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Depression and overweight are each associated with abnormal immune system activation. We sought to disentangle the extent to which depressive symptoms and overweight status contributed to increased inflammation and abnormal cortisol levels.
Participants were recruited through the Wellcome Trust NIMA Consortium. The sample of 216 participants consisted of 69 overweight patients with depression; 35 overweight controls; 55 normal-weight patients with depression and 57 normal-weight controls. Peripheral inflammation was measured as high-sensitivity C-Reactive Protein (hsCRP) in serum. Salivary cortisol was collected at multiple points throughout the day to measure cortisol awakening response and diurnal cortisol levels.
Overweight patients with depression had significantly higher hsCRP compared with overweight controls (p = 0.042), normal-weight depressed patients (p < 0.001) and normal-weight controls (p < 0.001), after controlling for age and gender. Multivariable logistic regression showed that comorbid depression and overweight significantly increased the risk of clinically elevated hsCRP levels ⩾3 mg/L (OR 2.44, 1.28–3.94). In a separate multivariable logistic regression model, overweight status contributed most to the risk of having hsCRP levels ⩾3 mg/L (OR 1.52, 0.7–2.41), while depression also contributed a significant risk (OR 1.09, 0.27–2). There were no significant differences between groups in cortisol awakening response and diurnal cortisol levels.
Comorbid depression and overweight status are associated with increased hsCRP, and the coexistence of these conditions amplified the risk of clinically elevated hsCRP levels. Overweight status contributed most to the risk of clinically elevated hsCRP levels, but depression also contributed to a significant risk. We observed no differences in cortisol levels between groups.
The history of pharmacological treatments for depression began in the 1950s, with the serendipitous discovery of the antidepressant potential of drugs like the tricyclic antidepressant, imipramine. Since then, many new, safer, and better tolerated, antidepressant drugs have appeared on the market (1), and now depression can be treated widely in primary care. However, finding a treatment effective for an individual patient is not a trivial task, with only around 30% of patients responding to their first antidepressant (AD) medication, most requiring multiple changes, and about one-third not responding at all (2).
Studies suggest that d-cycloserine (DCS) may have antidepressant potential through its interaction with the glycine site of the N-methyl-D-aspartate receptor; however, clinical evidence of DCS's efficacy as a treatment for depression is limited. Other evidence suggests that DCS affects emotional learning which may also be relevant for the treatment of depression and anxiety. The aim of the present investigation was to assess the effect of DCS on emotional processing in healthy volunteers and to further characterise its effects on emotional and autobiographical memory.
Forty healthy volunteers were randomly allocated to a single dose of 250 mg DCS or placebo in a double-blind design. Three hours later, participants performed an Emotional Test Battery [including Facial Expression Recognition Task (FERT), Emotional Categorisation Task (ECAT), Emotional Recall Task (EREC), Facial Dot-Probe Task (FDOT) and Emotional Recognition Memory Task (EMEM)] and an Autobiographical Memory Test (AMT). Also, participants performed the FERT, EREC and AMT tasks again after 24 h in order to assess longer lasting effects of a single dose of DCS.
DCS did not significantly affect the FERT, EMEM and FDOT performance but significantly increased emotional memory and classification for positive words v. negative words. Also, DCS enhanced the retrieval of more specific autobiographical memories, and this effect persisted at 24 h.
These findings support the suggestion that low-dose DCS increases specific autobiographical memory retrieval and positive emotional memory. Such effects make it an intriguing agent for further investigation in clinical depression, which is characterised by decreased autobiographical memory specificity and increased negative bias in memory recall. It also underscores the potential role of DCS as an adjunct to cognitive behavioural therapy in depression.
Animal experimental studies suggest that 5-HT4 receptor activation holds promise as a novel target for the treatment of depression and cognitive impairment. 5-HT4 receptors are post-synaptic receptors that are located in striatal and limbic areas known to be involved in cognition and mood. Consistent with this, 5-HT4 receptor agonists produce rapid antidepressant effects in a number of animal models of depression, and pro-cognitive effects in tasks of learning and memory. These effects are accompanied by molecular changes, such as the increased expression of neuroplasticity-related proteins that are typical of clinically useful antidepressant drugs. Intriguingly, these antidepressant-like effects have a fast onset of their action, raising the possibility that 5-HT4 receptor agonists may be a particularly useful augmentation strategy in the early stages of SSRI treatment. Until recently, the translation of these effects to humans has been challenging. Here, we review the evidence from animal studies that the 5-HT4 receptor is a promising target for the treatment of depression and cognitive disorders, and outline a potential pathway for the efficient and cost-effective translation of these effects into humans and, ultimately, to the clinic.
