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.

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.

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.

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.

An investigation of the effect of immediate and extended release venlafaxine on nocturnal melatonin and cortisol release in healthy adult volunteers.

The secretion of the hormone melatonin is particularly robust to the effect of pharmacological agents. Medications may alter melatonin levels through either altering adrenergic activity or affecting liver enzymes involved in melatonin metabolism. The aim of this study was to investigate the effect of venlafaxine, a third generation antidepressant with known adrenergic properties on melatonin secretion. A further aim of the study was to investigate the correlation between plasma and salivary measures on this medication. Eight healthy adult participants (four males, four females) took part in this double blind placebo controlled randomised trial. Participants were tested on 3 nights after taking venlafaxine XR (75 mg), venlafaxine IR (75 mg) or placebo. Participants were placed in a darkened room between 1900 and 0300 h and regular temperature readings, blood and saliva samples were drawn to assess melatonin and cortisol secretion in each condition. There was no significant effect of venlafaxine IR or XR on melatonin concentrations in plasma or saliva and no effects on other circadian parameters including cortisol and temperature. It was notable that the correlation between plasma and salivary melatonin levels became poor after drug treatment. These results indicate that at low doses the mixed serotonergic and noradrenergic drug venlafaxine has no effect on nocturnal melatonin concentrations.

Quetiapine augmentation in depressed patients with partial response to antidepressants.

OBJECTIVE: Clinical trials suggest between 30-50% of depressed patients have an inadequate outcome to antidepressant pharmacotherapy. Among the approaches to improve outcome has been augmentation with antipsychotic medications. We aim to investigate the efficacy and tolerability of augmentation with quetiapine in depressed patients with a partial response to antidepressants. METHODS: Patients with a Major Depressive Disorder (DSMIV) who had partial/no response to a stable dose of an Selective Serotonin Reuptake Inhibitors (SSRI)/SNRI were recruited. All patients received add-on quetiapine (200-600 mg nocte) in a 6-week trial. Outcome measures (HAMD, MADRS) were assessed at screening, baseline, weeks 1, 2, 4 and 6. Extrapyramidal symptoms (EPSEs) were assessed at baseline, weeks 2, 4 and 6. A neuropsychological battery of tests was administered at baseline, weeks 3 and 6. RESULTS: Nineteen patients entered the trial and 18 completed the trial per protocol. We report a rapid improvement in depression ratings over 6 weeks (p < 0.0005) and remission rates of 67% at week 1 and 94% at week 6. There was no evidence of EPSE and no worsening (and some improvement) of cognition. CONCLUSION: This suggests clinical benefits of quetiapine augmentation of SSRI/SNRI antidepressants with no worsening, and possible improvements in cognition.

Behavioural studies of spatial working memory dysfunction in schizophrenia: a quantitative literature review.

Cognitive impairments in schizophrenia have been recognized as a prominent feature of the illness. Research is now focusing on determining a relationship between neurocognitive impairments, and social and functional outcome. Despite a number of comprehensive reviews on neurocognitive measures and reports on spatial working memory abnormalities in patients with schizophrenia when compared to healthy volunteers, there have been no meta-analyses of the extent of the abnormality in this group of patients. We reviewed 33 studies (from 1992 to 2005) on spatial working memory impairment in schizophrenia with the aim of providing a quantitative assessment of the consistency and the magnitude of the deficit. From the quantitative data analysis, it is evident that patients with schizophrenia are consistently more impaired on the spatial working memory measures than healthy controls. These impairments may be related to social disability and explain some cognitive deficits that characterize the clinical presentation of schizophrenia.

The heritability of melatonin secretion and sensitivity to bright nocturnal light in twins.

The super-sensitivity of the neurohormone melatonin to light in patients with bipolar disorder provides evidence of the circadian nature of the disorder. This response has been proposed as an endophenotype for identifying people at risk of the disorder and guiding investigations of molecular genetic targets. However, before this response is used as an endophenotypic marker, the heritable nature of melatonin sensitivity in the normal population must be established. The aim of this study was to investigate the heritability of nocturnal melatonin secretion and sensitivity to light in monozygotic and dizygotic twins with no psychiatric history. This study investigated overall melatonin levels (between 2000 and 2400 h) and suppression by 500 lx of light (between 2400 and 0100 h) in 20 pairs of twins (nine monozygotic, 11 dizygotic). The results indicate that melatonin secretion is highly heritable with secretion in one twin being a significant predictor of secretion in their twin in both monozygotic and dizygotic pairs. In relation to light sensitivity, genetic loading appears to play a significant role with the greatest concordance between monozygotic twins, followed by dizygotic twins and finally low concordance in unrelated individuals. This provides additional support for the usefulness of melatonin sensitivity to light as a potential endophenotypic marker of bipolar affective disorder.

A comparative study of sertraline dosages, plasma concentrations, efficacy and adverse reactions in Chinese versus Caucasian patients.

