Monica Aas

Abnormal cortisol levels during the day and cortisol awakening response in first-episode psychosis: The role of stress and of antipsychotic treatment

First-episode psychosis (FEP) patients show hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis, but the mechanisms leading to this are still unclear. The aim of this study was to investigate the role of stress and antipsychotic treatment on diurnal cortisol levels, and on cortisol awakening response, in FEP. Recent stressful events, perceived stress and childhood trauma were collected in 50 FEP patients and 36 healthy controls using structured instruments. Salivary cortisol was obtained at awakening, at 15, 30, and 60min after awakening, and at 12 and 8pm. Patients experienced more recent stressful events, perceived stress and childhood trauma than controls (p<0.001). Patients had a trend for higher diurnal cortisol levels (p=0.055), with those with less than two weeks of antipsychotics showing significantly higher cortisol levels than both patients with more than two weeks of antipsychotics (p=0.005) and controls (p=0.002). Moreover, patients showed a blunted cortisol awakening response compared with controls, irrespectively of antipsychotic treatment (p=0.049). These abnormalities in patients were not driven by the excess of stressors: diurnal cortisol levels were negatively correlated with the number of recent stressful events (r=-0.36, p=0.014), and cortisol awakening response was positively correlated with a history of sexual childhood abuse (r=0.33, p=0.033). No significant correlations were found between perceived stress or severity of symptoms and cortisol levels, either diurnal or in the awakening response. Our study shows that antipsychotics normalize diurnal cortisol hyper-secretion but not the blunted cortisol awakening response in FEP; factors other than the excess of psychosocial stress explain HPA axis abnormalities in FEP.

Higher cortisol levels are associated with smaller left hippocampal volume in first-episode psychosis.

This study investigated the relationship between cortisol secretion and hippocampal volume in first-episode psychosis and healthy controls. Hippocampal volume was measured by magnetic resonance imaging (MRI) in 24 first-episode psychosis patients and in 18 healthy controls, together with diurnal cortisol levels. Twelve patients received a second MRI scan at 3-month follow-up. Diurnal cortisol levels were inversely correlated with left hippocampal volume in patients, both at baseline and at follow-up, while no correlation was found in controls. Our findings suggest that smaller hippocampal volume in first-episode psychosis can partly be explained by stress-related processes in the brain, as measured by cortisol hyper-secretion.

Childhood trauma is associated with severe clinical characteristics of bipolar disorders.

OBJECTIVE Beyond genetic risk variants, the pathophysiology of bipolar disorders is likely to be partly determined by environmental susceptibility factors. Our study is one of the first to investigate, in a large sample of well-characterized bipolar patients, associations between clinical presentations and childhood trauma subtypes, including neglect and abuse items. METHOD 587 patients with DSM-IV-defined bipolar disorder were recruited from France and Norway between 1996-2008 and 2007-2012, respectively. History of childhood trauma was obtained using the Childhood Trauma Questionnaire. Clinical variables were assessed with the Structured Clinical Interview for DSM-IV Axis I Disorders (Norwegian sample) or the Diagnostic Interview for Genetic Studies (French sample). RESULTS Earlier age at onset of bipolar illness, suicide attempts, rapid cycling, and an increased number of depressive episodes each had significant associations (P ≤ .001) with at least 1 subtype of childhood trauma (emotional abuse, sexual abuse, and emotional neglect). Multivariate analyses investigating trauma variables together showed that both emotional and sexual abuse were independent predictors of lower age at onset (P = .002 for each) and history of suicide attempts (OR = 1.60 [95% CI, 1.07 to 2.39], P = .023; OR = 1.80 [95% CI, 1.14 to 2.86], P = .012, respectively), while sexual abuse was the strongest predictor of rapid cycling (OR = 2.04 [95% CI, 1.21 to 3.42], P = .007). Females reported overall higher childhood trauma frequency and greater associations to clinical expressions than males (P values < .05). CONCLUSIONS Our results demonstrate consistent associations between childhood trauma and more severe clinical characteristics in bipolar disorder. Further, they show the importance of including emotional abuse as well as the more frequently investigated sexual abuse when targeting clinical characteristics of bipolar disorder.

BDNF val66met modulates the association between childhood trauma, cognitive and brain abnormalities in psychoses

OBJECTIVE Brain derived neurotrophic factor (BDNF) is important for brain development and plasticity, and here we tested if the functional BDNF val66met variant modulates the association between high levels of childhood abuse, cognitive function, and brain abnormalities in psychoses. METHOD 249 patients with a broad DSM-IV schizophrenia spectrum disorder or bipolar disorder were consecutively recruited to the TOP research study (mean±age: 30.7±10.9; gender: 49% males). History of childhood trauma was obtained using the Childhood Trauma Questionnaire. Cognitive function was assessed through a standardized neuropsychological test battery. BDNF val66met was genotyped using standardized procedures. A sub-sample of n=106 Caucasians with a broad DSM-IV schizophrenia spectrum disorder or bipolar disorder (mean±age: 32.67±10.85; 49% males) had data on sMRI. RESULTS Carriers of the Methionine (met) allele exposed to high level of childhood abuse demonstrated significantly poorer cognitive functioning compared to homozygotic Valine (val/val) carriers. Taking in consideration multiple testing, using a more conservative p value, this was still shown for physical abuse and emotional abuse, as well as a trend level for sexual abuse. Further, met carriers exposed to high level of childhood sexual abuse showed reduced right hippocampal volume (r(2)=0.43; p=0.008), and larger right and left lateral ventricles (r(2)=0.37; p=0.002, and r(2)=0.27; p=0.009, respectively). Our findings were independent of age, gender, diagnosis and intracranial volume. CONCLUSION Our data demonstrate that in patients with psychoses, met carriers of the BDNF val66met with high level of childhood abuse have more cognitive and brain abnormalities than all other groups.

