10 patients with panic disorder, and 10 normal controls. Baseline cortisol was significantly elevated in depressed as compared with panic patients, but not with controls. Depressed patients also tended to exhibit a greater absolute fall in plasma cortisol (5.2 +/- 4.0 micrograms/dl) compared with panic patients (1.7 +/- 2.4 micrograms/dl) (p less than 0.06, t-test). When expressed as a percentage of baseline, however, the cortisol response to clonidine did not differ significantly between diagnostic groups (p greater than 0.10). Basal levels of cortisol were highly correlated with the degree of decrease in cortisol induced by clonidine in the group of 30 subjects (r = -0.81, p less than 0.0001). These findings are discussed in the context of the utility of clonidine as a probe of the functional relatedness of the noradrenergic system and the HPA axis in these disorders.     

Corticotropin-releasing factor test in melancholic patients in depressed state versus recovery: a comparative study

PURPOSE: Basal adrenocorticotropin hormone (ACTH) and cortisol levels and their response to corticotropin-releasing factor (CRF) test were studied in melancholic depressive patients in depressed state and recovery, and compared with healthy controls. METHODS: Fifty-four outpatients diagnosed with unipolar depressive disorder with melancholic features according to DSM-IV and 23 healthy controls were included in the study. The Structured Clinical Interview for DSM-IV (SCID-IV) was used for diagnosis. Twenty-nine patients were in recovery, while 25 were in depressed state at the moment of the administration of the CRF test. FINDINGS: No differences were found between the recovered and depressed groups with respect to CRF test. Lower ACTH and higher cortisol levels with significant differences were shown in the neuroendocrine variables at 15, 30, and 60 min, and in peak response and increase, in the ACTH and cortisol response curves to CRF challenge between the groups of melancholic patients, both recovered and depressed, compared with the healthy control subjects. Moreover, recovered and depressed melancholic patients had a higher whole cortisol area under the curve with significant differences than the healthy control subjects. CONCLUSIONS: The crossover clinical status at the moment of the CRF test doesn't differentiate changes in the HPA axis in melancholic patients, while we did find significant differences in the group of healthy controls in comparison with the groups of melancholic patients both in depressive state and recovery. This supports the hypothesis that hypothalamic pituitary adrenal (HPA) axis shows alterations that remain in depressive patients even after recovery.     

Differences in hypothalamic–pituitary–adrenal axis functioning among children with ADHD predominantly inattentive and combined types

Some evidence suggests that the HPA axis may be dysfunctional in children with attention-deficit/hyperactivity disorder (ADHD). The aim of this study was to investigate whether a different pattern of HPA axis activity is found between the inattentive (I) and combined (C) subtypes of ADHD, in comparison with healthy control children. A total of 100 prepubertal subjects [52 children with ADHD combined type (ADHD-C), 23 children with ADHD predominantly inattentive type (ADHD-I), and 25 healthy control subjects] were studied. The effects of stress were studied by comparing cortisol responses to a psychosocial stressor, consisting of a public speaking task. Children with ADHD-I showed an elevated cortisol response to the psychosocial stressor, in contrast to children with ADHD-C who showed a blunted cortisol response to the psychosocial stressor. When a distinction was made between responders and non-responders (a subject was classified as a responder when there was an increase in cortisol reactivity), hyperactivity symptoms were clearly related to a lower cortisol reactivity to stress. The results indicate that a low-cortisol responsivity to stress may be a neurobiological marker for children with ADHD-C, but not for those with ADHD-I. Directions for future research and clinical implications are discussed.     

