A randomized controlled trial of brief and ultrabrief pulse right unilateral electroconvulsive therapy.

BACKGROUND: Some studies suggest better overall outcomes when right unilateral electroconvulsive therapy (RUL ECT) is given with an ultrabrief, rather than brief, pulse width. METHODS: The aim of the study was to test if ultrabrief-pulse RUL ECT results in less cognitive side effects than brief- pulse RUL ECT, when given at doses which achieve comparable efficacy. One hundred and two participants were assigned to receive ultrabrief (at 8 times seizure threshold) or brief (at 5 times seizure threshold) pulse RUL ECT in a double-blind, randomized controlled trial. Blinded raters assessed mood and cognitive functioning over the ECT course. RESULTS: Efficacy outcomes were not found to be significantly different. The ultrabrief group showed less cognitive impairment immediately after a single session of ECT, and over the treatment course (autobiographical memory, orientation). CONCLUSIONS: In summary, when ultrabrief RUL ECT was given at a higher dosage than brief RUL ECT (8 versus 5 times seizure threshold), efficacy was comparable while cognitive impairment was less.

Lifestyle medicine for depression.

The prevalence of depression appears to have increased over the past three decades. While this may be an artefact of diagnostic practices, it is likely that there are factors about modernity that are contributing to this rise. There is now compelling evidence that a range of lifestyle factors are involved in the pathogenesis of depression. Many of these factors can potentially be modified, yet they receive little consideration in the contemporary treatment of depression, where medication and psychological intervention remain the first line treatments. "Lifestyle Medicine" provides a nexus between public health promotion and clinical treatments, involving the application of environmental, behavioural, and psychological principles to enhance physical and mental wellbeing. This may also provide opportunities for general health promotion and potential prevention of depression. In this paper we provide a narrative discussion of the major components of Lifestyle Medicine, consisting of the evidence-based adoption of physical activity or exercise, dietary modification, adequate relaxation/sleep and social interaction, use of mindfulness-based meditation techniques, and the reduction of recreational substances such as nicotine, drugs, and alcohol. We also discuss other potential lifestyle factors that have a more nascent evidence base, such as environmental issues (e.g. urbanisation, and exposure to air, water, noise, and chemical pollution), and the increasing human interface with technology. Clinical considerations are also outlined. While data supports that some of these individual elements are modifiers of overall mental health, and in many cases depression, rigorous research needs to address the long-term application of Lifestyle Medicine for depression prevention and management. Critically, studies exploring lifestyle modification involving multiple lifestyle elements are needed. While the judicious use of medication and psychological techniques are still advocated, due to the complexity of human illness/wellbeing, the emerging evidence encourages a more integrative approach for depression, and an acknowledgment that lifestyle modification should be a routine part of treatment and preventative efforts.

'Help us, she's fading away': How to manage the patient with anorexia nervosa.

BACKGROUND: Although integral to the early detection and treatment of anorexia nervosa, there is a paucity of clear guidance available for general practitioners (GPs). This paper attempts to bridge the gap between the specialist and generalist literature to assist the busy GP feel confident in identifying and managing these patients. OBJECTIVE: On reading this article it is anticipated the GP will feel well equipped to screen for and provide ongoing treatment to patients who pre-sent with eating disorders, particularly anorexia nervosa. This paper provides guidance for the identification and ongoing management of patients with anorexia nervosa, and supporting their carers. DISCUSSION: People affected by eating disorders, particularly anorexia nervosa, may deny having a problem, minimise their symptoms and resist treatment yet engage partially with their GP throughout the course of their illness. There are well-validated, quick screening tools that the non-specialist can use to identify patients at high risk of having an eating disorder.

Speed of response in ultrabrief and brief pulse width right unilateral ECT.

