Effect of next-step antidepressant treatment on suicidal ideation: findings from the VAST-D trial.

BACKGROUND: Major depressive disorder (MDD) contributes to suicide risk. Treating MDD effectively is considered a key suicide prevention intervention. Yet many patients with MDD do not respond to their initial medication and require a 'next-step'. The relationship between next-step treatments and suicidal thoughts and behaviors is uncharted. METHOD: The VA Augmentation and Switching Treatments for Depression trial randomized 1522 participants to one of three next-step treatments: Switching to Bupropion, combining with Bupropion, and augmenting with Aripiprazole. In this secondary analysis, features associated with lifetime suicidal ideation (SI) and attempts (SA) at baseline and current SI during treatment were explored. RESULTS: Compared to those with SI only, those with lifetime SI + SA were more likely to be female, divorced, or separated, unemployed; and to have experienced more childhood adversity. They had a more severe depressive episode and were more likely to respond to 'next-step' treatment. The prevalence of SI decreased from 46.5% (694/1492) at baseline to 21.1% (315/1492) at end-of-treatment. SI during treatment was associated with baseline SI; low positive mental health, more anxiety, greater severity and longer duration of current MDD episode; being male and White; and treatment with S-BUP or C-BUP as compared to A-ARI. CONCLUSION: SI declines for most patients during next-step medication treatments. But about 1 in 5 experienced emergent or worsening SI during treatment, so vigilance for suicide risk through the entire 12-week acute treatment period is necessary. Treatment selection may affect the risk of SI.

Illness narratives and preferences for treatment among older veterans living with treatment-resistant depression and insomnia.

BACKGROUND: Despite the prevalence of comorbid late-life treatmentresistant depression (LLTRD) and insomnia in older adults, there is a gap in the literature describing patient factors, such as patients' beliefs about their illnesses and preferences for treatment, that can facilitate recovery. Therefore, we explored the perceptions and treatment preferences of older veterans with LLTRD and insomnia. METHODS: Semi-structured interviews were completed with 11 older veterans. A thematic analysis of the interviews was conducted. RESULTS: Four main themes were identified: 1. Insomnia and medical problems were considered to be significant contributors to depression, which was defined by low mood and anhedonia; 2. "Overthinking" was thought to be a cause of insomnia; 3. Participants' preference for psychotherapy was driven by their past experiences with therapy; and 4. Participants viewed patient education as a facilitator for compliance. CONCLUSIONS: Older veterans with LLTRD and insomnia have a preference for behavioral interventions. However, they lack knowledge about available treatment options, such as behavioral interventions for sleep that can improve both their sleep and mood while being a good fit with their illness narratives, such as "overthinking." There is a need for patient education, which should be offered early and often during treatment.

Risk Factors for Suicide in Older Inpatient Veterans with Schizophrenia.

Patients with schizophrenia have an elevated risk of suicidal behavior. We explored whether there were age differences in inpatients with schizophrenia admitted for suicidal behavior. We compared demographic/clinical characteristics of 76 inpatients aged > 59 to those < 60. All patients had a score greater > 0 on items 4 (active suicidality) and/or 5 (passive suicidality) on the Beck Scale for Suicidal Ideation for inclusion. There were no significant group differences with respect to race, education, depressive symptoms or negative symptoms. There was evidence suggesting that hallucinations appear to be less prominent in the older group. Future studies will determine whether these age related differences are stable over time and could account for potential age differences in suicidal behavior in individuals with schizophrenia.

Effect of insomnia treatments on depression: A systematic review and meta-analysis.