Associations between HPA axis functioning and level of anxiety in children and adolescents with an anxiety disorder

The hypothalamus-pituitary-adrenal (HPA) axis becomes active in response to stress. Hence, increased levels of anxiety in children and adolescents may be associated with changes in HPA-axis functioning. The aim of this study was to test if level of anxiety or specific anxiety disorders were associated with basal HPA axis activity in children and adolescents with an anxiety disorder. In 99 8- to 16-year-olds with an anxiety disorder, basal cortisol levels were assessed. It was tested if (1) cortisol levels correlated with the level of self-reported anxiety and (2) if cortisol levels were different for individuals with different anxiety disorders. In girls, low levels of anxiety were associated with a stronger rise in early morning cortisol concentrations. In both boys and girls, harm avoidance predicted low cortisol concentrations after awakening. Separation anxiety and physical anxiety symptoms predicted cortisol concentrations at noon. Differences between individuals with different anxiety disorders were not found. More research is needed regarding mechanisms that explain the associations that were found, and to investigate if treatment may influence HPA axis functioning in children and adolescents with an anxiety disorder.     

Basal activity of the hypothalamic-pituitary-adrenal axis in patients with depersonalization disorder

Depersonalisation disorder may occur during severe anxiety or following a traumatic event, suggesting a possible role of stress hormones. This study investigated basal activity of the hypothalamic-pituitary-adrenal (HPA) axis in patients with depersonalisation disorder. Salivary cortisol levels were measured at four time points over 12 h in patients with depersonalisation disorder (N=13), major depressive disorder (MDD, N=14) and healthy controls (N=13). Beck Depression Inventory scores were significantly higher in depersonalised subjects than controls, while MDD subjects demonstrated higher scores than both groups. Basal cortisol levels of depersonalised subjects were significantly lower than those of MDD subjects but not healthy controls. These results point to reduced basal activity of the HPA axis in depersonalisation disorder. This pilot study supports the distinction between depersonalisation disorder and major depressive disorder which should be examined in a larger sample.     

Increase in concentration of waking salivary cortisol in recovered patients with depression

OBJECTIVE: Dysfunction of the hypothalamic-pituitary-adrenal (HPA) axis with elevated plasma cortisol levels is characteristic of acute major depression. However, it is unclear whether HPA axis abnormalities are present in fully recovered patients. An increase in salivary cortisol levels after waking provides a simple, dynamic measure of HPA axis activity. The authors measured this increase in recovered depressed patients and in a healthy comparison group. METHOD: Salivary cortisol levels were measured upon waking and at 15-minute intervals for the next hour in 31 medication-free, recovered depressed patients and in 31 matched healthy comparison subjects. RESULTS: The increase in salivary cortisol levels that followed waking was significantly higher in the patients. CONCLUSIONS: Greater secretion of cortisol may be present in depressed subjects after clinical recovery and withdrawal of medication. This may put patients at risk of further episodes of depression as well as comorbid medical conditions, such as coronary heart disease.     

Salivary cortisol and psychopathology in children bereaved by the september 11, 2001 terror attacks.

BACKGROUND: Studies suggest that stressful events increase risk for childhood anxiety and depression and hypothalamic-pituitary-adrenal (HPA) axis dysregulation. This prospective longitudinal study evaluated relationships among severe psychosocial stress, psychiatric morbidity, and HPA axis function in children. METHODS: Forty-five children (mean age: 8.9 +/- 2.9 years) suffering parent death from September 11, 2001 terror attacks and 34 nonbereaved children (mean age: 9.3 +/- 2.5 years) were evaluated prospectively at 6-month intervals in this 2-year study. Assessments involved diagnostic interviews (Child Schedule for Affective Disorders and Schizophrenia [K-SADS]) for psychopathology and 3 days of baseline salivary cortisol and a salivary dexamethasone suppression test for HPA axis function. RESULTS: Bereaved children, but not nonbereaved children, had significantly increased rates of psychiatric disorders involving anxiety disorders, especially posttraumatic stress disorder (PTSD), after September 11, 2001 compared with retrospective assessments before September 11, 2001. Morning (AM) and 4:00 pm baseline cortisol were significantly and persistently higher for bereaved than nonbereaved children. Compared with bereaved children without psychopathology, bereaved children with PTSD had significantly lower 4:00 pm baseline cortisol and significantly greater 4:00 pm cortisol suppression. Children with generalized anxiety disorder had significantly less AM cortisol suppression than children without psychopathology. CONCLUSIONS: Children bereaved by sudden, unexpected parent death had persistent psychological dysfunction and HPA axis dysregulation in this study.     