Ultrabrief pulse width stimulation electroconvulsive therapy (ECT) results in less cognitive side-effects than brief pulse ECT, but recent work suggests that more treatment sessions may be required to achieve similar efficacy. In this retrospective analysis of subjects pooled from three research studies, time to improvement was analysed in 150 depressed subjects who received right unilateral ECT with a brief pulse width (at five times seizure threshold) or ultrabrief pulse width (at six times seizure threshold). Multivariate Cox regression analyses compared the number of treatments required for 50% reduction in depression scores (i.e. speed of response) in these two samples. The analyses controlled for clinical, demographic and treatment variables that differed between the samples or that were found to be significant predictors of speed of response in univariate analyses. In the multivariate analysis, older age predicted faster speed of response. There was a non-significant trend for faster time to 50% improvement with brief pulse ECT (p = 0.067). Remission rates were higher after brief pulse ECT than ultrabrief pulse ECT (p = 0.007) but response rates were similar. This study, the largest of its kind reported to date, suggests that fewer treatments may be needed to attain response with brief than ultrabrief pulse ECT and that remission rates are higher with brief pulse ECT. Further research with a larger randomized and blinded study is recommended.

Kava in the treatment of generalized anxiety disorder: a double-blind, randomized, placebo-controlled study.

Kava (Piper methysticum) is a plant-based medicine, which has been previously shown to reduce anxiety. To date, however, no placebo-controlled trial assessing kava in the treatment of generalized anxiety disorder (GAD) has been completed. A total of 75 participants with GAD and no comorbid mood disorder were enrolled in a 6-week double-blind trial of an aqueous extract of kava (120/240 mg of kavalactones per day depending on response) versus placebo. γ-Aminobutyric acid (GABA) and noradrenaline transporter polymorphisms were also analyzed as potential pharmacogenetic markers of response. Reduction in anxiety was measured using the Hamilton Anxiety Rating Scale (HAMA) as the primary outcome. Intention-to-treat analysis was performed on 58 participants who met inclusion criteria after an initial 1 week placebo run-in phase. Results revealed a significant reduction in anxiety for the kava group compared with the placebo group with a moderate effect size (P = 0.046, Cohen d = 0.62). Among participants with moderate to severe Diagnostic and Statistical Manual of Mental Disorders-diagnosed GAD, this effect was larger (P = 0.02; d = 0.82). At conclusion of the controlled phase, 26% of the kava group were classified as remitted (HAMA ≤ 7) compared with 6% of the placebo group (P = 0.04). Within the kava group, GABA transporter polymorphisms rs2601126 (P = 0.021) and rs2697153 (P = 0.046) were associated with HAMA reduction. Kava was well tolerated, and aside from more headaches reported in the kava group (P = 0.05), no other significant differences between groups occurred for any other adverse effects, nor for liver function tests. Standardized kava may be a moderately effective short-term option for the treatment of GAD. Furthermore, specific GABA transporter polymorphisms appear to potentially modify anxiolytic response to kava.

Pharmacogenetic polymorphisms and response to escitalopram and venlafaxine over 8 weeks in major depression.

OBJECTIVE: The objective of this study is to investigate the influence of the 5-HTTLPR (serotonin transporter-linked promoter region), cytochrome P450 2C19, and cytochrome P450 2D6 polymorphisms on escitalopram (ESC) and venlafaxine (VEN) responses in major depressive disorder. METHOD: A prospective multi-site study of 106 patients (Caucasian and Han Chinese ethnicities) with major depressive disorder treated with either ESC or VEN was conducted. The 17-item Hamilton Depression scale (HDRS), Clinical Global Impression Scale, and an adverse events scale (UKU) were assessed over 8 weeks, blind to genotype. RESULTS: At the 8-week end point, a significant HDRS reduction for both ESC and VEN occurred (p < 0.0001). The 5-HTTLPR l/l genotype was associated with significantly greater score reductions on the HDRS compared with s/s carriers (p = 0.016) among Caucasian subjects receiving ESC (n = 47). Response rates were significantly higher for l/l (92%) compared with l/s (61%) and s/s (46%) variants (p = 0.042). For every l allele a participant carried, there was a 3.33 (95% confidence interval 1.25, 8.84; p = 0.02) times greater odds of ESC response. No significant associations between any of the genotypes and adverse effects were found. CONCLUSION: Ethnicity may have differential effects on the 5-HTTLPR genotype-efficacy relationship. Results suggest that l/l allele for 5-HTTLPR is associated with a robust treatment response to ESC in Caucasian subjects only.

Pharmacological approaches to the management of schizophrenia: 10 years on.

