Elevations in hypothalamic–pituitary–adrenal (HPA) axis activity have been implicated in the origins and exacerbation of mental disorders. Several lines of investigation suggest HPA activity, indexed by increased cortisol, is elevated in patients with schizophrenia and other psychotic disorders. This study examined the relation of cortisol levels and longitudinal changes with psychotic outcomes in at-risk adolescents. Participants were 56 adolescents who met risk criteria for psychosis, namely, schizotypal personality disorder (n = 5), prodromal symptom criteria based on the Structured Interview for Prodromal Symptoms (n = 17), or both (n = 34). Of these, 14 subsequently met DSM–IV criteria for an Axis I psychotic disorder (schizophrenia, schizoaffective disorder, or mood disorder with psychotic features). Participants were assessed at baseline and then followed longitudinally. Salivary cortisol was sampled multiple times at initial assessment, interim follow-up, and 1-year follow-up. Area under the curve (AUC) was computed from the repeated cortisol measures. The findings indicate that at-risk subjects who subsequently developed psychosis showed significantly higher cortisol at the first follow-up, a trend at the 1-year follow-up, and a significantly larger AUC when compared to those who did not convert. A similar pattern of group differences emerged from analyses excluding those who may have converted prior to the 1-year follow-up. These findings converge with previous reports on HPA activity in psychosis, as well as theoretical assumptions concerning the effects of cortisol elevations on brain systems involved in psychotic symptoms. Future research with larger samples is needed to confirm and extend these results.
risk for psychosis; cortisol; adolescents
Temperament and personality traits such as neuroticism and behavioral inhibition are prospective predictors of the onset of depression and anxiety disorders. Exposure to stress is also linked to the development of these disorders, and neuroticism and inhibition may confer or reflect sensitivity to stressors. Several lines of research have documented hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis in some patients with major depression, as well as in children and non-human primates with inhibited temperaments. The present investigation tested the hypothesis that stress-reactive temperaments would be predictive of plasma adrenocorticotropin (ACTH) and cortisol concentrations in the dexamethasone/corticotropin-releasing hormone (Dex/CRH) test. Sixty adults completed diagnostic interviews and questionnaires assessing the temperament domains of novelty seeking and harm avoidance and symptoms of anxiety and depression. All subjects were free of any current or past Axis I psychiatric disorder. The Dex/CRH test was performed on a separate visit. A repeated measures general linear model (GLM) showed a main effect of harm avoidance in predicting cortisol concentrations in the test (F(1, 58) = 4.86, p < .05). The GLM for novelty seeking and cortisol response also showed a main effect (F(1, 58) = 5.28, p <.05). Higher cortisol concentrations were associated with higher levels of harm avoidance and lower levels of novelty seeking. A significant interaction of time with harm avoidance and novelty seeking (F(4, 53) = 3.37, p < .05) revealed that participants with both high levels of harm avoidance and low levels of novelty seeking had the highest cortisol responses to the Dex/CRH test. Plasma ACTH concentrations did not differ as a function of temperament. The results indicate that temperament traits linked to sensitivity to negative stimuli are associated with greater cortisol reactivity during the Dex/CRH test. Increased adrenocortical reactivity, which previously has been linked to major depression and anxiety disorders, may contribute to the association between temperament/personality traits and these disorders.
Cortisol; Dex/CRH test; HPA axis; temperament; personality; inhibition
Disturbances in serotonin neuroregulation and in hypothalamic-pituitary-adrenal axis activity are both likely, and possibly independent, factors in the genesis of suicidal behavior. This analysis considers whether clinically accessible measures of these two disturbances have additive value in the estimation of risk for suicide. Seventy-four inpatients with RDC major or schizoaffective depressive disorders entered a prospective follow-up study from 1978–1981, underwent a dexamethasone suppression test (DST) and had fasting serum cholesterol levels available in the medical record. As reported earlier, patients who had had an abnormal DST result were significantly more likely to commit suicide during follow-up. Serum cholesterol concentrations did not differ by DST result and low cholesterol values were associated with subsequent suicide when age and sex were included as covariates. These results indicate that, with the use of age-appropriate thresholds, serum cholesterol concentrations may be combined with DST results to provide a clinically useful estimate of suicide risk.