5-HT4 receptor stimulation has pro-cognitive and antidepressant-like effects in animal experimental studies; however, this pharmacological approach has not yet been tested in humans. Here we used the 5-HT4 receptor partial agonist prucalopride to assess the translatability of these effects and characterise, for the first time, the consequences of 5-HT4 receptor activation on human cognition and emotion.
Forty one healthy volunteers were randomised, double-blind, to a single dose of prucalopride (1 mg) or placebo in a parallel group design. They completed a battery of cognitive tests measuring learning and memory, emotional processing and reward sensitivity.
Prucalopride increased recall of words in a verbal learning task, increased the accuracy of recall and recognition of words in an incidental emotional memory task and increased the probability of choosing a symbol associated with a high likelihood of reward or absence of loss in a probabilistic instrumental learning task. Thus acute prucalopride produced pro-cognitive effects in healthy volunteers across three separate tasks.
These findings are a translation of the memory enhancing effects of 5-HT4 receptor agonism seen in animal studies, and lend weight to the idea that the 5-HT4 receptor could be an innovative target for the treatment of cognitive deficits associated with depression and other neuropsychiatric disorders. Contrary to the effects reported in animal models, prucalopride did not reveal an antidepressant profile in human measures of emotional processing.
Electroconvulsive therapy (ECT) possesses several key therapeutic actions, having antidepressant, anti-manic and antipsychotic effects. The adverse effects of ECT, particularly loss of autobiographical memories, are also of great clinical importance. Whether the same ‘mechanism’ underpins all these properties is unknown. Most information about the mechanistic effects of ECT has been obtained in relation to the treatment of depression and the current review will focus on this area.
Despite evidence of links between depression and violent outcomes, potential moderators of this association remain unknown. The current study tested whether a biological marker, cortisol, moderated this association in a longitudinal sample of adolescents.
Participants were 358 Dutch adolescents (205 boys) with a mean age of 15 years at the first measurement. Depressive symptoms, the cortisol awakening response (CAR) and violent outcomes were measured annually across 3 years. The CAR was assessed by two measures: waking cortisol activity (CAR area under the curve ground) and waking cortisol reactivity (CAR area under the curve increase). Within-individual regression models were adopted to test the interaction effects between depressive symptoms and CAR on violent outcomes, which accounted for all time-invariant factors such as genetic factors and early environments. We additionally adjusted for time-varying factors including alcohol drinking, substance use and stressful life events.
In this community sample, 24% of adolescents perpetrated violent behaviours over 3 years. We found that CAR moderated the effects of depressive symptoms on adolescent violent outcomes (βs ranged from −0.12 to −0.28). In particular, when the CAR was low, depressive symptoms were positively associated with violent outcomes in within-individual models, whereas the associations were reversed when the CAR was high.
Our findings suggest that the CAR should be investigated further as a potential biological marker for violence in adolescents with high levels of depressive symptoms.
C-reactive protein (CRP) is a candidate biomarker for major depressive disorder (MDD), but it is unclear how peripheral CRP levels relate to the heterogeneous clinical phenotypes of the disorder.
To explore CRP in MDD and its phenotypic associations.
We recruited 102 treatment-resistant patients with MDD currently experiencing depression, 48 treatment-responsive patients with MDD not currently experiencing depression, 48 patients with depression who were not receiving medication and 54 healthy volunteers. High-sensitivity CRP in peripheral venous blood, body mass index (BMI) and questionnaire assessments of depression, anxiety and childhood trauma were measured. Group differences in CRP were estimated, and partial least squares (PLS) analysis explored the relationships between CRP and specific clinical phenotypes.
Compared with healthy volunteers, BMI-corrected CRP was significantly elevated in the treatment-resistant group (P = 0.007; Cohen's d = 0.47); but not significantly so in the treatment-responsive (d = 0.29) and untreated (d = 0.18) groups. PLS yielded an optimal two-factor solution that accounted for 34.7% of variation in clinical measures and for 36.0% of variation in CRP. Clinical phenotypes most strongly associated with CRP and heavily weighted on the first PLS component were vegetative depressive symptoms, BMI, state anxiety and feeling unloved as a child or wishing for a different childhood.
CRP was elevated in patients with MDD, and more so in treatment-resistant patients. Other phenotypes associated with elevated CRP included childhood adversity and specific depressive and anxious symptoms. We suggest that patients with MDD stratified for proinflammatory biomarkers, like CRP, have a distinctive clinical profile that might be responsive to second-line treatment with anti-inflammatory drugs.
