Adjunctive Docosahexaenoic Acid in Residual Symptoms of Depression and Anxiety.

OBJECTIVE: The aim of the study is to examine the efficacy of omega-3 fatty acid as an adjunct to ongoing pharmacological treatments in patients with residual symptoms of depression and anxiety. METHODS/PROCEDURES: This randomized, double-blind, placebo-controlled, cross-over trial was conducted at a single private practice site. Participants were drawn from patients attending the practice.Patients meeting criteria had a 4-week run-in period where they continued to receive their prescribed medications and omega-3 supplements. Depression and anxiety ratings were assessed at recruitment and completion of the run-in phase. Patients were randomized to receive an omega-3 supplement (Neurospark) or placebo once daily for 8 weeks then crossed over to the alternative treatment. At the end of the double-blind, cross-over phase, patients received the supplement and were assessed after a 4-week run-out phase.Depression and anxiety symptoms were assessed using the Hamilton scales. Efficacy of treatment was assessed using a linear mixed model analysis with time, order of treatment, diagnosis, and their interaction as factors. Depression and anxiety scales were analyzed as independent measures. RESULTS: The study enrolled 47 patients (mean [SD] age, 46.1 [11.2] years; [59.6%] male). Depression scores did not significantly change across assessments ( P > 0.1); there was no effect of order of treatment ( P > 0.1) or an interaction between time, order of treatment, and psychiatric diagnosis ( P > 0.1). Anxiety scores were similarly unchanged across treatment visits and order of treatment, and there was no interaction between time, order of treatment, and psychiatric diagnosis. CONCLUSIONS: Omega-3 fatty acid supplementation did not significantly alter residual symptoms in this group of patients.

Psilocybin in neuropsychiatry: a review of its pharmacology, safety, and efficacy.

Psilocybin is a tryptamine alkaloid found in some mushrooms, especially those of the genus Psilocybe. Psilocybin has four metabolites including the pharmacologically active primary metabolite psilocin, which readily enters the systemic circulation. The psychoactive effects of psilocin are believed to arise due to the partial agonist effects at the 5HT2A receptor. Psilocin also binds to various other receptor subtypes although the actions of psilocin at other receptors are not fully explored. Psilocybin administered at doses sufficient to cause hallucinogenic experiences has been trialed for addictive disorders, anxiety and depression. This review investigates studies of psilocybin and psilocin and assesses the potential for use of psilocybin and a treatment agent in neuropsychiatry. The potential for harm is also assessed, which may limit the use of psilocybin as a pharmacotherapy. Careful evaluation of the number needed to harm vs the number needed to treat will ultimately justify the potential clinical use of psilocybin. This field needs a responsible pathway forward.

Diagnostic agreement and concordance between consultation-liaison psychiatry and non-psychiatric (medical and surgical) doctors: changes within junior doctor's terms.

OBJECTIVE: To investigate whether diagnostic agreement and concordance between non-psychiatric (medical and surgical) doctors and consultation-liaison psychiatry changes within junior doctors' terms. METHOD: This was a retrospective cohort analysis of referrals from medical and surgical units to a consultation-liaison psychiatry service. Diagnostic agreement was calculated across all diagnoses and expressed as a percentage. Diagnostic concordance (expressed using Cohen's Kappa) was calculated for the two most common diagnoses of depression and delirium. Diagnostic agreement and concordance in the first two weeks (Timepoint A) were compared to those in the last two weeks (Timepoint B) of junior doctors' terms. RESULTS: Around half the referrals (Timepoint A = 48.1%, Timepoint B = 54.0%) were excluded as no diagnosis was listed.Diagnostic agreement over all diagnoses was 31.7% (Timepoint A) and 29.9% (Timepoint B) and was not statistically different. Diagnostic concordance for depression increased from fair to moderate but was not statistically significant. Diagnostic concordance for delirium was substantial for both timepoints and were not statistically different. CONCLUSIONS: No statistically significant change in diagnostic accuracy over a junior doctors' term was found in this study.

Desvenlafaxine in the treatment of major depression: an updated overview.