Dexamethasone suppression test; cholesterol; cortisol; depressive disorder
Dysregulation of the hypothalamic–pituitary–adrenal (HPA) axis in adults with major depressive disorder is among the most consistent and robust biological findings in psychiatry. Given the importance of the adolescent transition to the development and recurrence of depressive phenomena over the lifespan, it is important to have an integrative perspective on research investigating the various components of HPA axis functioning among depressed young people. The present narrative review synthesizes evidence from the following five categories of studies conducted with children and adolescents: (1) those examining the HPA system’s response to the dexamethasone suppression test (DST); (2) those assessing basal HPA axis functioning; (3) those administering corticotropin-releasing hormone (CRH) challenge; (4) those incorporating psychological probes of the HPA axis; and (5) those examining HPA axis functioning in children of depressed mothers. Evidence is generally consistent with models of developmental psychopathology that hypothesize that atypical HPA axis functioning precedes the emergence of clinical levels of depression and that the HPA axis becomes increasingly dysregulated from child to adult manifestations of depression. Multidisciplinary approaches and longitudinal research designs that extend across development are needed to more clearly and usefully elucidate the role of the HPA axis in depression.
Depression; Childhood and adolescence; Hypothalamic–pituitary–adrenal (HPA) axis; Developmental psychopathology
A compelling association has been observed between cardiovascular disease (CVD) and depression, suggesting individuals with depression to be at significantly higher risk for CVD and CVD-related mortality. Systemic immune activation, hypothalamic–pituitary–adrenal (HPA) axis hyperactivity, arterial stiffness and endothelial dysfunction have been frequently implicated in this relationship. Although a differential epidemiological association between CVD and depression subtypes is evident, it has not been determined if this indicates subtype specific biological mechanisms. A comprehensive systematic literature search was conducted using PubMed and PsycINFO databases yielding 147 articles for this review. A complex pattern of systemic immune activation, endothelial dysfunction and HPA axis hyperactivity is suggestive of the biological relationship between CVD and depression subtypes. The findings of this review suggest that diagnostic subtypes rather than a unifying model of depression should be considered when investigating the bidirectional biological relationship between CVD and depression. The suggested model of a subtype-specific biological relationship between depression and CVDs has implications for future research and possibly for diagnostic and therapeutic processes.
biological mechanisms; cardiovascular disease; endothelial dysfunction; inflammation; subtypes of depression
Dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis is thought to be associated with more mood symptoms and worse cognitive functioning. This study examined whether variation in HPA axis activity underlies the association between mood symptoms and cognitive functioning.
In 65 bipolar patients cognitive functioning was measured in domains of psychomotor speed, speed of information processing, attentional switching, verbal memory, visual memory, executive functioning and an overall mean score. Severity of depression was assessed by the Inventory of Depressive Symptomatology-self rating version. Saliva cortisol measurements were performed to calculate HPA axis indicators: cortisol awakening response, diurnal slope, the evening cortisol level and the cortisol suppression on the dexamethasone suppression test. Regression analyses of depressive symptoms and cognitive functioning on each HPA axis indicator were performed. In addition we calculated percentages explanation of the association between depressive symptoms and cognition by HPA axis indicators. Depressive symptoms were associated with dysfunction in psychomotor speed, attentional switching and the mean score, as well as with attenuation in diurnal slope value. No association was found between HPA axis activity and cognitive functioning and HPA axis activity did not explain the associations between depressive symptoms and cognition.
As our study is the first one in this field specific for bipolar patients and changes in HPA-axis activity did not seem to explain the association between severity of depressive symptoms and cognitive functioning in bipolar patients, future studies are needed to evaluate other factors that might explain this relationship.
