Protocol and Rationale-The Efficacy of Minocycline as an Adjunctive Treatment for Major Depressive Disorder: A Double Blind, Randomised, Placebo Controlled Trial

Olivia May Dean,Michael Maes,Melanie Ashton,Lesley Berk,Buranee Kanchanatawan,Atapol Sughondhabirom,Sookjareon Tangwongchai,Chee Ng,Nathan Dowling,Gin S. Malhi,MIchael Berk 대한정신약물학회 2014 CLINICAL PSYCHOPHARMACOLOGY AND NEUROSCIENCE Vol.12 No.3

While current pharmacotherapies are efficacious, there remain a clear shortfall between symptom remission and functionalrecovery. With the explosion in our understanding of the biology of these disorders, the time is ripe for the investigation ofnovel therapies. Recently depression is conceptualized as an immune-inflammatory and nitro-oxidative stress related disorder. Minocycline is a tetracycline antibiotic that has anti-inflammatory, pro-oxidant, glutamatergic, neurotrophic and neuroprotectiveproperties that make it a viable target to explore as a new therapy. This double blind, randomised, placebo controlled adjunctivetrial will investigate the benefits of 200 mg/day of minocycline treatment, in addition to any usual treatment, as an adjunctivetreatment for moderate-severe major depressive disorder. Sixty adults are being randomised to 12 weeks of treatment (witha 4 week follow-up post-discontinuation). The primary outcome measure for the study is mean change on the Montgomery-Asberg Depression Rating Scale (MADRS), with secondary outcomes including the Social and Occupational FunctioningAssessment Scale (SOFAS), Clinical Global Impressions (CGI), Hamilton Rating Scale for Anxiety (HAM-A), Patient GlobalImpression (PGI), Quality of Life Enjoyment and Satisfaction Questionnaire (Q-LES-Q) and Range of Impaired Functioning Tool(LIFE-RIFT). Biomarker analyses will also be conducted at baseline and week 12. The study has the potential to provide newtreatment targets, both by showing efficacy with a new class of ‘antidepressant’ but also through the analysis of biomarkersthat may further inform our understanding of the pathophysiology of unipolar depression.

Exploring Clinical Subgroups of Participants with Major Depressive Disorder that may Benefit from Adjunctive Minocycline Treatment

Gerard Anmella,Alcy Meehan,Melanie Ashton,Mohammadreza Mohebbi,Giovanna Fico,Chee H. Ng,Michael Maes,Lesley Berk,Michele De Prisco,Ajeet B. Singh,Gin S. Malhi,Michael Berk,Seetal Dodd,Diego Hidalgo-Ma 대한정신약물학회 2024 CLINICAL PSYCHOPHARMACOLOGY AND NEUROSCIENCE Vol.22 No.1

Objective: To explore illness-related factors in patients with major depressive disorder (MDD) recipients of adjunctive minocycline (200 mg/day) treatment. The analysis included participants experiencing MDD from a 12-week, double blind, placebo-controlled, randomized clinical trial (RCT). Methods: This is a sub-analysis of a RCT of all 71 participants who took part in the trial. The impact of illness chronicity(illness duration and number of depressive episodes), systemic illness (endocrine, cardiovascular and obesity), adverse effects and minocycline were evaluated as change from baseline to endpoint (12-week) using ANCOVA. Results: There was a consistent but statistically non-significant trend on all outcomes in favour of the use of adjunctive minocycline for participants without systemic illness, less illness chronicity, and fewer adverse effects. Conclusion: Understanding the relationship between MDD and illness chronicity, comorbid systemic illness, and adverse effects, can potentially better characterise those individuals who are more likely to respond to adjunctive anti-inflammatory medications.