Declaration of interest
S.R.C. consults for Cambridge Cognition and Shire; and his input in this project was funded by a Wellcome Trust Clinical Fellowship (110049/Z/15/Z). E.T.B. is employed half time by the University of Cambridge and half time by GlaxoSmithKline; he holds stock in GlaxoSmithKline. In the past 3 years, P.J.C. has served on an advisory board for Lundbeck. N.A.H. consults for GlaxoSmithKline. P.d.B., D.N.C.J. and W.C.D. are employees of Janssen Research & Development, LLC., of Johnson & Johnson, and hold stock in Johnson & Johnson. The other authors report no financial disclosures or potential conflicts of interest.
The possible role of glutamate in the pathophysiology and treatment of depression is of intense current interest. Proton magnetic resonance spectroscopy (MRS) enables the detection of glutamate in the living human brain and meta-analyses of previous MRS studies in depressed patients have suggested that glutamate levels are decreased in anterior brain regions. Nevertheless, at conventional magnetic field strengths [1.5–3 Tesla (T)], it is difficult to separate glutamate from its metabolite and precursor, glutamine, with the two often being measured together as Glx. In contrast, MRS at 7 T allows clear spectral resolution of glutamate and glutamine.
We studied 55 un-medicated depressed patients and 50 healthy controls who underwent MRS scanning at 7 T with voxels placed in anterior cingulate cortex, occipital cortex and putamen (PUT). Neurometabolites were calculated using the unsuppressed water signal as a reference.
Compared with controls, depressed patients showed no significant difference in glutamate in any of the three voxels studied; however, glutamine concentrations in the patients were elevated by about 12% in the PUT (p < 0.001).
The increase in glutamine in PUT is of interest in view of the postulated role of the basal ganglia in the neuropsychology of depression and is consistent with elevated activity in the descending cortical glutamatergic innervation to the PUT. The basal ganglia have rarely been the subject of MRS investigations in depressed patients and further MRS studies of these structures in depression are warranted.
Persistent major depression that does not respond to adequate first- or
second-line treatment is a common problem in psychiatry. This article
updates evidence on recommended treatment strategies and reviews the
prospects of more experimental approaches. The main pharmacological
development in recent years has been the demonstration that several atypical
antipsychotic drugs are effective adjunctive agents in improving symptoms in
depression unresponsive to selective serotonin reuptake inhibitors, although
their adverse effect burden is high. There is optimism about novel
pharmacological strategies based on glutamatergic and anti-inflammatory
mechanisms. It is important to combine drug and psychological treatments
whenever possible. With persistent therapeutic engagement, the majority of
patients remit eventually, but subsequent relapse remains a problem.
Clinicians should pursue an active and collaborative treatment plan that
makes use of all effective therapeutic modalities and continues into the
Guze's famous essay on biological psychiatry – ‘Is there any other kind?’ –
argued that humans are biologically evolved creatures, therefore biological
processes must contribute importantly to psychiatric disorder. True enough,
though perhaps it was inevitable that ‘biological’ psychiatry would be
defined in opposition to other kinds of psychiatry like ‘psychosocial’,
which would then return to depict it as mindless, blind to context and
medically hegemonic. Pluralism is a great relief. Biological processes are
always involved, and we can try to utilise them for understanding and
treatment if it helps – but we don't have to. Biopsychosocial psychiatry –
is there any other kind?
Agomelatine is a new antidepressant, licensed for the treatment of unipolar major depression, with a mode of action that combines activation of melatonin receptors with blockade of 5-HT2C receptors. Agomelatine is notable for its short duration of action in the body and modest side-effect burden; however, a number of theoretical and practical challenges have limited its adoption into mainstream treatment in the UK. Current meta-analyses show marginal clinical benefits of agomelatine relative to placebo and an association with occasional increases in liver transaminases. Theoretically it is not clear whether agomelatine does block brain 5-HT2C receptors in humans at therapeutic doses and the optimum daily timing of administration in depression has not been clearly established. However, agomelatine's novel mode of action justifies further study, perhaps with the eventual aim of matching its use in depression to patients with specific disturbances in circadian rhythm.