BACKGROUND: Insomnia is frequently co-morbid with depression, with a bidirectional relationship between these disorders. There is evidence that insomnia-specific interventions, such as cognitive behavioral therapy for insomnia, may lead to improvements in depression. The purpose of this systematic review and meta-analysis is to determine whether treatment of insomnia leads to improved depression outcomes in individuals with both insomnia and depression. METHODS: We conduct a systematic review and meta-analysis to explore the effect of treatment for insomnia disorder on depression in patients with both disorders. RESULTS: Three thousand eight hundred and fifteen studies were reviewed, and 23 studies met inclusion criteria. Although all of the studies suggested a positive clinical effect of insomnia treatment on depression outcomes, most of the results were not statistically significant. Although the interventions and populations were highly variable, the meta-analysis indicates moderate to large effect size (ES) improvement in depression as measured with the Hamilton Depression Rating Scale (ES = -1.29, 95%CI [-2.11, -0.47]) and Beck Depression Inventory (ES = -0.68, 95%CI [-1.29, -0.06]). CONCLUSIONS: These results support that treating insomnia in patients with depression has a positive effect on mood. Future trials are needed to identify the subtypes of patients whose depression improves during treatment with insomnia-specific interventions, and to identify the mechanisms by which treating insomnia improves mood.

Specific depressive symptoms predict remission to aripiprazole augmentation in late-life treatment resistant depression.

OBJECTIVE: To identify which specific depressive symptoms predict remission to aripiprazole augmentation in late-life treatment resistant depression. METHODS: This is a secondary analysis of data from a late-life treatment resistant depression trial examining the safety and efficacy of aripiprazole augmentation. Participants aged 60 and above were randomized to aripiprazole augmentation (N = 91) versus placebo (N = 90). The main outcome was depression remission. Clinical predictors included individual Montgomery-Asberg Depression Rating Scale (MADRS) item scores categorized as symptomatic (scores >2) or nonsymptomatic (scores ≤2). RESULTS: Three MADRS items predicted depression remission with aripiprazole augmentation: symptomatic scores on sleep disturbance and nonsymptomatic scores on apparent sadness and inability to feel. The 2-way and 3-way interaction terms of these MADRS items were not significant predictors of remission; therefore, the models' ability to predict remission was not improved by combining the significant MADRS items. CONCLUSIONS: The identification of specific depressive symptoms, which can be clinically assessed, can be used to inform treatment decisions. Older adults with treatment resistant depression that present with sleep disturbances, lack of apparent sadness, or lack of inability to feel should be considered for aripiprazole augmentation.

Effect of Antidepressant Switching vs Augmentation on Remission Among Patients With Major Depressive Disorder Unresponsive to Antidepressant Treatment: The VAST-D Randomized Clinical Trial.

IMPORTANCE: Less than one-third of patients with major depressive disorder (MDD) achieve remission with their first antidepressant. OBJECTIVE: To determine the relative effectiveness and safety of 3 common alternate treatments for MDD. DESIGN, SETTING, AND PARTICIPANTS: From December 2012 to May 2015, 1522 patients at 35 US Veterans Health Administration medical centers who were diagnosed with nonpsychotic MDD, unresponsive to at least 1 antidepressant course meeting minimal standards for treatment dose and duration, participated in the study. Patients were randomly assigned (1:1:1) to 1 of 3 treatments and evaluated for up to 36 weeks. INTERVENTIONS: Switch to a different antidepressant, bupropion (switch group, n = 511); augment current treatment with bupropion (augment-bupropion group, n = 506); or augment with an atypical antipsychotic, aripiprazole (augment-aripiprazole group, n = 505) for 12 weeks (acute treatment phase) and up to 36 weeks for longer-term follow-up (continuation phase). MAIN OUTCOMES AND MEASURES: The primary outcome was remission during the acute treatment phase (16-item Quick Inventory of Depressive Symptomatology-Clinician Rated [QIDS-C16] score ≤5 at 2 consecutive visits). Secondary outcomes included response (≥50% reduction in QIDS-C16 score or improvement on the Clinical Global Impression Improvement scale), relapse, and adverse effects. RESULTS: Among 1522 randomized patients (mean age, 54.4 years; men, 1296 [85.2%]), 1137 (74.7%) completed the acute treatment phase. Remission rates at 12 weeks were 22.3% (n = 114) for the switch group, 26.9% (n = 136)for the augment-bupropion group, and 28.9% (n = 146) for the augment-aripiprazole group. The augment-aripiprazole group exceeded the switch group in remission (relative risk [RR], 1.30 [95% CI, 1.05-1.60]; P = .02), but other remission comparisons were not significant. Response was greater for the augment-aripiprazole group (74.3%) than for either the switch group (62.4%; RR, 1.19 [95% CI, 1.09-1.29]) or the augment-bupropion group (65.6%; RR, 1.13 [95% CI, 1.04-1.23]). No significant treatment differences were observed for relapse. Anxiety was more frequent in the 2 bupropion groups (24.3% in the switch group [n = 124] vs 16.6% in the augment-aripiprazole group [n = 84]; and 22.5% in augment-bupropion group [n = 114]). Adverse effects more frequent in the augment-aripiprazole group included somnolence, akathisia, and weight gain. CONCLUSIONS AND RELEVANCE: Among a predominantly male population with major depressive disorder unresponsive to antidepressant treatment, augmentation with aripiprazole resulted in a statistically significant but only modestly increased likelihood of remission during 12 weeks of treatment compared with switching to bupropion monotherapy. Given the small effect size and adverse effects associated with aripiprazole, further analysis including cost-effectiveness is needed to understand the net utility of this approach. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01421342.