Introduction: Major depressive disorder (MDD) remains one of the most prevalent mental health conditions. It is a chronic, relapsing condition and despite multiple treatment options, many patients fail to achieve remission of symptoms. Inadequacy of treatment has stimulated the search for agents with significant therapeutic advantages.Areas covered: This review examines literature concerning the use of desvenlafaxine in the treatment of MDD published since a previous analysis in this journal in 2014. Published papers were identified via a PubMed and Web of Science search and excluded congress presentations. Results from clinical trials in MDD, systematic reviews, and post hoc analyses in patient subgroups, are reviewed.Expert opinion: Desvenlafaxine was an effective antidepressant with favorable safety and tolerability in adults. Efficacy was demonstrated in the subgroup of peri- and post-menopausal women with MDD but not in children and adolescents. There is a relatively low potential for drug-drug interactions due to its metabolic profile. Hepatic impairment does not significantly alter dose requirements, whereas severe renal disease requires some adjustments of dose. Desvenlafaxine maybe suitable in patients with comorbid physical illnesses. Desvenlafaxine can be a first line consideration for the treatment of cases of MDD uncomplicated by medical comorbidities.

Agomelatine for depression: expanding the horizons?

INTRODUCTION: Agomelatine is an antidepressant with unique pharmacological actions; it is both a melatonin agonist and selective serotonin antagonist. Both actions combined are necessary for antidepressant efficacy. Effects on melatonin receptors enable resynchronisation of disrupted circadian rhythms with beneficial effects on sleep patterns. Areas covered: The issue of use of an antidepressant for depression co-morbid with somatic disorders is covered by the authors. A review of the literature from 2000 to August 2018 was undertaken using Scopus and Web of Science with the key words: agomelatine, depression, medical illness. Depression in Parkinson's disease, cardiovascular illness and type II diabetes is reviewed with evidence of efficacy. Bipolar depression and seasonal affective disorder may also react favourably. Agomelatine may have specific efficacy on symptoms of anhedonia. Expert opinion: Despite approval in some major jurisdictions, the drug has failed to gain registration in the United States. A defining issue may be questions about longer term efficacy: unequivocal effectiveness in placebo-controlled relapse prevention studies has not always been demonstrated. Continuation studies suggest maintenance of clinical responsiveness. A major disadvantage of the drug is its' potential hepatotoxicity and the need for repeated clinical laboratory tests.

Impairments of spatial working memory and attention following acute psychosocial stress.

Few studies have investigated the effect of an acute psychosocial stress paradigm on impaired attention and working memory in humans. Further, the duration of any stress-related cognitive impairment remains unclear. The aim of this study was to examine the effect of an acute psychosocial stress paradigm, the Trier Social Stress, on cognitive function in healthy volunteers. Twenty-three healthy male and female subjects were exposed to an acute psychosocial stress task. Physiological measures (salivary cortisol, heart rate and blood pressure) and subjective stress ratings were measured at baseline, in anticipation of stress, immediately post-stress and after a period of rest. A neuropsychological test battery including spatial working memory and verbal memory was administered at each time point. Acute psychosocial stress produced significant increases in cardiovascular and subjective measures in the anticipatory and post-stress period, which recovered to baseline after rest. Salivary cortisol steadily declined over the testing period. Acute psychosocial stress impaired delayed verbal recall, attention and spatial working memory. Attention remained impaired, and delayed verbal recall continued to decline after rest. Acute psychosocial stress is associated with an impairment of a broad range of cognitive functions in humans and with prolonged abnormalities in attention and memory.

Agomelatine, melatonin and depressive disorder.

Alteration of nocturnal melatonin production, along with circadian rhythm disturbance, has been demonstrated in several psychiatric disorders. It has been postulated that such disturbances might be causal reflecting a more fundamental abnormality of the function of the suprachiasmatic nucleus (SCN). The SCN contains the body's master 'clock' while the pineal-SCN nexus is intricate to the nighttime production of melatonin. The more compelling case for causality is made for major depressive disorder (MDD). Lending weight to this proposition is the introduction of agomelatine as an antidepressant agent. Through its actions on melatonin receptors agomelatine can resynchronise circadian rhythms. The circadian hypothesis would posit that normalisation of disturbance would be sufficient of itself to alleviate the symptoms of MDD. Thus, strategies designed to bring about resynchronisation of circadian rhythms should be therapeutically effective in depression. Critical examination of the efficacy of such interventions in MDD suggests that the circadian alteration may be necessary but is not sufficient for an antidepressant effect. Exogenous melatonin administration and bright light therapy have mixed results in limited controlled clinical evaluations. Furthermore, agomelatine has other actions which pre-clinical studies suggest are as important to its therapeutic effects as are its actions on melatonin receptors ipso facto its resynchronising properties. Whether circadian effects are antidepressant remains a moot point and awaits the clinical evaluation of highly selective resynchronising agents.

