Anthony J. Cleare

Evidence-based guidelines for treating depressive disorders with antidepressants: A revision of the 2008 British Association for Psychopharmacology guidelines

A revision of the 2008 British Association for Psychopharmacology evidence-based guidelines for treating depressive disorders with antidepressants was undertaken in order to incorporate new evidence and to update the recommendations where appropriate. A consensus meeting involving experts in depressive disorders and their management was held in September 2012. Key areas in treating depression were reviewed and the strength of evidence and clinical implications were considered. The guidelines were then revised after extensive feedback from participants and interested parties. A literature review is provided which identifies the quality of evidence upon which the recommendations are made. These guidelines cover the nature and detection of depressive disorders, acute treatment with antidepressant drugs, choice of drug versus alternative treatment, practical issues in prescribing and management, next-step treatment, relapse prevention, treatment of relapse and stopping treatment. Significant changes since the last guidelines were published in 2008 include the availability of new antidepressant treatment options, improved evidence supporting certain augmentation strategies (drug and non-drug), management of potential long-term side effects, updated guidance for prescribing in elderly and adolescent populations and updated guidance for optimal prescribing. Suggestions for future research priorities are also made.

Neural responses to sad facial expressions in major depression following cognitive behavioral therapy

BACKGROUND Affective facial processing is an important component of interpersonal relationships. The neural substrate has been examined following treatment with antidepressant medication but not with psychological therapies. The present study investigated the neural correlates of implicit processing of sad facial expressions in depression pretreatment and posttreatment with cognitive behavioral therapy (CBT). METHODS The patient group consisted of 16 medication-free subjects (mean age 40 years) with a DSM-IV diagnosis of acute unipolar major depression, and the comparison group were 16 matched healthy volunteers. Subjects participated in a prospective study with functional magnetic resonance imaging (fMRI) at weeks 0 and 16. During the fMRI scans, subjects performed an affect recognition task with facial stimuli morphed to display varying intensities of sadness. Patients received 16 sessions of CBT. Functional magnetic resonance imaging data were analyzed for the mean activation and differential response to variable intensity (load-response) of facial affect processing. RESULTS During an acute depressive episode, patients showed elevated amygdala-hippocampal activity relative to healthy individuals. Baseline dorsal anterior cingulate activity in patients showed a significant relationship with subsequent clinical response. CONCLUSIONS These data provide further support for elevated amygdala activity in depression and suggest that anterior cingulate activity may be a predictor of treatment response to both pharmacotherapy and CBT.

The effect of tryptophan depletion and enhancement on subjective and behavioural aggression in normal male subjects.

In order to investigate the link between aggression and 5-HT, we looked at effects of changes in plasma tryptophan on healthy male subjects. Twenty-four with high trait aggression (H) and 24 with low (L) drank an amino acid mixture with (T+) or without (T−) trytophan. These caused plasma tryptophan enhancement and depletion, respectively, at 4.5 h. Group H subjects given T− became more angry, aggressive, annoyed, hostile and quarrelsome on subjective measures, whereas those given T+ responded in the opposite way. On a behavioural measure of aggression, group H subjects responded more aggressively after T− than T+. In contrast, there was no consistent effect on subjective or behavioural aggression in group L subjects. Feelings of well-being in group H were decreased by T− and increased by T+. In group L, T+ reduced feelings of well-being, possibly due to the sedative effect of tryptophan in this group, which correlated positively with plasma trytophan concentration. Changes in plasma tryptophan are probably followed by changes in central 5-HT turnover. We conclude that, in those with pre-existing aggressive traits, acute falls in central 5-HT can cause increased subjective and objective aggression, while rises can have the opposite effect. The absence of changes in a low aggressive group suggests that the primary effect may be on impulsivity, possibly mediated by 5-HT1a receptors, expressing underlying aggressive traits. The findings on mood changes provide support for earlier reports of a lowering of mood with tryptophan depletion.

Failure to detect the novel retrovirus XMRV in chronic fatigue syndrome.

Background In October 2009 it was reported that 68 of 101 patients with chronic fatigue syndrome (CFS) in the US were infected with a novel gamma retrovirus, xenotropic murine leukaemia virus-related virus (XMRV), a virus previously linked to prostate cancer. This finding, if confirmed, would have a profound effect on the understanding and treatment of an incapacitating disease affecting millions worldwide. We have investigated CFS sufferers in the UK to determine if they are carriers of XMRV. Methodology Patients in our CFS cohort had undergone medical screening to exclude detectable organic illness and met the CDC criteria for CFS. DNA extracted from blood samples of 186 CFS patients were screened for XMRV provirus and for the closely related murine leukaemia virus by nested PCR using specific oligonucleotide primers. To control for the integrity of the DNA, the cellular beta-globin gene was amplified. Negative controls (water) and a positive control (XMRV infectious molecular clone DNA) were included. While the beta-globin gene was amplified in all 186 samples, neither XMRV nor MLV sequences were detected. Conclusion XMRV or MLV sequences were not amplified from DNA originating from CFS patients in the UK. Although we found no evidence that XMRV is associated with CFS in the UK, this may be a result of population differences between North America and Europe regarding the general prevalence of XMRV infection, and might also explain the fact that two US groups found XMRV in prostate cancer tissue, while two European studies did not.

