Felicity Ng

Oxidative stress in psychiatric disorders : evidence base and therapeutic implications

Oxidative stress has been implicated in the pathogenesis of diverse disease states, and may be a common pathogenic mechanism underlying many major psychiatric disorders, as the brain has comparatively greater vulnerability to oxidative damage. This review aims to examine the current evidence for the role of oxidative stress in psychiatric disorders, and its academic and clinical implications. A literature search was conducted using the Medline, Pubmed, PsycINFO, CINAHL PLUS, BIOSIS Preview, and Cochrane databases, with a time-frame extending to September 2007. The broadest data for oxidative stress mechanisms have been derived from studies conducted in schizophrenia, where evidence is available from different areas of oxidative research, including oxidative marker assays, psychopharmacology studies, and clinical trials of antioxidants. For bipolar disorder and depression, a solid foundation for oxidative stress hypotheses has been provided by biochemical, genetic, pharmacological, preclinical therapeutic studies and one clinical trial. Oxidative pathophysiology in anxiety disorders is strongly supported by animal models, and also by human biochemical data. Pilot studies have suggested efficacy of N-acetylcysteine in cocaine dependence, while early evidence is accumulating for oxidative mechanisms in autism and attention deficit hyperactivity disorder. In conclusion, multi-dimensional data support the role of oxidative stress in diverse psychiatric disorders. These data not only suggest that oxidative mechanisms may form unifying common pathogenic pathways in psychiatric disorders, but also introduce new targets for the development of therapeutic interventions.

Tobacco smoking as a risk factor for major depressive disorder: Population-based study

BACKGROUND Smoking is disproportionately prevalent among people with psychiatric illness. AIMS To investigate smoking as a risk factor for major depressive disorder. METHOD A population-based sample of women was studied using case-control and retrospective cohort study designs. Exposure to smoking was self-reported, and major depressive disorder diagnosed using the Structured Clinical Interview for DSM-IV-TR (SCID-I/NP). RESULTS Among 165 people with major depressive disorder and 806 controls, smoking was associated with increased odds for major depressive disorder (age-adjusted odds ratio (OR)=1.46, 95% CI 1.03-2.07). Compared with non-smokers, odds for major depressive disorder more than doubled for heavy smokers (>20 cigarettes/day). Among 671 women with no history of major depressive disorder at baseline, 13 of 87 smokers and 38 of 584 non-smokers developed de novo major depressive disorder during a decade of follow-up. Smoking increased major depressive disorder risk by 93% (hazard ratio (HR)=1.93, 95% CI 1.02-3.69); this was not explained by physical activity or alcohol consumption. CONCLUSIONS Evidence from cross-sectional and longitudinal data suggests that smoking increases the risk of major depressive disorder in women.

Glutathione: a novel treatment target in psychiatry

There is accumulating evidence for oxidative stress mechanisms as common pathophysiological pathways in diverse psychiatric disorders, which offers novel treatment targets in oxidation biology systems. Of these the glutathione system has the most favourable theoretical foundation, given its dominance as the most generic of cellular antioxidants. Clinically, this hypothesis has been supported by several recently published studies that have reported on the efficacy of N-acetylcysteine, a glutathione precursor, in the treatment of various psychiatric disorders. This article outlines the multidimensional evidence that currently exists for oxidative stress mechanisms in psychiatric disorders and specifically discusses glutathione as a promising novel therapeutic target.

The validity of the 21‐item version of the Depression Anxiety Stress Scales as a routine clinical outcome measure

Objective: This study aimed to test the validity of the 21-item Depression Anxiety Stress Scales (DASS-21) as a routine clinical outcome measure in the private in-patient setting. We hypothesized that it would be a suitable routine outcome instrument in this setting. Method: All in-patients treated at a private psychiatric hospital over a period of 24 months were included in the study. Data were collected on demographics, service utilization, diagnosis and a set of four routine measures both at admission and discharge. These measures consisted of the Clinical Global Impressions (CGI) scales, Health of the Nation Outcome Scales (HoNOS), the Mental Health Questionnaire (MHQ-14) and DASS-21. The results of these measures were compared. Results: Of 786 admissions in total, the number of fully completed (ie paired admission and discharge) data sets for the DASS-21 depression, anxiety and stress subscales were 337, 328 and 347, respectively. All subscales showed statistically significant reductions in mean scores from admission to discharge (P < 0.001) and were significantly correlated with all MHQ-14 subscales and significantly related to CGI scale categories. The total DASS-21 and total HoNOS scores were also significantly correlated. Conclusions: The findings from the present study support the validity of DASS-21 as a routine clinical outcome measure in the private in-patient setting.