Decreased adrenocorticotropic hormone and cortisol responses to stress in healthy adults reporting significant childhood maltreatment.

BACKGROUND: Preclinical research findings suggest that exposure to stress and concomitant hypothalamus-pituitary-adrenal (HPA) axis activation during early development can have permanent and potentially deleterious effects. A history of early-life abuse or neglect appears to increase risk for mood and anxiety disorders. Abnormal HPA response to stress challenge has been reported in adult patients with major depressive disorder and posttraumatic stress disorder. METHODS: Plasma adrenocorticotropin hormone (ACTH) and cortisol reactivity to the Trier Social Stress Test were examined in healthy adults (n = 50) without current psychopathology. Subjects with a self-reported history of moderate to severe childhood maltreatment (MAL) (n = 23) as measured by the Childhood Trauma Questionnaire were compared with subjects without such a history (CTL) (n = 27). RESULTS: Compared with CTLs, MAL subjects exhibited significantly lower cortisol and ACTH baseline-to-peak deltas. A significant group effect was seen in the (repeated measures) cortisol response to the stress challenge, reflecting lower concentrations among MAL subjects. A significant group x time effect characterized the relatively blunted ACTH response of the MAL group. Emotional neglect (-.34, p = .02) and sexual abuse (.31, p = .03) strongly predicted maximal cortisol release. CONCLUSIONS: In adults without diagnosable psychopathology, childhood maltreatment is associated with diminished HPA axis response to a psychosocial stressor. Possible explanations for the finding are discussed.     

The dexamethasone suppression test in prepubertal depressed children

The dexamethasone suppression test (DST) was performed in 50 hospitalized prepubertal children who met DSM-III criteria for major depressive episode, 18 hospitalized controls with a psychiatric disorder, and 18 nonhospitalized normal controls. Baseline and post-DST cortisol levels were measured at 8 a.m. and 4 p.m. The depressed children had consistently higher cortisol levels than the controls at baseline and post-DST. The DST was positive in 82% of depressed children, 28% of psychiatric controls, and 11% of normal controls. The results indicate that prepubertal depressed children may have abnormalities in the hypothalamic-pituitary-adrenal axis similar to those in adults with a major depressive illness.     

Co-occurring manic symptomatology influences HPA axis alterations in depression

Although dysfunctioning of the HPA axis is considered to be a core pathophysiological process in mood disorders, the evidence with regard to depression remains conflicting. This could partly be due to the large heterogeneity within mood disorders, since HPA axis abnormalities may also be associated with the extent of co-occurring manic symptomatology as is seen in bipolar disorder. In this study, patients with depressive disorder and bipolar spectrum disorders were studied with regard to their HPA axis functioning. In 304 healthy controls, 1134 patients with pure unipolar depressive disorder (UP), and 133 bipolar spectrum disorder patients (BD spectrum), cortisol was measured in 7 saliva samples to determine the 1 h cortisol awakening response (CAR), evening cortisol levels and cortisol suppression after a 0.5 mg dexamethasone suppression test. Both patient groups had overall higher CAR levels compared to controls, but only UP patients showed a higher increase over time in the CAR. A linear association was found between increasing bipolarity and cortisol diurnal slope: BD spectrum patients had a significantly higher diurnal slope than UP patients. Dexamethasone suppression did not differ between mood disorder diagnoses. The heterogeneity in HPA axis functioning in patients with depression can partially be explained by co-existing manic symptomatology, since an increase in the CAR appears to be more specific for pure depression whereas the presence of bipolarity is associated with an increase in the diurnal slope of cortisol.     