Low-dose hydrocortisone in chronic fatigue syndrome: a randomised crossover trial.

BACKGROUND Reports of mild hypocortisolism in chronic fatigue syndrome led us to postulate that low-dose hydrocortisone therapy may be an effective treatment. METHODS In a randomised crossover trial, we screened 218 patients with chronic fatigue. 32 patients met our strict criteria for chronic fatigue syndrome without co-morbid psychiatric disorder. The eligible patients received consecutive treatment with low-dose hydrocortisone (5 mg or 10 mg daily) for 1 month and placebo for 1 month; the order of treatment was randomly assigned. Analysis was by intention to treat. FINDINGS None of the patients dropped out. Compared with the baseline self-reported fatigue scores (mean 25.1 points), the score fell by 7.2 points for patients on hydrocortisone and by 3.3 points for those on placebo (paired difference in mean scores 4.5 points [95% CI 1.2-7.7], p=0.009). In nine (28%) of the 32 patients on hydrocortisone, fatigue scores reached a predefined cut-off value similar to the normal population score, compared with three (9%) of the 32 on placebo (Fishers exact test p=0.05). The degree of disability was reduced with hydrocortisone treatment, but not with placebo. Insulin stress tests showed that endogenous adrenal function was not suppressed by hydrocortisone. Minor side-effects were reported by three patients after hydrocortisone treatment and by one patient after placebo. INTERPRETATION In some patients with chronic fatigue syndrome, low-dose hydrocortisone reduces fatigue levels in the short term. Treatment for a longer time and follow-up studies are needed to find out whether this effect could be clinically useful.

The neuroendocrinology of chronic fatigue syndrome and fibromyalgia

BACKGROUND Disturbance of the HPA axis may be important in the pathophysiology of chronic fatigue syndrome (CFS) and fibromyalgia. Symptoms may be due to: (1) low circulating cortisol; (2) disturbance of central neurotransmitters; or (3) disturbance of the relationship between cortisol and central neurotransmitter function. Accumulating evidence of the complex relationship between cortisol and 5-HT function, make some form of hypothesis (3) most likely. We review the methodology and results of studies of the HPA and other neuroendocrine axes in CFS. METHOD Medline, Embase and Psychlit were searched using the Cochrane Collaboration strategy. A search was also performed on the Kings College CFS database, which includes over 3000 relevant references, and a citation analysis was run on the key paper (Demitrack et al. 1991). RESULTS One-third of the studies reporting baseline cortisol found it to be significantly low, usually in one-third of patients. Methodological differences may account for some of the varying results. More consistent is the finding of reduced HPA function, and enhanced 5-HT function on neuroendocrine challenge tests. The opioid system, and arginine vasopressin (AVP) may also be abnormal, though the growth hormone (GH) axis appears to be intact, in CFS. CONCLUSIONS The significance of these changes, remains unclear. We have little understanding of how neuroendocrine changes relate to the experience of symptoms, and it is unclear whether these changes are primary, or secondary to behavioural changes in sleep or exercise. Longitudinal studies of populations at risk for CFS will help to resolve these issues.

Functional polymorphisms in the interleukin-6 and serotonin transporter genes, and depression and fatigue induced by interferon-α and ribavirin treatment