Serotonin is a neurotransmitter conserved through at least 500 million years of nervous system evolution. Serotonin orchestrates adaptive responses to aversive stimuli in invertebrates and an analogous role can be discerned in the more complex behavioural repertoire displayed by mammals to adversity. However, this formulation fails to capture the range of human social behaviours influenced by serotonin, for example, affiliation, empathy and cooperation. In a psychopharmacology experiment I received paroxetine for three weeks. This boost in brain serotonin levels failed to alter my subjective ratings of mood and anxiety. My wife felt differently; ‘Can't you stay on it?’, she said.
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.
To determine whether young people without depression but at increased familial risk have altered metabolic and blood pressure markers relative to matched controls.
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.
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.
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.
Increasing interest surrounds potential neuroprotective or neurotrophic actions of antidepressants. While growing evidence points to important early clinical and neuropsychological effects of antidepressants, the time-course of any effect on neuronal integrity is unclear. This study used magnetic resonance spectroscopy to assess effects of short-term treatment with escitalopram on N-acetyl-aspartate (NAA), a marker of neuronal integrity. Thirty-nine participants with major depression were randomly assigned to receive either 10 mg escitalopram or placebo daily in a double-blind, parallel group design. On the seventh day of treatment, PRESS data were obtained from a 30×30×20 mm voxel placed in medial frontal cortex. Age and gender-matched healthy controls who received no treatment were also scanned. Levels of NAA were significantly higher in patients treated with escitalopram than in either placebo-treated patients (p<0.01) or healthy controls (p<0.01). Our findings are consistent with the proposition that antidepressant treatment in depressed patients can produce early changes in neuronal integrity.
Antidepressant prescribing is widespread. Nonetheless, response to antidepressants is variable. If it was possible to predict response to medication and thus tailor treatment accordingly, this would not only improve patient outcomes but may also have economic benefits.
To test the hypothesis that individuals with more severe depression would benefit more from noradrenaline reuptake inhibitors (NARIs) than selective serotonin reuptake inhibitors (SSRIs) compared with individuals with less severe depression.
Individuals recruited from UK primary care who met ICD-10 criteria for a depressive episode and scored 15 or more on the Beck Depression Inventory (BDI) were randomised to either an SSRI (citalopram 20mg daily) or a NARI (reboxetine 4mg twice daily). Randomisation was by means of a remote automated telephone system. The main outcome was depressive symptoms measured by the BDI total score 6 weeks after randomisation. (Trial registration: ISRCTN31345163.)
In total, 601 participants were randomised (citalopram: n = 298, reboxetine: n = 303). Ninety-one per cent were followed up at 6 weeks (citalopram: n = 274, reboxetine: n = 272). There was little evidence to support an interaction between treatment and severity of depression (interaction term: 0.02, 95% CI −0.59 to 0.62, P = 0.96). Adjustment for potential confounders (age, gender, employment status, history of depression, number of life events and social support) did not affect the findings (interaction term: 0.06, 95% CI −0.54 to 0.66, P = 0.85).
Treatment with NARIs does not confer any advantage over SSRI treatment for outcome in those with more severe depressive illness presenting in primary care.
Antidepressants exhibit a variety of pharmacological actions including
inhibition of the serotonin and noradrenaline transporters. We wished to
investigate whether genetic variation could be used to target or
personalise treatment, in a comparison of selective serotonin reuptake
inhibitors (SSRIs) with noradrenaline reuptake inhibitors (NARIs).
To test the hypothesis that patients homozygous for the long (insertion)
polymorphism of the serotonin transporter (5-HTTLPR) have an increased
response to SSRI antidepressants but not to NARI antidepressants.
In an individually randomised, parallel-group controlled trial, people
meeting criteria for a depressive episode who were referred by their
general practitioner were randomised to receive either citalopram (an
SSRI) or reboxetine (an NARI). Randomisation was by means of a remote
automated system accessed by telephone. The main outcome was depressive
symptoms, measured by Beck Depression Inventory (BDI) total score 6 weeks
after randomisation. The trial was registered with the International
Standard Randomised Controlled Trials Number registry
Altogether 298 participants were randomised to receive citalopram and 303
were randomised to reboxetine. At 6 weeks follow-up, complete data were
available for 258 participants taking citalopram and 262 taking
reboxetine. We found no evidence to support an influence of 5-HTTLPR on
outcome following antidepressant treatment. The interaction term for BDI
score at 6 weeks was 0.50 (95% CI −2.04 to 3.03, P =
0.70), which indicated that responses to the SSRI and NARI were similar
irrespective of 5-HTTLPR genotype.
It is unlikely that the 5-HTTLPR polymorphism alone will be clinically
useful in predicting response to antidepressants in people with