OBJECTIVE: To review the contemporary landscape regarding pharmacological treatments for schizophrenia. METHOD: Selective literature review. RESULTS: Newer antipsychotic agents include aripiprazole, asenapine, paliperidone, sertindole and ziprasidone. Each has some particular benefits and some shortcomings. Overall treatment efficacy (for positive symptoms at least) has not advanced substantially but some newer agents might have a better profile than older typical agents for negative and cognitive symptoms. Metabolic side effects and hyperprolactinaemia remain a problem with some of the newer agents and appropriate monitoring is required. CONCLUSIONS: Whilst newer antipsychotics have been welcome additions to our pharmacological armamentarium, mostly in terms of tolerability, we have still not seen a 'quantum leap' agent brought to market. Mechanisms of action apart from post-synaptic dopamine blockade appear worthy of further investigation in this regard.

Kava hepatotoxicity in traditional and modern use: the presumed Pacific kava paradox hypothesis revisited.

Kava, a Pacific herb consumed worldwide for medicinal, recreational and cultural purposes, has been associated with rare hepatotoxicity, and there is currently a critical need to determine this causation. The previously proposed Pacific kava paradox was based on the theory that kava hepatotoxicity was not observed following use of traditional aqueous extracts in the Pacific region, but was restricted to use of Western acetonic and ethanolic extracts. Subsequent cases analyzed by the World Health Organization and published case reports revealed that traditional aqueous extracts used in New Caledonia, Australia, the USA and Germany may also be hepatotoxic; thus, there is no longer a basis to sustain the previously proposed Pacific kava paradox. It appears that the primary cause of toxicity may reside in the time before the preparation of the various kava extracts, possibly attributed to poor quality of the raw material caused by mould hepatotoxins. Rigorous testing of kava raw material is urgently advised, in addition to Pan-Pacific kava manufacturing quality standards.

Medication attitudes and beliefs in patients with psychotic and affective disorders on maintenance treatment.

RATIONALE: Patient attitudes and beliefs regarding the cost-benefits of medications may influence treatment adherence. However, beliefs and attitudes about psychotropic medications have not been well studied across different clinical populations. OBJECTIVE: This study sought to compare medication attitudes, beliefs, and clinical characteristics in patients with psychotic disorders versus those with affective disorders. METHOD: Clinician-rated and self-report measures were used to assess the drug attitudes, beliefs, and clinical features of outpatients with affective and psychotic disorders on stable medications. RESULTS: There were no significant differences in the overall medication attitudes and beliefs scores between the clinical groups. The affective group, however, were less likely to believe that medications would prevent hospitalisation (p < 0.05) and were less likely to use an aid as a reminder to take their medication (p < 0.05). Medication attitudes and beliefs were found to have significant correlation with reported side effects (p < 0.01) but not with educational level and duration or severity of illness. CONCLUSIONS: Patients with psychotic disorders did not show more negative attitudes or beliefs about medication than those with affective disorders. It would be clinically important that equal care is taken to assess perceived drug side effects, and attitudes and beliefs about medications across diagnostic groups.

'Omic' genetic technologies for herbal medicines in psychiatry.

The field of genetics, which includes the use of 'omic' technologies, is an evolving area of science that has emerging application in phytotherapy. Omic studies include pharmacogenomics, proteomics and metabolomics. Herbal medicines, as monotherapies, or complex formulations such as traditional Chinese herbal prescriptions, may benefit from omic studies, and this new field may be termed 'herbomics'. Applying herbomics in the field of psychiatry may provide answers about which herbal interventions may be effective for individuals, which genetic processes are triggered, and the subsequent neurochemical pathways of activity. The use of proteomic technology can explore the differing epigenetic effects on neurochemical gene expression between individual herbs, isolated constituents and complex formulae. The possibilities of side effects or insufficient response to the herb can also be assessed via pharmacogenomic analysis of polymorphisms of cytochrome P450 liver enzymes or P-glycoprotein. While another novel application of omic technology is for the validation of the concept of synergy in individual herbal extracts and prescriptive formulations. Chronic administration of psychotropic herbal medicines may discover important effects on chromatin remodelling via modification of histone and DNA methylation. This paper focuses on the emerging field of herbomics, and is to our knowledge the first publication to explore this in the area of psychiatry.

Adjunctive nutraceuticals with standard pharmacotherapies in bipolar disorder: a systematic review of clinical trials.