Mental health treatment preferences and challenges of living with multimorbidity from the veteran perspective.

OBJECTIVE: To explore middle-aged and older veterans' current disease-management practices, mental health treatment preferences, and challenges of living with multiple chronic health conditions (i.e., multimorbidity). METHODS: Semi-structured qualitative interviews and self-report measures were collected from 28 middle-aged and older (50 years of age or older) veterans with multimorbidity. RESULTS: Our sample of veterans with multimorbidity was, on average, mildly depressed and anxious with elevated stress and disability. Veterans acknowledged the interaction of physical and emotional symptoms, which caused greater difficulty with health care management and daily functioning. Veterans had many concerns regarding their physical and emotional health conditions, such as continued disease progression and the addition of other emotional and physical health complications. Veterans also identified specific self-care approaches for disease management (e.g., medication, healthy lifestyle practices, and psychological stress management techniques), as well as barriers to engaging in care (e.g., money, transportation, and stigma). Participants preferred a combination of medication, psychotherapy, and healthy lifestyle practices for mental health treatment. The majority of participants (88.5%) agreed that these mental health treatments would be beneficial to integrate into disease management for older veterans with multimorbidity. Lastly, veterans provided an array of recommendations for improving Veteran's Administration services and reducing mental health stigma. CONCLUSIONS: These findings provide support for patient-centered approaches and integrated mental and physical health self-management in the Veteran's Administration for middle-aged and older veterans with multiple chronic conditions. Copyright © 2016 John Wiley & Sons, Ltd.

Sedative hypnotic use among veterans with a newly reported mental health disorder.

BACKGROUND: This study compared sedative hypnotic use by type of mental health diagnosis and determined factors associated with use among older veterans (65+ years) with a newly reported mental health disorder. METHODS: This study used data from veterans who received primary care services at VA Pittsburgh Healthcare System (VAPHS) from January 1, 2007 to December 31, 2011 (n = 879). RESULTS: Sedative hypnotics were commonly used in older veterans within 12-months following a newly reported mental health disorder (19.9%), particularly amongst those with insomnia (41.7%). The number of newly reported mental health disorders was a significant factor associated with sedative hypnotic use, with the odds of use increasing by more than 200% in older adults with two newly reported disorders compared to those with one newly reported mental health disorder. CONCLUSIONS: Continued efforts are needed to improve provider and patient awareness of the risks associated with sedative hypnotic use in older adults, as well as to increase access to and receipt of non-pharmacological mental health treatments for this vulnerable population.

Levels of symptom severity and functioning in four different definitions of subthreshold posttraumatic stress disorder in primary care veterans.