The objective of this study was to examine the modifying effect of gender on the association between early life trauma and the hypothalamic–pituitary–adrenal (HPA) axis response to a pharmacologic challenge and a social stress task in men and women. Participants (16 men, 23 women) were the control sample of a larger study examining HPA axis function. Individuals with major depressive disorder, posttraumatic stress disorder, bipolar disorder, or psychotic or eating disorders were excluded.
In two test sessions, subjects received 1 μg/kg of corticotropin-releasing hormone (CRH) intravenously and participated in the Trier Social Stress Test (TSST). Primary outcomes included plasma cortisol and corticotropin levels measured at baseline and more than five time points following the challenges. Predictors included gender and early life trauma, as measured by the Early Trauma Index. Using factor analysis, the domains general trauma, severe trauma, and the effects of trauma were established. Using regression, these constructs were used to predict differential HPA reactivity in men and women following the challenges.
The three factors accounted for the majority of the variance in the ETI. Following the CRH challenge, women had higher overall corticotropin response as dictated by the area under the curve analysis. There were no significant associations between trauma and neuroendocrine response to the TSST.
CRH challenge results indicate that gender differences in the impact of early trauma may help explain the differential gender susceptibility to psychopathology following adverse childhood events. This may help explain gender differences in some stress-sensitive psychiatric disorders.
trauma; gender; HPA axis; hypothalamic–pituitary–adrenal axis; cortisol; corticotropin
Depression is frequently reported in epilepsy patients; however, mechanisms of co-morbidity between epilepsy and depression are poorly understood. An important mechanism of depression is disinhibition within the hypothalamo-pituitary-adrenocortical (HPA) axis. We examined the functional state of the HPA axis in a rat model of co-morbidity between temporal lobe epilepsy and depression. Epilepsy was accompanied by the interictal elevation of plasma corticosterone, and by the positive combined dexamethasone/corticotropin releasing hormone test. The extent of the HPA hyperactivity was independent of recurrent seizures, but positively correlated with the severity of depressive behavior. We suggest that the observed hyperactivity of the HPA axis may underlie co-morbidity between epilepsy and depression.
Epilepsy; depression; co-morbidity; hypothalamo-pituitary-adrenocortical axis; chronic stress
Severe psychotic disorders, which on their own may be a risk factor for metabolic disorder and cardiovascular illness, are clinically compounded by the significant adverse side effects of antipsychotic medications. The majority of patients with severe psychotic disorders (i.e., schizophrenia, bipolar disorder, mania, and depression) must take antipsychotic medications to treat their psychoses and, subsequently, will require efficacious interventions to manage the metabolic consequences of pharmacologic treatment to mitigate excessive mortality associated with cardiovascular illness. We have reviewed the metabolic consequences of antipsychotic treatment and discussed pilot findings from a new nonpharmacologic intervention study looking at the clinical benefits of regular exercise as a management tool for the cardiometabolic risk factors in a cohort with severe mental illness.
Mental illness; Cardiometabolic disorder; Antipsychotics; Exercise
Depression is the most common psychiatric disorder worldwide. The burden of disease for depression goes beyond functioning and quality of life and extends to somatic health. Depression has been shown to subsequently increase the risk of, for example, cardiovascular, stroke, diabetes and obesity morbidity. These somatic consequences could partly be due to metabolic, immuno-inflammatory, autonomic and hypothalamic-pituitary-adrenal (HPA)-axis dysregulations which have been suggested to be more often present among depressed patients. Evidence linking depression to metabolic syndrome abnormalities indicates that depression is especially associated with its obesity-related components (for example, abdominal obesity and dyslipidemia). In addition, systemic inflammation and hyperactivity of the HPA-axis have been consistently observed among depressed patients. Slightly less consistent observations are for autonomic dysregulation among depressed patients. The heterogeneity of the depression concept seems to play a differentiating role: metabolic syndrome and inflammation up-regulations appear more specific to the atypical depression subtype, whereas hypercortisolemia appears more specific for melancholic depression. This review finishes with potential treatment implications for the downward spiral in which different depressive symptom profiles and biological dysregulations may impact on each other and interact with somatic health decline.