Agomelatine suppresses locomotor hyperactivity in olfactory bulbectomised rats: a comparison to melatonin and to the 5-HT(2c) antagonist, S32006.

The novel melatonergic agonist/5-HT(2C) antagonist agomelatine displays robust antidepressant properties in humans and is active in pre-clinical models predictive of antidepressant effects. In this study, we investigated its potential influence on the locomotor hyperactivity displayed by olfactory bulbectomised rats, a putative measure of potential antidepressant activity. In addition, we compared the actions of agomelatine to those of melatonin and S32006, a selective antagonist at 5-HT(2C) receptors. Vehicle, agomelatine (10 and 50mg/kg), melatonin (10 and 50mg/kg), S32006 (0.16mg/kg to 10mg/kg) and the prototypical tricyclic antidepressant, imipramine (10mg/kg), were administered by intraperitoneal injection for 14days to male, Sprague-Dawley sham-operated and bulbectomised rats. In agreement with previous studies, imipramine was active in the model and both the lower and higher doses of agomelatine also significantly and markedly reversed the bulbectomy-induced hyperactivity to a level comparable to that seen in sham operated animals, in which agomelatine exerted no effect. Similarly the 5-HT(2C) antagonist, S32006, dose-dependently and significantly attenuated hyperactivity of bulbectomised animals, albeit with a maximal effect somewhat less marked than that of agomelatine. On the other hand, melatonin did not affect the locomotor behaviour of bulbectomised rats. The activity of agomelatine in the model is consistent with its known antidepressant properties in the clinic.

Duloxetine in the acute and continuation treatment of major depressive disorder.

Duloxetine is a serotonin-noradrenaline reuptake inhibitor with indications for use in the short term, continuation and maintenance treatment of major depression. Although clinicians currently have access to a range of medications for the treatment of depression, a significant number of patients fail to respond or remit from their illness despite adequate trials of treatment with multiple agents. A developing concept is that antidepressant strategies that combine multiple mechanisms of action may have advantages over agents with single mechanisms (i.e., selective serotonin reuptake inhibitors). As a dual-acting agent, duloxetine offers the promise of advantages in terms of efficacy over selective serotonin reuptake inhibitors while retaining a favorable safety and tolerability profile in comparison to older agents. Likewise, duloxetine is of interest in the treatment of certain conditions commonly seen in conjunction with major depression, particularly anxiety and pain, both of which may respond more favorably to agents that act on both serotonin and noradrenaline neurotransmitter systems.

Dopamine D(1) receptor binding in the anterior cingulate cortex of patients with obsessive-compulsive disorder.

Functional neuroimaging studies in patients with obsessive-compulsive disorder (OCD) suggest there is a hyperactivation of the anterior cingulate cortex (ACC) during provocation of symptoms and conflict-inhibition tasks. Since dopamine, acting through D(1) receptors is suggested to modulate ACC activity, we hypothesised that there would be an altered D(1) binding potential (BP) in the ACC of OCD patients. Using [(11)C]-SCH23390 and positron emission tomography, we report significantly reduced D(1) BP in seven drug-free OCD patients compared with matched healthy controls. These findings suggest mesocortical dopamine inputs via D(1) receptors may play a role in the aetiology of OCD.

Continuation treatment of major depressive disorder: is there a case for duloxetine?

Duloxetine is a serotonin-noradrenaline reuptake inhibitor with established efficacy for the short-term treatment of major depressive disorder. Efficacy in continuation treatment (greater than six months of continuous treatment) has been established from both open and placebo-controlled relapse prevention and comparative studies. Seven published studies were available for review and showed that in both younger and older populations (aged more than 65 years) the acute efficacy of duloxetine was maintained for up to one year. Response to treatment was based on accepted criteria for remission of depression and in continuation studies remission rates were greater than 70%. Comparative studies showed that duloxetine was superior to placebo and comparable to paroxetine and escitalopram in relapse prevention. Importantly a study of duloxetine in patients prone to relapse of major depressive disorder showed that the medication was more effective than placebo in this difficult to treat population. Side effects of duloxetine during continuation treatment were predictable on the basis of the known pharmacology of the drug. In particular there were no significant life-threatening events which emerged with continued use of the medication. On the other hand vigilance is required since the data base on which to judge very rare events is limited by the relatively low exposure to the drug. Duloxetine has established both efficacy and safety for continuation treatment but its place as a first-line treatment of relapse prevention requires further experience. In particular further comparative studies against established agents would be useful in deciding the place of duloxetine in therapy.