The International Society for Bipolar Disorders (ISBD) consensus guidelines for the safety monitoring of bipolar disorder treatments

OBJECTIVES Safety monitoring is an important aspect of bipolar disorder treatment, as mood-stabilising medications have potentially serious side effects, some of which may also aggravate existing medical comorbidities. This paper sets out the International Society for Bipolar Disorders (ISBD) guidelines for the safety monitoring of widely used agents in the treatment of bipolar disorder. These guidelines aim to provide recommendations that take into consideration the balance between safety and cost-effectiveness, to highlight iatrogenic and preventive clinical issues, and to facilitate the broad implementation of therapeutic safety monitoring as a standard component of treatment for bipolar disorder. METHODS These guidelines were developed by an ISBD workgroup, headed by the senior author (MB), through an iterative process of serial consensus-based revisions. After this, feedback from a multidisciplinary group of health professionals on the applicability of these guidelines was sought to develop the final recommendations. RESULTS General safety monitoring recommendations for all bipolar disorder patients receiving treatment and specific monitoring recommendations for individual agents are outlined. CONCLUSIONS These guidelines are derived from evolving and often indirect data, with minimal empirical cost-effectiveness data available to provide guidance. These guidelines will therefore need to be modified to adapt to different clinical settings and health resources. Clinical acumen and vigilance remain critical ingredients for safe treatment practice.

The validity of the CGI severity and improvement scales as measures of clinical effectiveness suitable for routine clinical use.

OBJECTIVE The Clinical Global Impression Scale (CGI) is established as a core metric in psychiatric research. This study aims to test the validity of CGI as a clinical outcome measure suitable for routine use in a private inpatient setting. METHODS The CGI was added to a standard battery of routine outcome measures in a private psychiatric hospital. Data were collected on consecutive admissions over a period of 24 months, which included clinical diagnosis, demographics, service utilization and four routine measures (CGI, HoNOS, MHQ-14 and DASS-21) at both admission and discharge. Descriptive and comparative data analyses were performed. RESULTS Of 786 admissions in total, there were 624 and 614 CGI-S ratings completed at the point of admission and discharge, respectively, and 610 completed CGI-I ratings. The admission and discharge CGI-S scores were correlated (r = 0.40), and the indirect improvement measures obtained from their differences were highly correlated with the direct CGI-I scores (r = 0.71). The CGI results reflected similar trends seen in the other three outcome measures. CONCLUSIONS The CGI is a valid clinical outcome measure suitable for routine use in an inpatient setting. It offers a number of advantages, including its established utility in psychiatric research, sensitivity to change, quick and simple administration, utility across diagnostic groupings, and reliability in the hands of skilled clinicians.

The efficacy of adjunctive N-acetylcysteine in major depressive disorder: a double-blind, randomized, placebo-controlled trial.

OBJECTIVE Major depressive disorder (MDD) is one of the most common psychiatric disorders, conferring considerable individual, family, and community burden. To date, treatments for MDD have been derived from the monoamine hypothesis, and there is a paucity of emerging antidepressants, especially with novel mechanisms of action and treatment targets. N-acetylcysteine (NAC) is a redox-active glutathione precursor that decreases inflammatory cytokines, modulates glutamate, promotes neurogenesis, and decreases apoptosis, all of which contribute to the neurobiology of depression. METHOD Participants with a current episode of MDD diagnosed according to DSM-IV-TR criteria (N = 252) were treated with NAC or placebo in addition to treatment as usual for 12 weeks and were followed to 16 weeks. Data were collected between 2007 and 2011. RESULTS The omnibus interaction between group and visit for the Montgomery-Asberg Depression Rating Scale (MADRS), the primary outcome measure, was not significant (F₁,₅₂₀.₉ = 1.98, P = .067), and the groups did not separate at week 12 (t₃₆₀.₃ = -1.12, P = .265). However, at week 12, the scores on the Longitudinal Interval Follow-Up Evaluation-Range of Impaired Functioning Tool (LIFE-RIFT) differed from placebo (P = .03). Among participants with a MADRS score ≥ 25, NAC separated from placebo at weeks 6, 8, 12, and 16 (P < .05). Additionally, the rate of change between baseline and week 16 was significant (t₂₂₁.₀₃ = -2.11, P = .036). NAC treatment was superior to placebo at week 16 for secondary readouts of function and clinical impression. Remission and response were greater in the NAC group at week 16, but not at week 12. The NAC group had a greater rate of gastrointestinal and musculoskeletal adverse events. CONCLUSIONS Being negative at the week 12 end point, and with some positive secondary signals, the study provides only limited support for the role of NAC as a novel adjunctive therapy for MDD. These data implicate the pathways influenced by NAC in depression pathogenesis, principally oxidative and inflammatory stress and glutamate, although definitive confirmation remains necessary. TRIAL REGISTRATION www.anzctr.org.au Identifier: ACTRN12607000134426.