Depression; Metabolic syndrome; Inflammation; Cortisol; Autonomic Tone; Cardiovascular; Obesity; Symptom profile; Treatment
To examine if atypical depression may be associated with hypersuppression of the hypothalamic-pituitary-adrenal (HPA) axis.
Eight women with atypical major depression and 11 controls with no history of psychiatric illness, matched on age and body mass index, were challenged with low-dose dexamethasone (0.25 mg and 0.50 mg in random order and 1 week apart). Dexamethasone was self administered at 11 pm, and plasma cortisol samples were drawn at 8 am and 3 pm on the following day.
After the 0.50-mg dexamethasone challenge, mean suppression of morning cortisol was significantly greater in patients with atypical depression (91.9;, standard deviation [SD] 6.8%) than in the controls (78.3%, SD 10.7%; p < 0.01).
These preliminary data add to the growing body of literature that suggests atypical depression, in contrast to classic melancholia, may be associated with exaggerated negative feedback regulation of the HPA axis.
corticotropin-releasing hormone; depression, atypical, dexamethasone; hormones; hydrocortisone; mood disorders; stress
The dexamethasone/corticotropin releasing hormone (Dex/CRH) test has been proposed as a potential tool for identifying endophenotypes relevant to mood disorders. An exaggerated cortisol response to the test during major depressive episodes has been demonstrated for inpatients with melancholic or psychotic features. A diminished hormone response has been observed in chronically depressed outpatients.
Following a battery of self-report and interview assessments, 68 adults completed the Dex/CRH test. Thirty-four met structured interview criteria for current major depressive disorder and 34 age- and sex-matched control subjects had no current or lifetime DSM-IV depressive disorder. Effect of diagnosis on cortisol response to the Dex/CRH test was examined in a repeated measures general linear model.
The matched groups were equivalent with regard to childhood adversity. Cortisol response to the Dex/CRH test among subjects with current MDD was not significantly different from that seen in matched healthy controls. Independent of diagnosis, an exploratory analysis showed a trend-level association between maltreatment history and diminished cortisol response; no interactive effects with depression diagnosis were detected.
The results do not support the hypothesis that elevated cortisol response to the Dex/CRH test represents a marker for major depressive episodes.
Childhood abuse; Mood disorders; Depression; Cortisol; HPA axis; Early life stress
Stress sensitivity and HPA axis activity may be relevant to the development and expression of psychotic disorders. Cortisol secretion has been associated with positive symptoms both in patients with psychotic disorders and in young people at clinical risk for psychosis. Herein, we aimed to replicate these findings, to determine which positive symptoms may be associated with cortisol levels, and to explore any associations with affective symptoms and impaired stress tolerance.
Thirty-one clinical high risk patients were evaluated in cross-section for associations between salivary cortisol levels upon clinic entry at 11 am, demographic variables, and clinical symptoms.
Salivary cortisol levels were unrelated to medication exposure or demographics, except for higher levels in the ten females studied. Salivary cortisol bore no relationship to overall positive symptom severity but was associated with anxiety, as well as with suspiciousness and impaired stress tolerance, which were themselves highly intercorrelated.
Cortisol secretion in the context of a putative novel social situation (i.e. clinic entry) may be a biological correlate of suspiciousness, impaired stress tolerance and affective symptoms in individuals vulnerable to developing psychosis. These associations are consistent with findings from experience sampling studies in individuals at risk for psychosis as well as basic studies of animal models of schizophrenia.
Cortisol; Psychosis; Schizophrenia; Risk; Prodrome; Prodromal
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 Post-Traumatic Stress Disorder.
Plasma adrenocorticotropin (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).
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 × 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.