OBJECTIVE: Studies using augmentation of pharmacotherapies with nutraceuticals in bipolar disorder (BD) have been conducted and preliminary evidence in many cases appears positive. To date, however, no specialized systematic review of this area has been conducted. We present the first systematic review of clinical trials using nutrient-based nutraceuticals in combination with standard pharmacotherapies to treat BD. A subsequent aim of this report was to discuss posited underlying mechanisms of action. METHODS: PubMed, CINAHL, Web of Science, and Cochrane Library databases, and grey literature were searched during mid-2010 for human clinical trials in English using nutraceuticals such as omega-3, N-acetyl cysteine (NAC), inositol, and vitamins and minerals, in combination with pharmacotherapies to treat bipolar mania and bipolar depression. A review of the results including an effect size analysis (Cohen's d) was subsequently conducted. RESULTS: In treating bipolar depression, positive evidence with large effect sizes were found for NAC (d=1.04) and a chelated mineral and vitamin formula (d=1.70). On the outcome of bipolar mania, several nutraceuticals reduced mania with strong clinical effects: a chelated mineral formula (d=0.83), L-tryptophan (d=1.47), magnesium (d=1.44), folic acid (d=0.40), and branched-chain amino acids (d=1.60). Mixed, but mainly positive, evidence was found for omega-3 for bipolar depression, while no evidentiary support was found for use in mania. No significant effect on BD outcome scales was found for inositol (possibly due to small samples). CONCLUSIONS: BD treatment outcomes may potentially be improved by additional use of certain nutraceuticals with conventional pharmacotherapies. However, caution should be extended in interpreting the large effects of several isolated studies, as they have not yet been replicated in larger trials.

Re-introduction of kava (Piper methysticum) to the EU: is there a way forward?

Kava (Piper methysticum) is an effective anxiolytic that has been withdrawn from various consumer markets in European countries due to concerns over its hepatotoxicity. It is plausible that the reported hepatotoxicity may be due in part to plant substitution, or an incorrect cultivar, or plant parts being used (such as leaves or bark); thus both the plant chemotype and the plant part used may be critical factors. If re-institution of kava in the EU is to occur, more evidence is required to determine its safety and efficacy. Furthermore, according to current evidence, the study of traditional water soluble rhizome extracts using a noble cultivar of kava may be advised. The Kava Anxiety-Lowering Medication (KALM) project is due to start in late 2010 to address these considerations. The KALM project uses an aqueous rhizome extract of a noble cultivar of kava in participants with generalised anxiety and Generalised Anxiety Disorder (GAD). The project comprises of 1) an acute RCT, kava (180 mg of kavalactones) versus oxazepam and placebo in 20 anxious people, testing effects on cognition, mood, anxiety, and driving; 2) an 8-week RCT comparing kava (120 mg kavalactones) versus placebo in 100 patients with GAD. To assess differences between dosages, non-responders at 3 weeks will be titrated to 240 mg of kavalactones. The project will also assess the effects of kava on liver function tests and its side effects profile. A novel component of the project is the pharmacogenomic exploration of phenotypical responses (GABA system and cytochrome P450 markers). The results of the study may be of benefit to sufferers of anxiety and the future economy of the Pacific islands, potentially providing an important step in the way forward with kava.

Kava: a comprehensive review of efficacy, safety, and psychopharmacology.

OVERVIEW: Kava (Piper methysticum) is a South Pacific psychotropic plant medicine that has anxiolytic activity. This effect is achieved from modulation of GABA activity via alteration of lipid membrane structure and sodium channel function, monoamine oxidase B inhibition, and noradrenaline and dopamine re-uptake inhibition. Kava is available over the counter in jurisdictions such as the USA, Australia and New Zealand. Due to this, a review of efficacy, safety and clinical recommendations is advised. OBJECTIVE: To conduct a comprehensive review of kava, in respect to efficacy, psychopharmacology, and safety, and to provide clinical recommendations for use in psychiatry to treat generalized anxiety disorder (GAD). METHODS: A review was conducted using the electronic databases MEDLINE, CINAHL, PsycINFO and the Cochrane Library during mid 2010 of search terms relating to kava and GAD. A subsequent forward search was conducted of key papers using Web of Science cited reference search. RESULTS: The current weight of evidence supports the use of kava in treatment of anxiety with a significant result occurring in four out of six studies reviewed (mean Cohen's d = 1.1). Safety issues should however be considered. Use of traditional water soluble extracts of the rhizome (root) of appropriate kava cultivars is advised, in addition to avoidance of use with alcohol and caution with other psychotropic medications. Avoidance of high doses if driving or operating heavy machinery should be mandatory. For regular users routine liver function tests are advised. CONCLUSIONS: While current evidence supports kava for generalized anxiety, more studies are required to assess comparative efficacy and safety (on the liver, cognition, driving, and sexual effects) versus established pharmaceutical comparators.