A role for glutathione in the pathophysiology of bipolar disorder and schizophrenia? Animal models and relevance to clinical practice.

The tripeptide, glutathione (gamma-glutamylcysteinylglycine) is the primary endogenous free radical scavenger in the human body. When glutathione (GSH) levels are reduced there is an increased potential for cellular oxidative stress, characterised by an increase and accruement of reactive oxygen species (ROS). Oxidative stress has been implicated in the pathology of schizophrenia and bipolar disorder. This could partly be caused by alterations in dopaminergic and glutamatergic activity that are implicated in these illnesses. Glutamate and dopamine are highly redox reactive molecules and produce ROS during normal neurotransmission. Alterations to these neurotransmitter pathways may therefore increase the oxidative burden in the brain. Furthermore, mitochondrial dysfunction, as a source of oxidative stress, has been documented in both schizophrenia and bipolar disorder. The combination of altered neurotransmission and this mitochondrial dysfunction leading to oxidative damage may ultimately contribute to illness symptoms. Animal models have been established to investigate the involvement of glutathione depletion in aspects of schizophrenia and bipolar disorder to further characterise the role of oxidative stress in psychopathology. Stemming from preclinical evidence, clinical studies have recently shown antioxidant precursor treatment to be effective in schizophrenia and bipolar disorder, providing a novel clinical angle to augment often suboptimal conventional treatments.

Going up in smoke: Tobacco smoking is associated with worse treatment outcomes in mania

BACKGROUND This study aimed to compare the treatment responses between smokers and non-smokers in bipolar mania clinical trials. METHODS Post-hoc analysis was conducted on data collected from three double-blind, randomised controlled trials in bipolar mania that had similar inclusion criteria. Patients were randomised to olanzapine (N=70) or placebo (N=69) for 3 weeks in Trial 1, olanzapine (N=234) or haloperidol (N=216) for 12 weeks in Trial 2, and olanzapine (N=125) or divalproex (N=126) for 47 weeks in Trial 3. This study analysed the Young Mania Rating Scale (YMRS) total scores and Clinical Global Impressions scale for bipolar disorder (CGI-BP) mania severity scores between smokers and non-smokers for each trial and for the pooled data from all three trials, using a mixed-effects model repeated measures approach. RESULTS For the pooled data, non-smokers showed superior treatment outcomes on both the YMRS (P=0.002) and CGI-BP (P<0.001), as well as longer time to discontinuation for any cause utilising Kaplan-Meier survival curves. For the individual trials, non-smokers showed greater improvement than smokers on both CGI-BP and YMRS in both treatment arms of Trial 2 (CGI-BP: haloperidol P=0.011, olanzapine P=0.042; YMRS: haloperidol P=0.010, olanzapine P=0.019), and in the olanzapine arm of Trial 3 (CGI-BP: P=0.002; YMRS: P=0.006). No significant difference in outcomes was found between smokers and non-smokers in Trial 1. LIMITATIONS Post-hoc design, categorical definition of smoking status, unavailable antipsychotic drug levels, confounding effects of trial medications and substance abuse. CONCLUSIONS Smoking appears to be associated with worse treatment outcomes in mania.

Is this D vitamin to worry about? Vitamin D insufficiency in an inpatient sample

Objective: The aim of the present study was to investigate the relationship between reduced serum vitamin D levels and psychiatric illness. Method: This study was an audit of serum 25-hydroxyvitamin D (25-OHD) levels measured routinely in a sample of 53 inpatients in a private psychiatric clinic. These levels were compared with those of controls without psychiatric illness. Results: The median levels of serum 25-OHD were 43.0 nmol L−1 (range 20–102 nmol L−1) in the patient population, 46.0 nmol L−1 (range 20–102 nmol L−1) in female patients (n =33) and 41.5 nmol L−1 (range 22–97 nmol L−1) in male patients (n =20). The proportion of vitamin D insufficiency (serum 25-OHD ≤50 nmol L−1) in this patient population was 58%. Furthermore, 11% had moderate deficiency (serum 25-OHD ≤25 nmol L−1). There was a 29% difference between mean levels in the patient population and control sample (geometric mean age- and season-adjusted levels: 46.4 nmol L−1 (95% confidence interval (CI) =38.6–54.9 nmol L−1) vs 65.3 nmol L−1 (95%CI =63.2–67.4 nmol L−1), p <0.001). Conclusion: Low levels of serum 25-OHD were found in this patient population. These data add to the literature suggesting an association between vitamin D insufficiency and psychiatric illness, and suggest that routine monitoring of vitamin D levels may be of benefit given the high yield of clinically relevant findings.