Salivary cortisol is associated with diagnosis and severity of late-life generalized anxiety disorder

Age-associated alterations in hypothalamic-pituitary-adrenal (HPA) axis functioning may make individuals more susceptible to HPA dysregulation in the context of mood and anxiety disorders. Little to no research has been done to examine HPA axis function in generalized anxiety disorder (GAD), particularly in late-life GAD, the most prevalent anxiety disorder in the elderly. The study sample consisted of 71 GAD subjects and 40 nonanxious comparison subjects over 60 years of age. We examined the hypotheses that elderly individuals with GAD will have elevated salivary cortisol levels compared to nonanxious subjects, and that elevated cortisol levels in GAD will be associated with measures of symptom severity. We report that late-life GAD is characterized by elevated basal salivary cortisol levels, with higher peak cortisol levels and larger areas under the curve, compared to nonanxious subjects. Additionally, severity of GAD as measured by the GAD Severity Scale and the Penn State Worry Questionnaire are positively correlated with cortisol levels. These data demonstrate HPA axis dysfunction in late-life GAD and suggest the need for additional research on the influence of aging on HPA axis function in mood and anxiety disorders.     

Neuroendocrinological mechanisms of actions of antidepressant drugs

Noradrenaline or serotonin (5-HT) reuptake-inhibiting antidepressants such as reboxetine or citalopram acutely stimulate cortisol and adrenocorticotrophic hormone (ACTH) secretion in healthy volunteers, whereas mirtazapine acutely inhibits the ACTH and cortisol release, probably due to its antagonism at central 5-HT(2) and/or H(1) receptors. These differential effects of antidepressants on cortisol and ACTH secretion in healthy subjects after single administration are also reflected by their different time course in the down-regulation of hypothalamic-pituitary-adrenocortical (HPA) axis hyperactivity in depressed patients as assessed by serial dexamethasone (DEX)/corticotrophin-releasing hormone (CRH) tests: Reuptake-inhibiting antidepressants such as reboxetine gradually normalise HPA axis hyperactivity in depressed patients during several weeks of treatment via up-regulation of mineralocorticoid and glucocorticoid receptor function and by step-by-step restoration of the disturbed feedback control. By contrast, mirtazapine markedly reduces HPA axis activity in depressed patients within 1 week, but there is a partial re-enhancement of HPA hormone secretion after several weeks of therapy. In all studies performed to date, the short-term effects of daily treatment with antidepressants on the DEX/CRH test results are comparable in responders and nonresponders. Moreover, a reduction in HPA axis activity is not necessarily followed by a favourable clinical response and some depressed patients keep on showing nonsuppression in the DEX/CRH test despite clinical improvement. Therefore, the importance of HPA axis dysregulation for the short-term efficacy of antidepressants continues to be a matter of debate. However, there are convincing data suggesting that persisting nonsuppression in the DEX/CRH test despite clinical remission predicts an enhanced risk for relapse of depressive symptomatology with respect to the medium- and long-term outcome.     

Late-life depressive symptoms are associated with both hyperactivity and hypoactivity of the hypothalamo-pituitary-adrenal axis.

OBJECTIVE: Although depression has been associated with hyperactivity of the hypothalamo-pituitary-adrenal (HPA) axis, recent studies among depressed elderly have found decreased cortisol levels, which may be due to underlying physical frailty associated with HPA-axis hypoactivity. The authors examined the relationship between urinary cortisol level and late-life depressive symptoms. The authors also explored whether hypo- and hypercortisolemic depressive symptoms are qualitatively different. METHODS: Data are from 881 community-dwelling participants, average age 74.2 years, of the Aging in the Chianti Area Study. Depressive symptoms were assessed using the Center for Epidemiologic Studies Depression Scale (CES-D) scale and cortisol levels were determined in 24-hour urine samples. RESULTS: Mean urinary cortisol level was 98.9 microg/24 hours (SD=47.8), and 31% of the sample had significant depressive symptoms (CES-D > or =16). There was no linear association between urinary cortisol level and depressive symptoms; however, there was a nonlinear association between urinary cortisol level and depressive symptoms. Older persons in the lowest and highest urinary cortisol deciles were 2.2 and 1.9 times more likely to have significant depressive symptoms than older persons in all other deciles. Depressed persons with low cortisol presented more physical frailty than depressed persons with high cortisol. CONCLUSION: Late-life depressive symptoms are associated with both hyperactivity and hypoactivity of the HPA axis, which suggests distinct mechanisms for these associations.     