A consensus statement for safety monitoring guidelines of treatments for major depressive disorder.

OBJECTIVE: This paper aims to present an overview of screening and safety considerations for the treatment of clinical depressive disorders and make recommendations for safety monitoring. METHOD: Data were sourced by a literature search using MEDLINE and a manual search of scientific journals to identify relevant articles. Draft guidelines were prepared and serially revised in an iterative manner until all co-authors gave final approval of content. RESULTS: Screening and monitoring can detect medical causes of depression. Specific adverse effects associated with antidepressant treatments may be reduced or identified earlier by baseline screening and agent-specific monitoring after commencing treatment. CONCLUSION: The adoption of safety monitoring guidelines when treating clinical depression is likely to improve overall physical health status and treatment outcome. It is important to implement these guidelines in the routine management of clinical depression.

Group-based psychosocial intervention for bipolar disorder: randomised controlled trial.

BACKGROUND: Psychosocial interventions have the potential to enhance relapse prevention in bipolar disorder. AIMS: To evaluate a manualised group-based intervention for people with bipolar disorder in a naturalistic setting. METHOD: Eighty-four participants were randomised to receive the group-based intervention (a 12-week programme plus three booster sessions) or treatment as usual, and followed up with monthly telephone interviews (for 9 months post-intervention) and face-to-face interviews (at baseline, 3 months and 12 months). RESULTS: Participants who received the group-based intervention were significantly less likely to have a relapse of any type and spent less time unwell. There was a reduced rate of relapse in the treatment group for pooled relapses of any type (hazard ratio 0.43, 95% CI 0.20-0.95; t(343) = -2.09, P = 0.04). CONCLUSIONS: This study suggests that the group-based intervention reduces relapse risk in bipolar disorder.

Sexual side-effects of contemporary antidepressants: review.

The aim of the present study was to review the sexual side-effects of contemporary antidepressants in Australia, comparing the selective serotonin re-uptake inhibitors (SSRIs) with venlafaxine, reboxetine, mirtazepine, duloxetine, bupropion, desvenlafaxine and agomelatine. Double-blind, randomized comparative studies of these antidepressants that included assessment of sexual dysfunction with validated rating scales in patients with major depressive disorder were identified from the literature using MEDLINE, EMBASE and PsychINFO databases. Bupropion and duloxetine caused significantly less sexual dysfunction than the SSRIs in short-term studies and reboxetine significantly less in both short- and longer term studies. Bupropion and agomelatine caused significantly less sexual dysfunction than venlafaxine. The evidence for mirtazepine having an advantage over the SSRIs is lacking and there are currently insufficient data for desvenlafaxine. Well-designed comparative studies of contemporary antidepressants with direct assessment of sexual side-effects as the primary outcome measure are scarce. Future studies should be randomized, double-blind, active controlled trials in sexually active subjects with major depressive disorder. There should be direct assessment of sexual function and depression using reliable, validated rating scales before and during treatment. Studies should assess treatment-emergent effects in patients with normal function and resolution of baseline dysfunction over treatment, in both the short and long term. Further research should compare available instruments for measuring sexual function, and include separate analyses of both remitters/non-remitters and male/female subjects.

STAR*D: has it taught us anything about the management of depression?

OBJECTIVE: The aim of this paper was to review the large US National Institute of Mental Health-sponsored depression intervention effectiveness study, STAR*D, in order to evaluate critically its relevance for Australasian clinicians. CONCLUSIONS: STAR*D is a landmark study which tried to address issues of effectiveness rather than efficacy, of a number of interventions for depression. However, methodological shortcomings limit the utility of the study in informing Australasian clinical practice.