Treatment of cognitive dysfunction in chronic schizophrenia by augmentation of atypical antipsychotics with buspirone, a partial 5-HT(1A) receptor agonist.

OBJECTIVES: To assess effects of a semi-acute administration of buspirone in comparison to a placebo on cognitive function and negative symptoms in patients with schizophrenia and schizoaffective disorder. METHODS: In a 6-week, double-blind, placebo-controlled, independent groups study 18 subjects (14 males, four females) received in random order either placebo or buspirone (15-30 mg/day). A neuropsychological assessment using the Hopkins verbal learning test (HVLT) simple reaction time (SRT), choice reaction time (CRT), n-back spatial working memory task and the stroop colour and word test was performed at baseline and final visit. Symptom rating scales were administered at testing weeks 0, 2, 4 and 6. RESULTS: Repeated measures ANOVA was used to examine changes in performance on tests over time. There were no statistically significant differences between placebo and buspirone treatments on either cognitive function measures or symptom ratings. CONCLUSION: Semi-acute adjunct treatment with buspirone may be too short to be clinically efficacious in patients with schizophrenia. Intrinsic activation of 5-HT(1A) receptors by atypical antipsychotics may hinder the ability of buspirone to further improve cognitive functions. Buspirone did not affect clinical outcomes for this chronically ill group of patients being treated with atypical antipsychotic drugs.

Dopamine D1 receptor binding in the striatum of patients with obsessive-compulsive disorder.

BACKGROUND: Obsessive-compulsive disorder (OCD) is a chronic anxiety disorder of unknown aetiology. Psychopharmacological studies have suggested a role for the neurotransmitter serotonin however further evidence for serotonin in the aetiology of OCD is conflicted. The authors used positron emission tomography (PET) to examine the binding of the dopamine D(1) receptor antagonist [(11)C]-SCH23390 to D(1) receptors in the striatum of drug-free OCD patients compared with healthy controls. METHODS: Seven drug-free patients (two drug naïve) with OCD and seven age, gender and education matched healthy controls underwent positron emission tomography with [(11)C]-SCH23390. Binding Potentials (BP) at D(1) receptors were calculated for the caudate nucleus and putamen. Correlations between BP values for basal ganglia regions and clinical measures were performed in OCD patients. RESULTS: The BP for [(11)C]-SCH23390 at D(1) receptors in OCD patients was significantly reduced in both caudate nucleus (0.59+/-0.06 vs 0.88+/-0.06, p<0.05) and putamen (0.89+/-0.06 vs 1.14+/-0.06, p<0.05) compared with healthy controls. No correlations were found between D(1) BP and symptom measures. LIMITATIONS: The main limitations of this study are the small sample size and the PET methodology which does not allow for disaggregation of Bmax and Kd values for D(1) receptor binding of [(11)C]-SCH23390. CONCLUSIONS: The finding of downregulation of D(1) receptors in the striatum of OCD patients suggests increased nigrostriatal dopaminergic drive in OCD. If confirmed, this finding provides support for trials of novel treatments in OCD based on dopaminergic system blockade.

Abnormal dose-response melatonin suppression by light in bipolar type I patients compared with healthy adult subjects.

OBJECTIVE: Among potential endophenotypes proposed for bipolar affective disorder focusing on circadian abnormalities associated with the illness has particularly high face validity. Melatonin sensitivity to light is one circadian endophenotype proposed as useful in bipolar disorder. The aim of this study was to investigate melatonin sensitivity to light over a range of light intensities in order to compare and contrast responses in bipolar I patients with those of healthy adult volunteers. METHODS: The study included seven patients (4 females, 3 males) with bipolar I disorder and 34 control participants (22 females, 12 males) with no personal or family history of affective illness. Melatonin sensitivity to light was determined in all patients and participants across a range of light intensities (0, 200, 500 and 1000 lux). RESULTS: The results indicated that patients showed melatonin super-sensitivity to light in comparison with controls, a response that was consistent across the entire light intensity range investigated. CONCLUSION: The study provides further evidence for a super sensitive response in bipolar I patients and suggests that its potential usefulness as an endophenotypic marker of the illness is deserving of further research.