This prospective 6-week study examined the differences in dosage and steady state plasma concentrations of sertraline in Chinese versus Caucasian depressed patients. Two groups of Chinese patients from different geographical sites and a group of Caucasian patients were evaluated with clinical measures during an initial dose of 50 mg/day, with subsequent doses adjusted clinically. The results of 17 Australian Chinese (ACHI), 13 Malaysian Chinese (MCHI) and 15 Australian Caucasians (AC) were analysed. Despite controlling for weight, the AC subjects received a significantly higher dose than both the ACHI (P = 0.002) and the MCHI groups (P = 0.012). However, the mean sertraline concentration to dose ratios at weeks 1 and 6 were not significantly different between the three groups. Sertraline was effective and well tolerated in both ethnic groups with few adverse events. Although there was a lack of difference between groups in the pharmacokinetic results, Chinese depressed patients appeared to require lower dosages with consequently lower plasma concentrations of sertraline compared to Caucasian patients to achieve clinical efficacy. Further studies of the dosages, kinetics and adverse effects of selective serotonin reuptake inhibitors linked with genotyping are necessary.

Effect of sodium valproate on nocturnal melatonin sensitivity to light in healthy volunteers.

Sensitivity of the pineal hormone melatonin to bright light at night has been proposed as a putative marker of bipolar affective disorder. Patients with bipolar disorder have a super-sensitive melatonin response to light. No studies have investigated whether super-sensitivity is due to agents used to treat the illness or is associated with the disorder per se. We investigated the effect of valproate on this phenomenon. Melatonin sensitivity to light was determined on two nights in 12 healthy volunteers (5M, 7F). Between testing nights participants received 200 mg of valproate b.d. for 5 days. Valproate significantly decreased the sensitivity of melatonin to light. On the other hand, valproate had no effect on overall melatonin secretion or dim light melatonin onset. The ability of valproate to decrease the sensitivity of melatonin to light may relate to its therapeutic effect in bipolar disorder--an ability to lengthen circadian period similar to that of lithium.

Attenuation of benzodiazepine withdrawal anxiety in the rat by serotonin antagonists.

Administration of benzodiazepines is known to be associated with tolerance and a withdrawal syndrome on abrupt cessation. The aetiology of the withdrawal syndrome is not known but a role for the serotonin (5HT) system is suspected. The aim of the current study was to investigate the usefulness of 5-HT2 antagonists in the treatment of benzodiazepine withdrawal syndrome in the rat. Male Wistar rats were treated with either diazepam (4 mg/kg) or vehicle for 14 days, then abruptly withdrawn for 24h. Animals were tested in the social interaction paradigm and elevated plus maze. Some diazepam-withdrawn rats were pre-treated with 5HT2 antagonists 60 min before behavioural testing. Acute withdrawal from benzodiazepines significantly reduced social interaction between pairs compared to vehicle or diazepam-treated animals. Similarly, for the elevated plus maze withdrawn animals made fewer entries and spent less time on the open arms than did vehicle or diazepam-treated animals. Single doses of 5-HT2 antagonists, mianserin (5mg/kg) and ritanserin (1mg/kg), effectively ameliorated withdrawal anxiety in the rat, returning behavioural function in the social interaction test and elevated plus maze to levels comparable to vehicle-treated animals.

Brain serotonin depletion by lesions of the median raphe nucleus enhances the psychotomimetic action of phencyclidine, but not dizocilpine (MK-801), in rats.

We have previously shown that brain serotonin depletion by lesions of the median raphe nucleus (MRN) causes enhancement of phencyclidine-induced locomotor hyperactivity [S. Kusljic, D.L. Copolov, M. van den Buuse, Differential role of serotonergic projections arising from the dorsal and median raphe nuclei in locomotor hyperactivity and prepulse inhibition, Neuropsychopharmacology 28 (2003) 2138-2147]. In this study, we extend our previous work by (1) comparing the effect of phencyclidine with that of another NMDA receptor antagonist, dizocilpine (MK-801); (2) investigate behavioral changes in more detail; (3) assess in detail the effect of raphe lesions on regional serotonin levels in the brain. Male Sprague-Dawley rats received microinjection of the serotonergic neurotoxin 5,7-dihydroxytryptamine into the MRN or dorsal raphe nucleus (DRN). The effects of treatment with saline, phencyclidine and MK-801 on locomotor activity were determined 2 weeks after the surgery. MRN lesions caused serotonin depletion in the dorsal hippocampus, whereas DRN lesions caused serotonin depletion in the frontal cortex, striatum and ventral hippocampus. There was a significant increase in phencyclidine-induced locomotor hyperactivity in the MRN-lesioned group compared to sham-operated controls. Further analysis of behavior showed that phencyclidine-induced hyperambulation, but not stereotypy or rearing, was significantly higher in MRN-lesioned rats compared to controls. In contrast, there was no significant effect of the lesions on the psychotomimetic effect of MK-801. These results indicate that a hyposerotonergic state induced by destruction of projections from the MRN leads to altered brain circuitry that is responsible for the regulation of phencyclidine-but not MK-801-induced locomotor hyperactivity. Thus, MRN projections may play an inhibitory role in mechanisms involved in symptoms of schizophrenia.

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.