Is there a link between childhood trauma, cognition, and amygdala and hippocampus volume in first-episode psychosis?

Patients with psychosis have higher rates of childhood trauma, which is also associated with adverse effects on cognitive functions such as attention, concentration and mental speed, language, and verbal intelligence. Although the pathophysiological substrate for this association remains unclear, these cognitive deficits may represent the functional correlate of changes observed in relation to trauma exposure in structures such as the amygdala and the hippocampus. Interestingly, these structures are often reported as altered in psychosis. This study investigated the association between childhood trauma, cognitive function and amygdala and hippocampus volume, in first-episode psychosis. We investigated 83 patients with first-episode psychosis and 63 healthy controls. All participants underwent an MRI scan acquired with a GE Sigma 1.5-T system, and a standardized neuropsychological assessment of general cognition, memory, processing speed, executive function, visuo-spatial abilities, verbal intelligence, and language. In a subsample of the patients (N=45) information on childhood trauma was collected with the Childhood Experience of Care and Abuse Questionnaire (CECA.Q). We found that amygdala, but not hippocampus, volume was significantly smaller (p=0.001) in patients compared to healthy controls. There was a trend level interaction for hippocampus volume between group and sex (p=0.056). A history of childhood trauma was associated with both worse cognitive performance and smaller amygdala volume. This smaller amygdala appeared to mediate the relationship between childhood trauma and performance on executive function, language and verbal intelligence in patients with psychosis. This points to a complex relationship between childhood trauma exposure, cognitive function and amygdala volume in first-episode psychosis.

Serotonin Transporter Gene Polymorphism, Childhood Trauma, and Cognition in Patients With Psychotic Disorders

OBJECTIVE The functional polymorphism in the promoter region of the SLC6A4/5-HTT serotonin transporter gene (5-HTTLPR) has been linked to altered stress response. Carriers of the short (s-) allele have increased negative psychological reactions and stress hormone release compared with carriers of the long (l-) allele, interacting with severe life events including childhood trauma. High stress levels are associated with cognitive impairments in a variety of clinical and experimental studies. Patients with psychotic disorders are characterized both by more childhood traumatic events and abnormal stress responses and by significant but highly variable cognitive dysfunction. We hypothesize that 5-HTTLPR variations and long-term effects of childhood trauma interact and contribute to some of the variation in cognitive dysfunction seen in patients with psychotic disorders. METHODS Patients with psychotic disorders (schizophrenia and affective spectrums) were recruited from a catchment area-based treatment organization. History of childhood abuse was obtained by the Childhood Trauma Questionnaire. Cognitive function was assessed through a comprehensive, standardized neuropsychological test battery. 5-HTTLPR genotypes were analyzed using standard polymerase chain reaction. RESULTS We observed a significant interaction between 5-HTTLPR variants and childhood trauma across cognitive domains; here, homozygotic s-carriers exposed to high levels of childhood trauma (physical neglect and abuse) had significantly poorer cognitive functioning than all other groups. CONCLUSIONS Our results need replication but underline the importance of investigating childhood trauma and its interaction with genetic markers when studying cognitive dysfunction in patients with psychotic disorders.

The role of childhood trauma in bipolar disorders

This review will discuss the role of childhood trauma in bipolar disorders. Relevant studies were identified via Medline (PubMed) and PsycINFO databases published up to and including July 2015. This review contributes to a new understanding of the negative consequences of early life stress, as well as setting childhood trauma in a biological context of susceptibility and discussing novel long-term pathophysiological consequences in bipolar disorders. Childhood traumatic events are risk factors for developing bipolar disorders, in addition to a more severe clinical presentation over time (primarily an earlier age at onset and an increased risk of suicide attempt and substance misuse). Childhood trauma leads to alterations of affect regulation, impulse control, and cognitive functioning that might decrease the ability to cope with later stressors. Childhood trauma interacts with several genes belonging to several different biological pathways [Hypothalamic–pituitary–adrenal (HPA) axis, serotonergic transmission, neuroplasticity, immunity, calcium signaling, and circadian rhythms] to decrease the age at the onset of the disorder or increase the risk of suicide. Epigenetic factors may also be involved in the neurobiological consequences of childhood trauma in bipolar disorder. Biological sequelae such as chronic inflammation, sleep disturbance, or telomere shortening are potential mediators of the negative effects of childhood trauma in bipolar disorders, in particular with regard to physical health. The main clinical implication is to systematically assess childhood trauma in patients with bipolar disorders, or at least in those with a severe or instable course. The challenge for the next years will be to fill the gap between clinical and fundamental research and routine practice, since recommendations for managing this specific population are lacking. In particular, little is known on which psychotherapies should be provided or which targets therapists should focus on, as well as how childhood trauma could explain the resistance to mood stabilizers.