Tobacco Use in Bipolar Disorder

Daniel Thomson,MIchael Berk,Seetal Dodd,Marta Rapado-Castro,Shae E. Quirk,Pernille K. Ellegaard,Lesley Berk,Olivia M. Dean 대한정신약물학회 2015 CLINICAL PSYCHOPHARMACOLOGY AND NEUROSCIENCE Vol.13 No.1

Tobacco use in mental health in general and bipolar disorder in particular remains disproportionally common, despite declining smoking rates in the community. Furthermore, interactions between tobacco use and mental health have been shown, indicating the outcomes for those with mental health disorders are impacted by tobacco use. Factors need to be explored and addressed to improve outcomes for those with these disorders and target specific interventions for people with psychiatric illness to cease tobacco smoking. In the context of bipolar disorder, this review explores; the effects of tobacco smoking on symptoms, quality of life, suicidal behaviour, the biological interactions between tobacco use and bipolar disorder, the interactions between tobacco smoking and psychiatric medications, rates and factors surrounding tobacco smoking cessation in bipolar disorder and suggests potential directions for research and clinical translation. The importance of this review is to bring together the current understanding of tobacco use in bipolar disorder to highlight the need for specific intervention.

Atypical Antipsychotics for Bipolar Disorder: Overblown or Blown Over?

Felicity Ng,Seetal Dodd,Michael Berk 대한정신약물학회 2007 CLINICAL PSYCHOPHARMACOLOGY AND NEUROSCIENCE Vol.5 No.2

Objective:Developments in the pharmacological treatment of bipolar disorder are of much interest, as the chronicity and disability of the disorder become better understood, and as treatment goals have shifted to emphasise early control of illness course and maintenance of euthymia in addition to acute episodic remission. Atypical antipsychotics have emerged as treatment options, and this paper aims to review the evidence for their role in bipolar disorder. Methods:A MEDLINE search was conducted for publications up till October 2006. Results:The search yielded a number of randomised, controlled clinical trials of various atypical antipsychotics as monotherapy or adjunctive therapy in bipolar disorder. The majority of such trials have investigated their efficacy in acute mania, with fewer studies devoted to acute bipolar depression or maintenance treatment. There are no specific trials on mixed states, which have mainly been studied together with bipolar mania. The most robust evidence supports a class effect of atypical agents in the treatment of mania. Conclusions:There are placebo-controlled trials that support the efficacy of olanzapine and quetiapine in bipolar depression, and of olanzapine and aripiprazole as maintenance treatment. There is strong support for the role of atypical antipsychotics in bipolar disorder management despite a relatively narrow literature base, chiefly for the treatment of mania. However, these findings need to be replicated, and further investigation is warranted to clarify their spectrum of efficacy in bipolar disorder. Objective:Developments in the pharmacological treatment of bipolar disorder are of much interest, as the chronicity and disability of the disorder become better understood, and as treatment goals have shifted to emphasise early control of illness course and maintenance of euthymia in addition to acute episodic remission. Atypical antipsychotics have emerged as treatment options, and this paper aims to review the evidence for their role in bipolar disorder. Methods:A MEDLINE search was conducted for publications up till October 2006. Results:The search yielded a number of randomised, controlled clinical trials of various atypical antipsychotics as monotherapy or adjunctive therapy in bipolar disorder. The majority of such trials have investigated their efficacy in acute mania, with fewer studies devoted to acute bipolar depression or maintenance treatment. There are no specific trials on mixed states, which have mainly been studied together with bipolar mania. The most robust evidence supports a class effect of atypical agents in the treatment of mania. Conclusions:There are placebo-controlled trials that support the efficacy of olanzapine and quetiapine in bipolar depression, and of olanzapine and aripiprazole as maintenance treatment. There is strong support for the role of atypical antipsychotics in bipolar disorder management despite a relatively narrow literature base, chiefly for the treatment of mania. However, these findings need to be replicated, and further investigation is warranted to clarify their spectrum of efficacy in bipolar disorder.

