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Background: Depression is associated with increased risk of several general medical conditions, including diabetes and cardiovascular disease. The nature of the association is complex and may involve bidirectional causation or a common pathophysiology., Aims: To determine whether young people without depression but at increased familial risk have altered metabolic and blood pressure markers relative to matched controls., Method: We studied young people (n = 85), who had a parent with depression but no personal history of depressive illness (FH+) and healthy controls (n = 69). Cardiovascular risk profile was assessed by a fasting blood sample to measure insulin, glucose, lipids and high-sensitivity C-reactive protein (CRP) and blood pressure was measured centrally and peripherally. Arterial stiffness and waking cortisol concentration were also measured., Results: Compared with controls, the FH+ group demonstrated increased peripheral and central systolic blood pressure, increased arterial stiffness and diminished insulin sensitivity but they did not differ from controls in measures of lipids, CRP or waking cortisol., Conclusions: Our data suggest that young people at increased familial risk of depression show evidence of altered cardiovascular risk profile in young adulthood even in the absence of depressive symptoms. It is possible therefore that vulnerability to conditions such as hypertension and diabetes may precede the onset of major depression and may share common risk factors.

Background: The processing of aversive stimuli in patients with major depression is associated with increased neural activity in limbic areas while the activity in cortical regulatory regions is diminished. The aim of the present study was to examine whether related neural abnormalities might be present in young people at increased familial risk of depression but with no personal history of illness., Methods: We used a block designed functional magnetic resonance imaging to measure the neural responses to a task involving the matching of emotional facial expressions in 29 young people (age 16-21 years) who had a biological parent with a history of major depression, and 30 age- and gender-matched controls., Results: Relative to the controls, the participants with increased familial risk of depression (FH) had diminished responses in left dorsolateral prefrontal cortex (DLPFC) to the presentation of fearful faces while the activity in the amygdala did not distinguish the groups., Limitations: FH participants had more depressive symptomatology than the controls. Their FH status was based on self-report., Conclusions: Young people at increased familial risk of depression show evidence of decreased cortical regulation of aversive stimuli. Further studies will be needed to ascertain if this abnormality might predispose to the eventual development of clinical depression., (Copyright © 2010 Elsevier B.V. All rights reserved.)

Using proton magnetic resonance spectroscopy (MRS), we have demonstrated regional abnormalities in cortical γ-aminobutyric acid (GABA) and glutamate in medication-free recovered depressed patients. It is unclear whether these changes represent an underlying trait vulnerability to depression, or an after-effect of episodes of illness or its treatment. We sought to examine this question by examining a group of high-risk, never-depressed, individuals. We used MRS to measure GABA and glutamate in parieto-occipital cortex in young people (ages 16-21 yr) with a family history of parental depression (n=24) but no personal history of illness and a control group without a history of depression in any first-degree relative (n=28). Participants with a parental history of depression had significantly higher levels of glutamate than controls in parieto-occipital cortex (F₁,₄₇=5.5, p=0.02). These findings suggest that abnormalities in glutamate neurotransmission may reflect a trait marker of vulnerability to depression.

Background: Patients with depression show abnormalities in the neural circuitry supporting working memory. These abnormalities apparently persist into clinical remission, raising the possibility that they might be trait markers indicating vulnerability to depression., Methods: We studied 17 young people who had a depressed parent but no personal history of depressive illness (FH) and 15 healthy control subjects with no family history of depression. Participants performed a verbal working memory task of varying cognitive load (n-back) while undergoing functional magnetic resonance imaging scanning. We used multiple regression analyses to assess overall capacity (1-, 2-, 3-back vs. 0-back) as well as linear and quadratic modulation of cognitive demand., Results: Performance accuracy and response latency did not differ between groups, and overall capacity was similar. However, for both linear and quadratic load response activity, FH participants showed greater activation in lateral occipital cortex, superior temporal cortex, and superior parietal cortex., Conclusions: Our data suggest that, as in depressed patients, maintenance of task performance in FH participants is associated with a significant increase in the load-response activity of the cortical regions involved in working memory. This neural abnormality could form part of the predisposition to develop depressive disorders., (Copyright 2010 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Background: We previously found that children of parents with depression showed impaired performance on a task of emotional categorisation., Aims: To test the hypothesis that children of parents with depression would show abnormal neural responses in the anterior cingulate cortex, a brain region involved in the integration of emotional and cognitive information., Method: Eighteen young people (mean age 19.8 years) with no personal history of depression but with a biological parent with a history of major depression (FH+ participants) and 16 controls (mean age 19.9 years) underwent functional magnetic resonance imaging while completing an emotional counting Stroop task., Results: Controls showed significant activation in the pregenual anterior cingulate cortex to both positive and negative words during the emotional Stroop task. This activation was absent in FH+ participants., Conclusions: Our findings show that people at increased familial risk of depression demonstrate impaired modulation of the anterior cingulate cortex in response to emotionally valenced stimuli.