Four definitions of subthreshold posttraumatic stress disorder (PTSD) were compared in 815 veterans seen in Veterans Affairs Medical Center primary care clinics. We compared PTSD Checklist (PCL) scores and Short Form 36 (SF-36) scores between participants meeting criteria for one of the subthreshold PTSD definitions (based on Schnurr, Marshall, Blanchard, or Stein) to those with and without PTSD. Using regression, those meeting subthreshold criteria by any of the four definitions had lower mental and physical health functioning and higher PCL scores relative to those without PTSD; they also had higher mental health functioning and lower PCL scores relative to those with PTSD. With SF-36 physical functioning scores, only those meeting the Stein definition differed from the group with PTSD. Thus, these definitions appear to distinguish individuals who are qualitatively different from individuals with no PTSD or with PTSD and are nearly equivalent in their ability to discriminate individuals.

Does age moderate the relationship between depressive symptoms and suicidal ideation in middle-aged and older patients with schizophrenia and subthreshold depression?

BACKGROUND: Suicidal deaths in middle-aged and older individuals with schizophrenia are a public health concern. Depression and schizophrenia are major risk factors for suicide. However, it is unknown whether age moderates the relationship between depression and suicidal ideation in patients with schizophrenia and subthreshold depression. METHODS: Suicidal ideation was assessed with the InterSePT Scale for Suicidal Ideation and the Clinical Global Impression-Suicide Severity Scale in outpatients older than 39 years with schizophrenia and subthreshold depression (n = 213). Using linear regression, we examined whether depression (based on Calgary Depression Rating Scale scores), age, and "age by depressive symptoms" predicted suicidal ideation. RESULTS: Depressive symptoms predicted suicidal ideation. Neither age nor "depressive symptoms by age" predicted suicidal ideation. CONCLUSIONS: In this population, age does not appear to moderate the relationship between depressive symptoms and suicidal behavior. Thus, assessing depressive symptoms as a risk factor is important at all ages in this population.

Does antidepressant treatment improve cognition in older people with schizophrenia or schizoaffective disorder and comorbid subsyndromal depression?

BACKGROUND: Subsyndromal symptoms of depression (SSD) in patients with schizophrenia are common and clinically important. While treatment of depression in major depressive disorder may partially ameliorate cognitive deficits, the cognitive effects of antidepressant medications in patients with schizophrenia or schizoaffective disorder and SSD are unknown. METHODS: The goal of this study was to assess the impact of SSD and their treatment on cognition in participants with schizophrenia or schizoaffective disorder aged ≥40 years. Participants were randomly assigned to a flexible dose treatment with citalopram or placebo augmentation of their current medication for 12 weeks. An ANCOVA compared improvement in the cognitive composite scores, and a linear model determined the moderation of cognition on treatment effects based on the Hamilton Depression Rating Scale and the Calgary Depression Rating Scale scores between treatment groups. RESULTS: There were no differences between the citalopram and placebo groups in changes in cognition. Baseline cognitive status did not moderate antidepressant treatment response. CONCLUSIONS: Although there are other cogent reasons why SSD in schizophrenia warrant direct intervention, treatment does not substantially affect the level of cognitive functioning. Given the effects of cognitive deficits associated with schizophrenia on functional disability, there remains an ongoing need to identify effective means of directly ameliorating them.

Functional CRH variation increases stress-induced alcohol consumption in primates.