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.
Trier Social Stress Test; HPA Axis; Childhood; Abuse; Cortisol; ACTH; Reactivity; Endophenotype
Hypothalamic-pituitary-adrenal (HPA) axis dysfunction in mood disorders is one of the most robust findings in biological psychiatry. However, considerable debate surrounds the nature of the core abnormality, its cause, consequences and treatment implications.
To review the evidence for the role of HPA axis dysfunction in the pathophysiology of mood disorders with particular reference to corticosteroid receptor pathology.
A selective review of the published literature in this field, focusing on human studies.
The nature of basal HPA axis dysregulation described in both manic and depressed bipolars appears to be similar to those described in MDD. But studies using the dexamethasone/ corticotropin releasing hormone (dex/CRH) test and dexamethasone suppression test (DST) have shown that HPA axis dysfunction is more prevalent in bipolar than in unipolar disorder. There is robust evidence for corticotropin releasing hormone (CRH) hyperdrive and glucocorticoid receptor (GR) dysfunction in mood disorders, with increasing evidence for disorders within the AVP system.
HPA axis dysfunction is prevalent in patients with mood disorder, particularly those with psychotic disorders and bipolar affective disorder. This may be secondary to genetic factors, early life adversities or both. Dysfunction of GR may be the underlying abnormality and preliminary findings suggest that it is a potential target for novel therapies.
Declaration of interest:
Mood disorders; pathophysiology; Glncocorticoid Receptor
This study investigated basal and stress-induced HPA axis alterations in dissociative disorders (DD).
Forty-six subjects with DD without lifetime PTSD, 35 subjects with PTSD, and 58 HC subjects, free of current major depression, were studied as inpatients. After a 24-hour urine collection and hourly blood sampling for ambient cortisol determination, a low-dose dexamethasone suppression test was administered, followed by the Trier Social Stress Test.
The DD group had significantly elevated urinary cortisol compared to the HC group, more pronounced in the absence of lifetime major depression, whereas the PTSD and HC groups did not differ. The DD group demonstrated significantly greater resistance to, and faster escape from, dexamethasone suppression compared to the HC group, whereas the PTSD and HC groups did not differ. The three groups did not differ in cortisol stress reactivity, but both psychiatric groups demonstrated a significant inverse correlation between dissociation severity and cortisol reactivity, after controlling for all other symptomatology. The PTSD subgroup with comorbid DD tended to have blunted reactivity compared to the HC group.
The study demonstrates a distinct pattern of HPA axis dysregulation in DD, emphasizing the importance of further study of stress response systems in dissociative psychopathology.
cortisol; HPA axis; neuroendocrinology; dissociative disorders; PTSD; stress
Since clinical and biological research and optimal clinical practice require stability of diagnoses over time, we determined stability of ICD-10 psychotic-disorder diagnoses, and sought predictors of diagnostic instability.
Patients (N=500) hospitalized for first-psychotic illnesses were diagnosed by ICD-10 criteria at baseline and 24 months, based on extensive prospective assessments, to evaluate the longitudinal stability of specific categorical diagnoses, and predictors of diagnostic change.
Diagnostic-stability averaged 90.4%, ranking: schizoaffective disorder (100%) > mania with psychosis (99.0%) > mixed-affective episode (94.9%) > schizophrenia (94.6%) > delusional disorder (88.2%) > severe, psychotic, depressive episode (85.2%) > acute psychosis with/without schizophrenia symptoms = unspecified psychosis (all 66.7%) ≫ acute schizophrenia-like psychosis (28.6%). Diagnoses changed by 24 months of follow-up, to: schizoaffective disorders (37.5%), bipolar disorder (25.0%), schizophrenia (16.7%) or unspecified non-organic psychosis (8.3%), mainly through emerging affective features. By logistic-regression, diagnostic-change was associated with Schneiderian first-rank psychosis symptoms at intake > lack of premorbid substance use.