We investigated the impact of the administration of a tyrosine-depleting amino acid mixture compared to a balanced mixture on measures of mood, craving and selective processing of smoking-related cues in healthy cigarette smokers instructed to abstain from smoking for 12 h prior to, and during, the experiment. A modified stroop task was used to index selective processing of smoking-related cues. We observed evidence for an increase in subjective craving among males, and an attenuation of the selective processing of smoking-related cues compared to control cues among females, in the tyrosine-depleting condition compared to the balanced condition. No effects of mixture were observed on measures of subjective mood. These results tentatively support for the role of dopaminergic neurotransmission in mediating the response of cigarette smokers to smoking-related cues. In addition, these results also provide further evidence for sex differences in the factors that maintain cigarette smoking, in particular with respect to conditioned reinforcement of smoking behaviour, and suggest that the relationship between subjective craving and selective processing of smoking-related cues may differ in males and females.

Negative biases in emotional information processing are characteristic of patients with acute depression and may persist after clinical recovery. It is not clear, however, whether such biases are present before the onset of the depressive disorder. The aim of the present study was to examine whether young people at risk of depression, by virtue of having a depressed biological parent (FH+), demonstrate negative biases in tasks of emotional facial recognition and emotional categorization. We also assessed whether task performance and the influence of parental depression are modified by allelic variation in the serotonin transporter (5HTT) gene. We found that the FH+ participants did not show evidence of negative biases relative to matched controls. They were, however, significantly slower to perform a task of emotional categorization. 5HTT genotype did not influence emotional processing significantly. We conclude that negative biases in emotional processing do not appear to be present in people with a family history of depression. However, impairment in emotional categorization could identify a high-risk phenotype and may indicate that people at genetic risk of depression have difficulty in using "mood as information".

Objective: Cortisol hypersecretion is one of the most reliable biological abnormalities in major depression, but it is uncertain if it represents an illness marker or a trait vulnerability to mood disorder. The present study sought to answer this question by measuring waking salivary cortisol levels in young people at familial risk of depression but with no personal history of mood disorder., Method: The authors studied 49 young people who had not been depressed themselves but who had a parent with a history of major depression (FH+) and a comparison group of 55 participants who had no personal history of depression and no reported depression in a first-degree relative. The authors measured the amount of cortisol secreted in saliva during the first 30 minutes after awakening on a workday and on a nonworkday., Results: The amount of cortisol secreted by the FH+ subjects was greater than that of the comparison subjects on both workdays (mean=698 nmol x minutes/liter, SD=243, versus mean=550, SD=225) and nonworkdays (mean=633 nmol x minutes/liter, SD=216, versus mean=492, SD=166). The increase in cortisol secretion was not accounted for by differences in parental attachment, life events, personality, or current mental state., Conclusions: Hypersecretion of cortisol can be detected in asymptomatic individuals at genetic risk of depression and may represent an illness endophenotype. Further studies will be needed to find out if increased waking salivary cortisol levels can predict individual risk of illness and whether the increased cortisol secretion has implications for general health and cognitive function.

The role of dopamine (DA) pathways in the pathophysiology of depressive disorder is poorly understood. However, because DA plays a key role in motivational behavior, it is important to study in a disorder characterized by anhedonia, lack of energy and psychomotor retardation. A recently developed dietary manipulation ('tyrosine (TYR) depletion') offers a novel method to assess the role of DA in major depression. We studied 15 euthymic women with a past history of recurrent depression, who received a 74 g amino-acid drink lacking TYR and phenylalanine (PHE) (TYR-free) and a balanced (BAL) amino acid drink on two separate occasions in a double-blind, random-order, crossover design. Plasma prolactin levels rose following the TYR-free drink relative to the balanced mixture, while performance on a spatial recognition memory task was impaired. However, relative to the BAL drink, the TYR-free drink did not lower objective or subjective measures of mood. We conclude that as in healthy volunteers, TYR depletion in euthymic subjects, with a past history of major depression, attenuated DA function, as reflected in increased plasma prolactin levels and decreased spatial memory performance. However ratings of depression were unaffected, suggesting that disruption of dopaminergic function by this manipulation does not induce a lowering of mood in individuals vulnerable to depression.