Multiple-therapy-resistant major depressive disorder: a clinically important concept.

Many novel therapeutic options for depression exist that are either not mentioned in clinical guidelines or recommended only for use in highly specialist services. The challenge faced by clinicians is when it might be appropriate to consider such 'non-standard' interventions. This analysis proposes a framework to aid this decision.Declaration of interestIn the past 3 years R.H.M.W. has received support for research, expenses to attend conferences and fees for lecturing and consultancy work (including attending advisory boards) from various pharmaceutical companies including Astra Zeneca, Cyberonics, Eli Lilly, Janssen, LivaNova, Lundbeck, MyTomorrows, Otsuka, Pfizer, Roche, Servier, SPIMACO and Sunovion. D.M.B.C. has received fees from LivaNova for attending an advisory board. In the past 3 years A.J.C. has received fees for lecturing from Astra Zeneca and Lundbeck; fees for consulting from LivaNova, Janssen and Allergan; and research grant support from Lundbeck.In the past 3 years A.C. has received fees for lecturing from pharmaceutical companies namely Lundbeck and Sunovion. In the past 3 years A.L.M. has received support for attending seminars and fees for consultancy work (including advisory board) from Medtronic Inc and LivaNova. R.M. holds joint research grants with a number of digital companies that investigate devices for depression including Alpha-stim, Big White Wall, P1vital, Intel, Johnson and Johnson and Lundbeck through his mindTech and CLAHRC EM roles. M.S. is an associate at Blueriver Consulting providing intelligence to NHS organisations, pharmaceutical and devices companies. He has received honoraria for presentations and advisory boards with Lundbeck, Eli Lilly, URGO, AstraZeneca, Phillips and Sanofi and holds shares in Johnson and Johnson. In the past 3 years P.R.A.S. has received support for research, expenses to attend conferences and fees for lecturing and consultancy work (including attending an advisory board) from life sciences companies including Corcept Therapeutics, Indivior and LivaNova. In the past 3 years P.S.T. has received consultancy fees as an advisory board member from the following companies: Galen Limited, Sunovion Pharmaceuticals Europe Ltd, myTomorrows and LivaNova. A.H.Y. has undertaken paid lectures and advisory boards for all major pharmaceutical companies with drugs used in affective and related disorders and LivaNova. He has received funding for investigator initiated studies from AstraZeneca, Eli Lilly, Lundbeck and Wyeth.

Symptoms of generalized anxiety disorder but not panic disorder at age 15 years increase the risk of depression at 18 years in the Avon Longitudinal Study of Parents and Children (ALSPAC) cohort study.

BACKGROUND: Generalized anxiety disorder (GAD) and panic disorder (PD) differ in their biology and co-morbidities. We hypothesized that GAD but not PD symptoms at the age of 15 years are associated with depression diagnosis at 18 years. METHOD: Using longitudinal data from the Avon Longitudinal Study of Parents and Children (ALSPAC) birth cohort we examined relationships of GAD and PD symptoms (measured by the Development and Well-Being Assessment) at 15 years with depression at 18 years (by the Clinical Interview Schedule - Revised) using logistic regression. We excluded adolescents already depressed at 15 years and adjusted for social class, maternal education, birth order, gender, alcohol intake and smoking. We repeated these analyses following multiple imputation for missing data. RESULTS: In the sample with complete data (n = 2835), high and moderate GAD symptoms in adolescents not depressed at 15 years were associated with increased risk of depression at 18 years both in unadjusted analyses and adjusting for PD symptoms at 15 years and the above potential confounders. The adjusted odds ratio (OR) for depression at 18 years in adolescents with high relative to low GAD scores was 5.2 [95% confidence interval (CI) 3.0-9.1, overall p < 0.0001]. There were no associations between PD symptoms and depression at 18 years in any model (high relative to low PD scores, adjusted OR = 1.3, 95% CI 0.3-4.8, overall p = 0.737). Missing data imputation strengthened the relationship of GAD symptoms with depression (high relative to low GAD scores, OR = 6.2, 95% CI 3.9-9.9) but those for PD became weaker. CONCLUSIONS: Symptoms of GAD but not PD at 15 years are associated with depression at 18 years. Clinicians should be aware that adolescents with GAD symptoms may develop depression.

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.