High prevalence of childhood trauma in patients with schizophrenia spectrum and affective disorder

OBJECTIVE Childhood trauma (CT) is a major risk factor for various psychiatric disorders. We wanted to determine the prevalence of CT in a catchment area-based sample of schizophrenia spectrum and affective disorder (including bipolar disorder and depressive episodes with psychotic features) and to explore potential differences in types of CT between the diagnostic groups. METHOD Three hundred five patients were recruited consecutively from psychiatric units at 3 major hospitals in Oslo, Norway, diagnosed with Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition. Traumatic childhood events were assessed with Childhood Trauma Questionnaire. RESULTS Eighty-two percent of the patients had experienced one or more CT events, the most frequent subtype of trauma being emotional neglect. The schizophrenia spectrum group reported significantly more physical abuse and physical neglect than the affective group. CONCLUSION A high prevalence of CT in patients with severe mental disorder was detected. This reminds us of the importance of exploring this issue when we treat such patients. The mechanisms behind these differences are unclear. Further research is needed to study potential associations between CT and the clinical picture of the disorder.

Interplay between childhood trauma and BDNF val66met variants on blood BDNF mRNA levels and on hippocampus subfields volumes in schizophrenia spectrum and bipolar disorders

OBJECTIVE Here we investigated a two hit gene environment model in relation to functional genomic factors (BDNF mRNA), and volume of hippocampal subfields in schizophrenia spectrum and bipolar disorders, focusing on both an environmental (childhood trauma) and genetic risk factor (BDNF val66met). METHOD A total of 323 patients with a broad DSM-IV schizophrenia spectrum disorder or bipolar disorder were consecutively recruited. A history of childhood trauma was obtained using the Childhood Trauma Questionnaire. BDNF DNA and RNA were analyzed using standardized procedures. A subsample of n = 108 underwent MRI scanning, and the FreeSurfer was used to obtain measures of hippocampal subfield. All MRI data were corrected for age and gender, with post-hoc analysis correcting for ICV. RESULTS A history of childhood trauma or being a met carrier of the BDNF val66met was associated with significantly reduced BDNF mRNA level. Additive effects were observed between a history of childhood trauma and BDNF val66met, in the direction of met carriers with high levels of childhood trauma having the lowest BDNF mRNA levels. Lastly, met carriers reporting high levels of childhood trauma (specifically sexual or physical abuse) had significantly reduced hippocampal subfield volumes CA2/3 and CA4 dentate gyrus. CONCLUSION The current findings demonstrate that the reduced BDNF mRNA levels found in psychosis may be associated with both a history of childhood trauma and BDNF val66met variants. Further, our study supports a two hit model including a history of childhood trauma as well as genetic vulnerability (met carriers of the BDNF val66met) behind reduced volume of hippocampal subfields in psychosis. This was specifically found for areas important for neurogenesis, the CA2/3 and the CA4 DG.

Additive effects of childhood abuse and cannabis abuse on clinical expressions of bipolar disorders

BACKGROUND Previous studies of bipolar disorders indicate that childhood abuse and substance abuse are associated with the disorder. Whether both influence the clinical picture, or if one is mediating the association of the other, has not previously been investigated. METHOD A total of 587 patients with bipolar disorders were recruited from Norway and France. A history of childhood abuse was obtained using the Childhood Trauma Questionnaire. Diagnosis and clinical variables, including substance abuse, were based on structured clinical interviews (Structured Clinical Interview for DSM-IV Axis I disorders or French version of the Diagnostic Interview for Genetic Studies). RESULTS Cannabis abuse was significantly associated with childhood abuse, specifically emotional and sexual abuse (χ 2 = 8.63, p = 0.003 and χ 2 = 7.55, p = 0.006, respectively). Cannabis abuse was significantly associated with earlier onset of the illness (z = -4.17, p < 0.001), lifetime history of at least one suicide attempt (χ 2 = 11.16, p = 0.001) and a trend for rapid cycling (χ 2 = 3.45, p = 0.06). Alcohol dependence was associated with suicide attempt (χ 2 = 10.28, p = 0.001), but not with age at onset or rapid cycling. After correcting for possible confounders and multiple testing, a trend was observed for an interaction between cannabis abuse and childhood abuse and suicide attempt (logistic regression: r 2 = 0.06, p = 0.039). Significant additive effects were also observed between cannabis abuse and childhood abuse on earlier age at onset (p < 0.001), increased rapid cycling and suicide attempt (logistic regression: r 2 = 0.03-0.04, p < 0.001). No mediation effects were observed; childhood abuse and cannabis abuse were independently associated with the disorder. CONCLUSIONS Our study is the first to demonstrate significant additive effects, but no mediation effects, between childhood abuse and cannabis abuse on increased clinical expressions of bipolar disorders.