We found some psychotic-disorder diagnoses to be more stable by ICD-10 than DSM-IV criteria in the same patients, with implications for revisions of both diagnostic systems.
diagnosis; stability; first-episode; follow-up; ICD-10; prediction; psychosis
Several decades of research link childhood parental loss with risk for major depression and other forms of psychopathology. A large body of preclinical work on maternal separation and some recent studies of humans with childhood parental loss have demonstrated alterations of hypothalamic-pituitary-adrenal (HPA) axis function which could predispose to the development of psychiatric disorders.
Eighty-eight healthy adults with no current Axis I psychiatric disorder participated in this study. Forty-four participants experienced parental loss during childhood, including 19 with a history of parental death and 25 with a history of prolonged parental separation. The loss group was compared to a matched group of individuals who reported no history of childhood parental separation or childhood maltreatment. Participants completed diagnostic interviews and questionnaires and the dexamethasone/corticotropin-releasing hormone (Dex/CRH) test. Repeated measures general linear models were used to test the effects of parental loss, a measure of parental care, sex, and age on the hormone responses to the Dex/CRH test.
Parental loss was associated with increased cortisol responses to the test, particularly in males. The effect of loss was moderated by levels of parental care; participants with parental desertion and very low levels of care had attenuated cortisol responses. ACTH responses to the Dex/CRH test did not differ significantly as a function of parental loss.
These findings are consistent with the hypothesis that early parental loss induces enduring changes in neuroendocrine function.
childhood parental loss; parental death; depression; cortisol; HPA axis
In the last decade, a substantial number of population-based studies have suggested that childhood trauma is a risk factor for psychosis. In several studies, the effects held after adjusting for a wide range of potentially confounding variables, including genetic liability for psychosis. Less is known about the mechanisms underlying the association between childhood trauma and psychosis. Possible pathways include relationships between negative perceptions of the self, negative affect, and psychotic symptoms, as well as biological mechanisms such as dysregulated cortisol and increased sensitivity to stress. Psychotic patients with a history of childhood trauma tend to present with a variety of additional problems, including post-traumatic stress disorder, greater substance abuse, higher levels of depression and anxiety, and more frequent suicide attempts. Initial studies suggest that trauma-specific treatments are as beneficial for these patients as for other diagnostic groups.
child abuse; trauma; psychosis; schizophrenia; etiology; treatment
Major Depressive Disorder (MDD) is one of the most prevalent and costly of all psychiatric disorders. The hypothalamic pituitary adrenal (HPA)-axis, which regulates the hormonal response to stress, has been found to be disrupted in depression. HPA dysregulation may represent an important risk factor for depression. To examine a possible genetic underpinning of this risk factor without the confound of current or lifetime depression, we genotyped 84 never-disordered young girls, over a third of whom were at elevated risk for depression, to assess the association between a polymorphism in the promoter region of the serotonin transporter (5-HTT) gene and diurnal variation in HPA-axis activity. This 5-HTT-linked polymorphic region (5-HTTLPR) has been previously found to interact with stress to increase risk for depression. We found 5-HTTLPR to be significantly associated with diurnal cortisol levels: girls who were homozygous for the short allele had higher levels of waking (but not afternoon or evening) cortisol than did their long-allele counterparts. This finding suggests that genetic susceptibility to HPA-axis dysregulation, especially apparent in levels of waking cortisol, is detectable in individuals as young as nine years of age.