Corticotropin-releasing factor (CRF), encoded by the CRH gene, is a key integrator of stress responses, and, as such, CRH gene variation may contribute to individual differences in susceptibility to stress-related pathology. In rhesus macaques, a single nucleotide polymorphism (SNP) is found within the CRH promoter (-248C--> T). Here, we assessed whether this variant influenced stress responding and, because increased CRF system activity drives alcohol drinking in rodents, we examined whether it predicted voluntary alcohol consumption as a function of prior stress exposure. Using a hypothalamic nuclear extract, we showed that the -248 T allele resulted in increased DNA protein interactions relative to the C allele. In vitro, the T allele resulted in CRH promoter activity that was higher following both stimulation with forskolin and treatment with dexamethasone. Endocrine and behavioral responses to social separation stress (release of ACTH and cortisol, and suppression of environmental exploration, respectively) were higher among carriers of the T allele, particularly among those exposed to early adversity in the form of peer rearing. We also found that T allele carriers with a history of early life adversity consumed more alcohol in a limited-access paradigm. Our data suggest that CRH promoter variation that confers increased stress reactivity increases the risk for alcohol use disorders in stress-exposed individuals.

Case-control study of the relationship of functioning to suicide in a community-based sample of individuals with schizophrenia in China.

Suicide is a leading cause of premature death among people with schizophrenia. Some studies indicate that increased difficulties in functioning are associated with suicidality in persons with schizophrenia. We conducted a secondary analysis of 74 suicides (cases) and 24 accidental deaths (controls) among persons with schizophrenia identified in a national psychological autopsy study in China. Between cases and controls, we compared the effect of schizophrenia on work, daily activities, emotions, social relationships and self-care at the time the illness was most severe. There was no difference in the overall maximum dysfunction associated with the illness between groups. None of the 5 measures (work, activities, emotions, relationships, self-care) were different between the two groups. This study of individuals with DSM-IV schizophrenia who died by suicide in a non-western culture only partially supports findings from clinical studies in western cultures.

Narrative evolution and assimilation of problematic experiences in a case of pharmacotherapy for schizophrenia.

This case study applied the assimilation model to examine the changing narrative of an outpatient with schizophrenia and symptoms of depression across a successful pharmacotherapy. The assimilation model describes how clients assimilate painful, problematic experiences. Therapeutic progress is understood to reflect increasing assimilation, measured by the Assimilation of Problematic Experiences Scale (APES). The authors used a 15-min semistructured interview (Problematic Experiences Questionnaire) to elicit narrative descriptions of the patient's problems and coping across five interviews throughout his 12-week treatment. They describe how the patient's narrative and APES ratings of his main problems by two clinicians changed in concert through treatment, explain these developments using assimilation concepts, and interpret the results in relation to assimilation and insight in schizophrenia.

Treatment of subsyndromal depressive symptoms in middle-age and older patients with schizophrenia: effect of age on response.

OBJECTIVE: The authors hypothesized that age would moderate the response of patients with schizophrenia and subsyndromal depression (SSD) treated citalopram with depressive symptoms and other outcomes. Also, older patients would exhibit more side effects with citalopram. METHODS: Participants of 40 years or older had schizophrenia or schizoaffective disorder with SSD. Patients randomly received flexible dosing of citalopram or placebo augmentation of their antipsychotic medication. Linear regression determined whether age had any moderating effect on depressive symptoms, global psychopathology, negative symptoms, mental functioning, and quality of life. Age-related side effects were examined. RESULTS: There were no significant drug group by age interaction in depressive or psychotic symptoms, mental Short Form-12, or quality of life scores. Similarly, there were few age-related side effect differences. CONCLUSION: Symptoms in younger and older patients with schizophrenia and SSD treated with citalopram seem to respond similarly. Adverse events do not seem to differ with age.

The relationship of marital status and clinical characteristics in middle-aged and older patients with schizophrenia and depressive symptoms.