Examining cortisol rhythmicity and responsivity to stress in children with Tourette syndrome

BACKGROUND: Tourette syndrome (TS) is characterized by motor and vocal tics, which are often exacerbated by stress. The hypothalamic-pituitary-adrenocortical (HPA) axis, a major stress response system is thus of interest for understanding TS. METHODS: Diurnal cortisol rhythms were estimated in medication-free children 7-13 years with TS (N=20) and healthy age-matched controls (N=16). Salivary samples were collected on 3 consecutive days from the home. HPA responsivity was assessed by examining cortisol in response to a mock and real MRI scan. RESULTS: The results of diurnal rhythmicity revealed a trend showing marginally lower evening cortisol for the TS group. By contrast, the TS group had higher cortisol levels in response to the stressor. There were strong, negative correlations between evening cortisol and tic severity as well as diurnal cortisol and anxiety. CONCLUSIONS: The children with TS showed increased cortisol in response to the MRI environment, supporting a model of enhanced HPA responsivity. The lower evening cortisol may be the result of chronic daily stress. Alternatively, the negative associations between cortisol and reported anxiety and tics may reflect biologically based anxiolytic properties of tic expression. Taken together, the results clearly implicate involvement of the HPA axis in the neuropathology of TS.     

The cortisol awakening response is blunted in psychotherapy inpatients suffering from depression

Determining the salivary awakening cortisol response (ACR) is a non-invasive, reliable method to detect changes in the hypothalamus-hypopituitary-adrenal (HPA) axis. Although a role of the HPA axis in depression is widely recognized, data on the ACR in depressive patients are still scarce and inconsistent. The present study assessed the ACR in depressed patients admitted for inpatient psychotherapy and a comparison group of other psychiatric diagnoses under the same conditions. The ACR was found to be attenuated in depressed as compared to non-depressed patients. This finding is in contrast to previous studies in healthy subjects or depressed outpatients and suggests a blunted rather than an exacerbated HPA reactivity. Further studies will be needed to disentangle the complex relationship between depression and the ACR.     

Salivary cortisol in women with and without perimenstrual mood changes

An increase in the activity of the hypothalamic–pituitary–adrenal axis (HPA axis) is frequently associated with major depression. During the premenstrual phase of their reproductive cycle some women experience depressive mood changes that are proposed to be of similar intensity to that experienced during periods of major depression. This study examined the secretion of cortisol, the end-product in the HPA axis, at different stages of the menstrual cycle in women with and without premenstrual depression. Women who experienced only mild physical and emotional changes in the premenstrual phase of their cycle had a significantly higher cortisol secretion on a premenstrual day (measured hourly) compared to a postmenstrual day. Those who were significantly more depressed premenstrually showed the opposite pattern of cortisol secretion with significantly lower levels on the premenstrual day compared with the postmenstrual day. Across the menstrual cycle, women who were significantly more depressed premenstrually also had lower evening cortisol levels in their premenstrual phase. The results of this study indicate that, unlike major depression where the underlying neurological changes are manifest as overactivity of the HPA axis, premenstrual depressive changes are associated with reduced HPA axis activity. Premenstrual depression may, therefore, be similar neurologically to seasonal affective disorder, which is associated with underactivity of the HPA axis.