Depression and fatigue are frequent side effects of interferon-α (IFN-α) treatment, and there is compelling evidence that the inflammatory response system (including interleukin-6, IL-6) and the serotonergic system is important in the pathophysiology of such symptoms. Functional polymorphisms in the promoter region of the IL-6 gene (rs1800795) and serotonin transporter gene (5-HTTLPR) have been identified as regulating these systems. The present study aimed to determine if these polymorphisms were associated with the development of depression and fatigue during IFN-α and ribavirin treatment. Ninety-eight Caucasian patients receiving pegylated IFN-α and ribavirin treatment for chronic hepatitis C virus at Kings College Hospital, London, and Emory University Hospital, Atlanta, participated in this prospective cohort study. Symptoms of depression and fatigue were measured before treatment and at weeks 4, 8, 12 and 24 during treatment. The ‘low IL-6’ synthesizing genotype (CC) was associated with significantly fewer symptoms of depression (effect size=0.7 at week 24; F=9.4, d.f.=436, P=0.002). The ‘high transcription’ serotonin transporter (5-HTT) genotype (LL) was also associated with significantly fewer symptoms of depression, but with a much smaller effect (effect size=0.2 at week 24; F=4.5, d.f.=436, P=0.03). Neither polymorphisms were associated with symptoms of fatigue (IL-6: F=1.2, d.f.=430, P=0.2; 5-HTT: F=0.5, d.f.=430, P=0.5). The smaller effects of the 5-HTT polymorphism on depression may be explained by an interaction between the genes (F=5.0, d.f.=434, P=0.02): the ‘protective’ effect of the 5-HTTLPR polymorphism was evident only in the presence of the ‘low IL-6’ genotype (F=5.4, d.f.=64, P=0.02), not in the presence of the ‘high IL-6’ genotype (F=2.2, d.f.=369, P=0.1). The association between the IL-6 polymorphism and reduced risk of depressive symptoms confirms the role of the inflammatory response system in the pathophysiology of IFN-α-induced depression; in contrast, the effect of the 5-HTT gene was small and perhaps dependent on the status of the inflammatory response.

The HPA axis and the genesis of chronic fatigue syndrome

Many studies of patients with long-standing chronic fatigue syndrome (CFS) have found alterations to the hypothalamo-pituitary-adrenal (HPA) axis, including mild hypocortisolism, heightened negative feedback and blunted responses to challenge. However, recent prospective studies of high-risk cohorts suggest that there are no HPA axis changes present during the early stages of the genesis of fatiguing illnesses. Moreover, HPA axis changes can be reversed by modifying behavioural features of the illness, such as inactivity, deconditioning and sleep disturbance. Nevertheless, raising levels of cortisol pharmacologically can temporarily alleviate symptoms of fatigue. This article presents the case that there is no specific change to the HPA axis in CFS and that the observed changes are of multifactorial aetiology, with some factors occurring as a consequence of the illness. Nevertheless, the HPA axis might play a role in exacerbating or perpetuating symptoms late on in the course of the illness.

Hypothalamic-pituitary-adrenal axis dysfunction in chronic fatigue syndrome.

The weight of current evidence supports the presence of the following factors related to hypothalamic–pituitary–adrenal (HPA) axis dysfunction in patients with chronic fatigue syndrome (CFS): mild hypocortisolism; attenuated diurnal variation of cortisol; enhanced negative feedback to the HPA axis; and blunted HPA axis responsiveness. Furthermore, HPA axis changes seem clinically relevant, as they are associated with worse symptoms and/or disability and with poorer outcomes to standard treatments for CFS. Regarding etiology, women with CFS are more likely to have reduced cortisol levels. Studies published in the past 8 years provide further support for a multifactorial model in which several factors interact to moderate HPA axis changes. In particular, low activity levels, depression and early-life stress appear to reduce cortisol levels, whereas the use of psychotropic medication can increase cortisol. Addressing these factors—for example, with cognitive behavioral therapy—can increase cortisol levels and is probably the first-line approach for correcting HPA axis dysfunction at present, as steroid replacement is not recommended. Given what is now a fairly consistent pattern of findings for the type of HPA axis changes found in CFS, we recommend that future work focuses on improving our understanding of the cause and relevance of these observed changes.

Tryptophan depletion reduces right inferior prefrontal activation during response inhibition in fast, event-related fMRI

Rationale and objectiveIn animal and human studies, the neurotransmitter serotonin (5-hydroxytryptamine; 5-HT) has been implicated in mediating impulsiveness and aggression. To test the hypothesis that 5-HT modulates neuro-cognitive brain activation during inhibitory control, we examined the effect of acute tryptophan depletion (ATD), a dietary challenge, which has been shown to decrease 5-HT synthesis in the brain, on functional brain activation during a go/no-go task.MethodsNine healthy, right-handed volunteers performed a rapid, event-related go/no-go task in two functional magnetic resonance imaging (fMRI) scanning sessions, 5 h after either a tryptophan-free or a balanced amino acid drink in a double-blind, sham depletion-controlled, counterbalanced, crossover design. The task required subjects to selectively execute or inhibit a motor response. Tryptophan depletion significantly lowered total plasma tryptophan concentration by 80%, but did not significantly alter inhibitory performance or mood ratings.ResultsATD significantly reduced right orbito-inferior prefrontal activation during the no-go condition, and increased activation in superior and medial temporal cortices.ConclusionsThese findings provide neuro-functional evidence of a serotonergic modulation of right inferior prefrontal during inhibitory motor control. The increased engagement of temporal brain regions may reflect compensatory mechanisms.