BACKGROUND: This study examines the relationship of marital status to depression, positive and negative symptoms, quality of life, and suicidal ideation among 211 patients with schizophrenia-spectrum disorders and subsyndromal depressive symptoms. We hypothesized that single participants would have more severe symptomatology than married and cohabitating participants. METHODS: Outpatients, age 40 or older, were diagnosed with schizophrenia or schizoaffective disorders using the MINI Structured Clinical Interview for DSM-IV Axis 1 Disorders. Participants exhibited a score of >8 on the Hamilton Rating Scale for Depression but did not meet criteria for a major depressive episode. RESULTS: Participants who were married or cohabitating had a later age of onset of first psychotic episode or hospitalization than those who were single (age, 29.35 vs 24.21). Married participants rated their quality of life higher than those who were single (mean Quality of Life Scale scores, 72.28 vs 53.87) and had less suicidal ideation than those who were divorced, widowed, or separated (7.4% vs 29.2%). CONCLUSIONS: In middle-aged and older individuals with schizophrenia or schizoaffective disorder and depressive symptoms, marriage appeared to enhance quality of life and protect against suicidal ideation. Efforts that focus on providing additional support for those who are experiencing divorce or separation could prove to be lifesaving for these individuals.

Treatment of subsyndromal depressive symptoms in middle-aged and older adults with schizophrenia: effect on functioning.

BACKGROUND: Subsyndromal symptoms of depression (SSD) in patients with schizophrenia are common and clinically important. SSRI's appear to be helpful in alleviating depressive symptoms in patients with schizophrenia who have SSD in patients age 40 and greater. It is not known whether SSRI's help improve functioning in this population. We hypothesized that treating this population with the SSRI citalopram would lead to improvements in social, mental and physical functioning as well as improvements in medication management and quality of life. METHODS: Participants were 198 adults > or = 40 years old with schizophrenia or schizoaffective disorder who met study criteria for subsyndromal depression based on having two or more of the nine DSM-IV symptoms of a major depressive episode, for at least 2 weeks, and a Hamilton depression rating scale (HAM-D 17) score > or = 8. Patients were randomly assigned to flexible-dose treatment with citalopram or placebo augmentation of their current antipsychotic medication(s) which was stable for 1 month. Subjects were assessed with the following functional scales at baseline and at the end of the 12-week trial: (1) social skills performance assessment (SSPA), (2) medication management ability assessment (MMAA), (3) mental and physical components of the medical outcomes study SF-12 Scale, and (4) the Heinrichs quality of life scale (QOLS). Analysis of covariance (ANCOVA) was used to compare differences between endpoint scores of the citalopram and placebo treated groups, controlling for site and baseline scores. ANCOVAs were also used to compare differences in the above endpoint scores in responders versus non-responders (responders = those with > 50% reduction in depressive symptoms). RESULTS: Overall, the citalopram group had significantly higher SSPA, mental functioning SF-12, and quality of life scale (QOLS) scores compared to the placebo group. There was no effect on MMAA or physical functioning SF-12 scores. Responders had significantly better endpoint mental SF-12 and QOLS scores compared to non-responders. Response to citalopram in terms of depressive symptoms mediated the effect of citalopram on mental functioning, but not on the quality of life. CONCLUSIONS: Citalopram augmentation of antipsychotic treatment in middle aged and older patients with schizophrenia and subsyndromal depression appears to improve social and mental health functioning as well as quality of life. Thus it is important for clinicians to monitor these aspects of functioning when treating this population of patients with schizophrenia with SSRI agents.

Heterogeneity of neuroendocrine stress responses in aging rat strains.

Hyperactivity of the hypothalamo-pituitary-adrenocortical (HPA) axis is linked with age-related decrements in cognition and neuronal survival. However, the nature and extent of age-related HPA axis deficits vary considerably across and indeed, within strains. The current study was designed to assess variance in HPA axis function using two rodent models commonly used in aging studies: Fischer 344 (F344) and F344/Brown-Norway F1 hybrid rats (F344/BN). We examined both basal and stress-induced ACTH and corticosterone (CORT) release in two stress contexts thought to differ in intensity: novel environment ('mild') and restraint ('intense'). Variability of the data was tested with a modification of the Brown-Forsythe test of homoscedasticity. The results indicated that F344 rats exhibit greater peak HPA responses. Furthermore, in most cases variability was increased in aged rats relative to young and middle-aged rats of the same strain, indicative of the emergence of individual differences in stress responsivity amongst older rats. The results suggest that these older rat strains may be useful models to further assess individual differences in neuroendocrine aging.