serotonin transporter; 5-HTTLPR; diurnal cortisol; HPA-axis; depression; stress
Clinicians treating older patients with schizophrenia are often challenged by patients presenting with both depressive and psychotic features. The presence of co-morbid depression impacts negatively on quality of life, functioning, overall psychopathology and the severity of co-morbid medical conditions. Depressive symptoms in patients with schizophrenia include major depressive episodes (MDEs) that do not meet criteria for schizoaffective disorder, MDEs that occur in the context of schizoaffective disorder and subthreshold depressive symptoms that do not meet criteria for MDE. Pharmacological treatment of patients with schizophrenia and depression involves augmenting antipsychotic medications with antidepressants. Recent surveys suggest that clinicians prescribe antidepressants to 30% of inpatients and 43% of outpatients with schizophrenia and depression at all ages. Recent trials addressing the efficacy of this practice have evaluated selective serotonin reuptake inhibitors (SSRIs) such as fluoxetine, sertraline, fluvoxamine and citalopram. These trials have included only a small number of subjects and few older subjects participated; furthermore, the efficacy results have been mixed. Although no published controlled psychotherapeutic studies have specifically targeted major depression or depressive symptoms in older patients with schizophrenia, psychosocial interventions likely play a role in any comprehensive management plan in this population of patients.
Our recommendations for treating the older patient with schizophrenia and major depression involve a stepwise approach. First, a careful diagnostic assessment to rule out medical or medication causes is important as well as checking whether patients are adherent to treatments. Clinicians should also consider switching patients to an atypical antipsychotic if they are not taking one already. In addition, dose optimization needs to be targeted towards depressive as well as positive and negative psychotic symptoms. If major depression persists, adding an SSRI is a reasonable next step; one needs to start with a low dose and then cautiously titrate upward to reduce depressive symptoms. If remission is not achieved after an adequate treatment duration (8–12 weeks) or with an adequate dose (similar to that used for major depression without schizophrenia), switching to another agent or adding augmenting therapy is recommended.
We recommend treating an acute first episode of depression for at least 6–9 months and consideration of longer treatment for patients with residual symptoms, very severe or highly co-morbid major depression, ongoing episodes or recurrent episodes. Psychosocial interventions aimed at improving adherence, quality of life and function are also recommended. For patients with schizophrenia and subsyndromal depression, a similar approach is recommended.
Psychosis accompanying major depression in patients without schizophrenia is common in elderly patients and is considered a primary mood disorder; for these reasons, it is an important syndrome to consider in the differential diagnosis of older patients with mood and thought disturbance. Treatment for this condition has involved electroconvulsive therapy (ECT) as well as combinations of antidepressant and antipsychotic medications. Recent evidence suggests that combination treatment may not be any more effective than antidepressant treatment alone and ECT may be more efficacious overall.
Depression may be a precursor to substance use disorder in some youngsters, and substance abuse might complicate the subsequent course of depression. This study examined whether hypothalamic-pituitary-adrenal (HPA) activity and stressful life experiences are related to the development of substance use disorder in depressed and nondepressed adolescents, and whether substance use disorder predicts a worsening course of depression.
Urinary-free cortisol was measured for 3 nights in 151 adolescents with no prior history of substance use disorder (55 depressed, 48 at high risk for depression, and 48 normal subjects). Information was obtained on recent stressful life experiences. The participants were followed for up to 5 years to assess the onset of substance use disorder, course of depression, and stressful experiences. The relationships among depression, cortisol as a measure of HPA activity, stressful experiences, and substance use disorder were examined.
Elevated cortisol was associated with onset of substance use disorder. Stressful life experiences moderated this relationship. Cortisol and stress accounted for the effects of a history or risk of depression on the development of substance use disorder. Substance use disorder was associated with higher frequency of subsequent depressive episodes.
Higher cortisol prior to the onset of substance use disorder may indicate vulnerability to substance use disorder. Stressful experiences increase the risk for substance use disorder in such vulnerable youth. The high prevalence of substance use disorders in depressed individuals may be explained, in part, by high levels of stress and increased HPA activity.