Effect of interferon-α on cortical glutamate in patients with hepatitis C: a proton magnetic resonance spectroscopy study.

BACKGROUND: The development of depressive symptomatology is a recognized complication of treatment with the cytokine interferon-α (IFN-α) and has been seen as supporting inflammatory theories of the pathophysiology of major depression. Major depression has been associated with changes in glutamatergic activity and recent formulations of IFN-induced depression have implicated neurotoxic influences that could also lead to changes in glutamate function. The present study used magnetic resonance spectroscopy (MRS) to measure glutamate and its major metabolite glutamine in patients with hepatitis C who received treatment with pegylated IFN-α and ribavirin. METHOD: MRS measurements of glutamate and glutamine were taken from a 25 × 20 × 20 mm voxel including the pregenual anterior cingulate cortex in 12 patients before and after 4-6 weeks of treatment with IFN. RESULTS: IFN treatment led to an increase in cortical levels of glutamine (p = 0.02) and a significant elevation in the ratio of glutamine to glutamate (p < 0.01). Furthermore, changes in glutamine level correlated significantly with ratings of depression and anxiety at the time of the second scan. CONCLUSIONS: We conclude that treatment with IFN-α is associated with MRS-visible changes in glutamatergic metabolism. However, the changes seen differ from those reported in major depression, which suggests that the pathophysiology of IFN-induced depression may be distinct from that of major depression more generally.

The pharmacology of anxiety.

Understanding the neurochemistry of anxiety is of fundamental importance in the development and use of novel anxiolytics. Through measuring peripheral markers of brain biochemistry, direct pharmacological challenges and brain neuroimaging techniques our understanding of this field has increased substantially in the past few decades. We review the four most studied neurotransmitter systems with respect to in anxiety disorders: gamma amino-butyric acid, serotonin, noradrenaline and dopamine. We have focussed upon clinical studies to highlight the current techniques used to determine brain neurochemistry in vivo. Future research in this field will greatly benefit from recent advances in neuroimaging techniques and the discovery of novel ligands targeting specific receptors.

Potential novel anxiolytic drugs.

Anxiety disorders are common and disabling conditions. Current drug treatment methods have limitations including resistance, delayed efficacy and side effects. The advent of sophisticated imaging techniques and the production of highly selective receptor ligands have increased our knowledge of the biological mechanisms underpinning anxiety. Our aim is to review recent discoveries in important neurological systems to provide an understanding of important current anxiolytic targets. Some of these systems, such as GABA, have been implicated in anxiety disorders for decades, but a recent greater understanding is enabling more sophisticated targeting of treatments. In other systems, including the neuropeptides, we have now developed the pharmacological tools in human subjects to begin exploring their relationship to anxiety disorders. We review GABA, serotonin, glutamate, noradrenaline, dopamine and some neuropeptides herein.

Vagus nerve stimulation for depression: efficacy and safety in a European study.

BACKGROUND: Vagus nerve stimulation (VNS) therapy is associated with a decrease in seizure frequency in partial-onset seizure patients. Initial trials suggest that it may be an effective treatment, with few side-effects, for intractable depression. METHOD: An open, uncontrolled European multi-centre study (D03) of VNS therapy was conducted, in addition to stable pharmacotherapy, in 74 patients with treatment-resistant depression (TRD). Treatment remained unchanged for the first 3 months; in the subsequent 9 months, medications and VNS dosing parameters were altered as indicated clinically. RESULTS: The baseline 28-item Hamilton Depression Rating Scale (HAMD-28) score averaged 34. After 3 months of VNS, response rates (> or = 50% reduction in baseline scores) reached 37% and remission rates (HAMD-28 score <10) 17%. Response rates increased to 53% after 1 year of VNS, and remission rates reached 33%. Response was defined as sustained if no relapse occurred during the first year of VNS after response onset; 44% of patients met these criteria. Median time to response was 9 months. Most frequent side-effects were voice alteration (63% at 3 months of stimulation) and coughing (23%). CONCLUSIONS: VNS therapy was effective in reducing severity of depression; efficacy increased over time. Efficacy ratings were in the same range as those previously reported from a USA study using a similar protocol; at 12 months, reduction of symptom severity was significantly higher in the European sample. This might be explained by a small but significant difference in the baseline HAMD-28 score and the lower number of treatments in the current episode in the European study.