Brief behavioral treatment for insomnia in older adults with late-life treatment-resistant depression and insomnia: a pilot study.

OBJECTIVE: Brief Behavioral Treatment for Insomnia (BBTI) is an efficacious treatment of insomnia in older adults. Behavioral treatments for insomnia can also improve depression. However, it is unknown if BBTI is feasible or has an effect in patients with insomnia and late-life treatment resistant depression (LLTRD). The aims of this study were two-fold, to test: 1) the feasibility (defined by acceptability and retention rates) of BBTI and 2) the therapeutic potency of BBTI on symptoms of insomnia and depression. METHODS: Eleven older Veterans with LLTRD and insomnia were recruited in a randomized control trial to receive immediate (4-weeks of BBTI followed by 3-weeks of phone call check-ins and a final in-person 8-week assessment) or delayed (3-weeks of treatment as usual [wait-list control] followed by 4-weeks of BBTI and a final in-person 8-week assessment) BBTI. The primary outcome measures included the Patient Health Questionnaire (minus the sleep item) and the Insomnia Severity Index. RESULTS: BBTI was found to be feasible in older Veterans with insomnia and LLTRD; all participants recommended BBTI and retention rates were 90.9%. There was no difference in treatment effect between the immediate BBTI and delayed BBTI groups at week 4. After both groups (immediate and delayed) received BBTI, improvements were seen in both insomnia (d = 1.06) and depression (d = 0.54) scores. CONCLUSIONS: BBTI is a feasible treatment for insomnia in older adults with LLTRD. BBTI may be an effective adjunctive treatment for depression. Larger adequately-powered trials are required to confirm these preliminary findings.

Effects of trauma-related audiovisual stimulation on cerebrospinal fluid norepinephrine and corticotropin-releasing hormone concentrations in post-traumatic stress disorder.

BACKGROUND: Although elevated concentrations of both corticotropin-releasing hormone (CRH) and norepinephrine are present in the cerebrospinal fluid (CSF) of patients with post-traumatic stress disorder (PTSD), the effects of exposure to traumatic stimuli on these stress-related hormones in CSF are unknown. METHODS: A randomized, within-subject, controlled, cross-over design was used, in which patients with war-related PTSD underwent 6-h continuous lumbar CSF withdrawal on two occasions per patient (6-9 weeks apart). During one session the patients watched a 1-h film containing combat footage (traumatic film) and in the other a 1-h film on how to oil paint (neutral film). At 10-min intervals, we quantified CRH and norepinephrine in CSF, and ACTH and cortisol in plasma, before, during, and after symptom provocation. Subjective anxiety and mood were monitored using 100-mm visual analog scales. Blood pressure and heart rate were obtained every 10min from a left leg monitor. RESULTS: Eight of 10 patients completed two CSF withdrawal procedures each. A major drop in mood and increases in anxiety and blood pressure occurred during the traumatic relative to the neutral videotape. CSF norepinephrine rose during the traumatic film relative to the neutral videotape; this rise directly correlated with magnitude of mood drop. In contrast, CSF CRH concentrations declined during the trauma-related audiovisual stimulus, both absolutely and relative to the neutral stimulus; the magnitude of CRH decline correlated with degree of subjective worsening of anxiety level and mood. Plasma cortisol concentrations were lower and ACTH levels similar during the stress compared with the neutral videotape. CONCLUSIONS: CSF concentrations of the stress hormones norepinephrine and CRH differentially change after exposure to 1h of trauma-related audiovisual stimulation in chronic, combat-related PTSD. While the CSF norepinephrine increase was postulated, the decline in CSF CRH levels is surprising and could be due to audiovisual stress-induced increased uptake of CSF CRH into brain tissue, increased CRH utilization, increased CRH degradation, or to an acute stress-related inhibition or suppression of CRH secretion.