Major depression (MD) is a common psychiatric disorder with a complex and multifactor aetiology. Potential mechanisms associated with the pathogenesis of this disorder include monoamine deficits, hypothalamic-pituitary-adrenal (HPA) axis dysfunctions, inflammatory and/or neurodegenerative alterations. An increased secretion and reactivity of cortisol together with an altered feedback inhibition are the most widely observed HPA abnormalities in MD patients. Glucocorticoids, such as cortisol, are vital hormones that are released in response to stress, and regulate metabolism and immunity but also neuronal survival and neurogenesis. Interestingly depression is highly prevalent in infectious, autoimmune and neurodegenerative diseases and at the same time, depressed patients show higher levels of pro-inflammatory cytokines. Since communication occurs between the endocrine, immune and central nervous system, an activation of the inflammatory responses can affect neuroendocrine processes, and vice versa. Therefore, HPA axis hyperactivity and inflammation might be part of the same pathophysiological process: HPA axis hyperactivity is a marker of glucocorticoid resistance, implying ineffective action of glucocorticoid hormones on target tissues, which could lead to immune activation; and, equally, inflammation could stimulate HPA axis activity via both a direct action of cytokines on the brain and by inducing glucocorticoid resistance. In addition, increased levels of pro-inflammatory cytokines also induce the production of neurotoxic end products of the tryptophan–kynurenine pathway. Although the evidence for neurodegeneration in MD is controversial, depression is comorbid with many other conditions where neurodegeneration is present. Since several systems seem to be involved interacting with each other, we cannot unequivocally accept the simple model that glucocorticoids induce neurodegeneration, but rather that elevated cytokines, in the context of glucocorticoid resistance, are probably the offenders. Chronic inflammatory changes in the presence of glucocorticoid resistance may represent a common feature that could be responsible for the enhanced vulnerability of depressed patients to develop neurodegenerative changes later in life. However, further studies are needed to clarify the relative contribution of glucocorticoids and inflammatory signals to MD and other disorders.
Cytokines; Depression; Glucocorticoid resistance; Glucocorticoids; Kynurenine pathway; Neurodegeneration
Thirty patients of Major Depressive Disorder, Schizophrenia and normal healthy controls each, received an overnight dexamethasone suppression test. Plasma and urinary Cortisol measurements showed that depressed patients had increased adrenocortical activity before dexamethasone and they showed an abnormal early escape from suppression which had a relationship with severity of depression. An attempt has been made to differentiate depressives from schizophrenics by abnormally high Cortisol values. Post-dexamethasone urinary Cortisol as well as combined urinary Cortisol and plasma Cortisol abnormal values gave the best pointers of differentiation. A nonsignificant trend of higher values was observed in bipolar and retarded depressives. Schizophrenics did not differ from normals at any stage.
Previous research suggests that patients with psychotic major depression (PMD) may differ from those with nonpsychotic major depression (NMD) not only in terms psychotic features, but also in their depressive symptom presentation. The present study contrasted the rates and severity of depressive symptoms in outpatients diagnosed with PMD versus NMD.
The sample consisted of 1,112 patients diagnosed with major depression, of which 60 (5.3%) exhibited psychotic features. Depressive symptoms were assessed by trained diagnosticians at intake using the Structured Clinical Interview for DSM-IV and supplemented by severity items from the Schedule for Affective Disorders and Schizophrenia.
PMD patients were more likely to endorse the presence of weight loss, insomnia, psychomotor agitation, indecisiveness, and suicidality compared to NMD patients. Furthermore, PMD patient showed higher levels of severity on several depressive symptoms, including depressed mood, appetite loss, insomnia, psychomotor disturbances (agitation and retardation), fatigue, worthlessness, guilt, cognitive disturbances (concentration and indecisiveness), hopelessness, and suicidal ideation. The presence of psychomotor disturbance, insomnia, indecisiveness, and suicidal ideation were predictive of diagnostic status even after controlling for the effects of demographic characteristics and other symptoms.
These findings are consistent with past research suggesting that PMD is characterized by a unique depressive symptom profile in addition to psychotic features and higher levels of overall depression severity. The identification of specific depressive symptoms in addition to delusions/hallucinations that can differentiate PMD versus NMD patients can aid in the early detection of the disorder. These investigations also provide insights into potential treatment targets for this high-risk population.