Impact of Cannabis Use on Long-Term Remission in Bipolar I and Schizoaffective Disorder

김성완,Seetal Dodd,Lesley Berk,Jayashri Kulkarni,Anthony de Castella,Paul B. Fitzgerald,김재민,윤진상,MIchael Berk 대한신경정신의학회 2015 PSYCHIATRY INVESTIGATION Vol.12 No.3

ObjectiveaaTo investigate the impact of regular cannabis use on long-term remission of mood symptoms in bipolar spectrum disorders. MethodsaaThe 24-month prospective observational study included patients (n=239) with bipolar I disorder and schizoaffective disorder, bipolar type. Participants were classified as regular cannabis users (three times or more per week) or non-users. The primary outcome measure was the achievement of remission on the evaluations during the 24 months. ResultsaaOf the 234 participants for whom data was available, 25 (10.7%) were regular cannabis users, and the group comprised significantly more males than females. In the total population, cannabis use was significantly associated with decreased likelihood of remission during the 24-month follow-up period. Subgroup analyses showed that cannabis use was significantly associated with lower remission rates on the Hamilton Depression Rating Scale in females (n=139) and patients prescribed mood stabilizers alone (n=151), whereas in males (n=95) and patients prescribed olanzapine and/or a mood stabilizer (n=83), cannabis use was significantly associated with lower remission rates on the Young Mania Rating Scale. Remission rates were lowest in the concurrent cannabis and tobacco smoking group (n=22) followed by the tobacco smoking only group (n=97), and the non-smoker group (n=116). The post-hoc analysis revealed that all remission rates were significantly lower in the concurrent cannabis and the tobacco smoking group compared to the non-smoker group. ConclusionaaCannabis use negatively affects the long-term clinical outcome in patients with bipolar spectrum disorders. A comprehensive assessment and integrated management of cannabis use are required to achieve better treatment outcomes for bipolar spectrum disorders.

Effects of Persisting Emotional Impact from Child Abuse and Norepinephrine Transporter Genetic Variation on Antidepressant Efficacy in Major Depression: A Pilot Study

Ajeet Bhagat Singh,Chad A. Bousman,Chee Hong Ng,Keith Byron,MIchael Berk 대한정신약물학회 2015 CLINICAL PSYCHOPHARMACOLOGY AND NEUROSCIENCE Vol.13 No.1

Objective: Previous studies suggest child abuse and serotonergic polymorphism influence depression susceptibility and antidepressant efficacy. Polymorphisms of the norepinephrine transporter (NET) may also be involved. Research in the area is possibly clouded by under reporting of abuse in researcher trials. Methods: Adults (n=51) with major depressive disorder has 8 weeks treatment with escitalopram or venlafaxine. Abuse history was obtained, the ongoing emotional impact of which was measured with the 15-item impact of event scale (IES-15). The 17-item Hamilton Depression Rating Scale (HDRS) was applied serially. Two NET polymorphisms (rs2242446 and rs5569) were assayed, blinded to HDRS ratings and abuse history. Results: No subjects reporting abuse with high impact in adulthood (IES-15 ≥26, n=12) remitted; whereas 77% reporting low impact (IES-15 <26; n=26) remitted (p<0.001). Subjects reporting high impact abuse (n=12) had a 50-fold (95% confidence interval=4.85-514.6) greater odds of carrying rs2242446-TT genotype, but the small sample size leaves this finding vulnerable to type I error. Conclusion: The level of persisting impact of child abuse appears relevant to antidepressant efficacy, with susceptibility to such possibly being influence by NET rs2242446 polymorphism. Larger studies may be merited to expand on this pilot level finding given potential for biomarker utility.

Mixed Methods Thematic Analysis of a Randomised Controlled Trial of Adjunctive Mitochondrial Agents for Bipolar Depression

Samantha E. Russell,Anna L. Wrobel,Olivia M. Dean,Michael Berk,Seetal Dodd,Chee H. Ng,Gin S. Malhi,Susan M. Cotton,Jerome Sarris,Alyna Turner 대한정신약물학회 2022 CLINICAL PSYCHOPHARMACOLOGY AND NEUROSCIENCE Vol.20 No.2

Objective: There is often a shortfall in recovery following treatment for an episode of bipolar disorder (BD). Exploration of participant’s experience provides vital information to enhance statistical outcomes for novel therapy trials. This study used mixed-methods to explore participants’ experience of a trial testing N -acetyl cysteine (NAC) and mitochondrially active nutraceuticals for BD depression. Methods: Case report forms from a randomised controlled trial (RCT) of BD depression (n = 148) were analysed using a pragmatic adaption of grounded theory and thematic analysis. Results: Thematic analysis of 148 study participants indicated numerous changes in participant experience over time. For example, perceived environmental stressors reported by participants decreased over the trial in both treatment groups. Quantitative analysis of the themes revealed more positive theme reports in the combination treatment arm compared to the placebo arm and there were more negative themes identified in the placebo arm, compared to the NAC arm. Conclusion: This approach revealed additional results not elucidated in the primary quantitative analysis. This emphasises the value of mixed-methods research in capturing participants’ experiences in RCTs and detecting possible latent benefits and risks. Such methods can detect latent target signals in novel therapy trials conducted in BD and generate novel hypotheses.

N-Acetyl Cysteine in the Treatment of Obsessive Compulsive and Related Disorders: A Systematic Review

Georgina Oliver,Olivia Dean,David Camfield,Scott Blair-West,Chee Ng,Michael Berk,Jerome Sarris 대한정신약물학회 2015 CLINICAL PSYCHOPHARMACOLOGY AND NEUROSCIENCE Vol.13 No.1

Objective: Obsessive compulsive and related disorders are a collection of debilitating psychiatric disorders in which the role of glutamate dysfunction in the underpinning neurobiology is becoming well established. N-acetyl cysteine (NAC) is a glutamate modulator with promising therapeutic effect. This paper presents a systematic review of clinical trials and case reports exploring the use of NAC for these disorders. A further objective was to detail the methodology of current clinical trials being conducted in the area. Methods: PubMed, Web of Science and Cochrane Library Database were searched for human clinical trials or case reports investigating NAC in the treatment of obsessive compulsive disorder (OCD) or obsessive compulsive related disorders. Researchers with known involvement in NAC studies were contacted for any unpublished data. Results: Four clinical trials and five case reports/series were identified. Study durations were commonly 12-weeks, using 2,400-3,000 mg/day of NAC. Overall, NAC demonstrates activity in reducing the severity of symptoms, with a good tolerability profile and minimal adverse effects. Currently there are three ongoing randomized controlled trials using NAC for OCD (two adults and one pediatric), and one for excoriation. Conclusion: Encouraging results have been demonstrated from the few pilot studies that have been conducted. These results are detailed, in addition to a discussion of future potential research.

Association Between Vitamin D Insufficiency and Metabolic Syndrome in Patients With Psychotic Disorders

Taeyoung Yoo,Wonsuk Choi,JinHee Hong,JuYeon Lee,JaeMin Kim,IlSeon Shin,SooJin Yang,Paul Amminger,Michael Berk,JinSang Yoon,SungWan Kim 대한신경정신의학회 2018 PSYCHIATRY INVESTIGATION Vol.15 No.4

Objective-This study examined the association between vitamin D and metabolic syndrome in patients with psychotic disorders. Methods-The study enrolled 302 community-dwelling patients with psychotic disorders. Sociodemographic and clinical characteristics, including blood pressure, physical activity, and dietary habit were gathered. Laboratory examinations included vitamin D, lipid profile, fasting plasma glucose, HbA1c, liver function, and renal function. Vitamin D insufficiency was defined as <20 ng/mL. Clinical characteristics associated with vitamin D insufficiency were identified. Results-Among the 302 participants, 236 patients (78.1%) had a vitamin D insufficiency and 97 (32.1%) had metabolic syndrome. Vitamin D insufficiency was significantly associated with the presence of metabolic syndrome (p=0.006) and hypertension (p=0.017). Significant increases in triglycerides and alanine transaminase were observed in the group with a vitamin D insufficiency (p=0.002 and 0.011, respectively). After adjusting for physical activity and dietary habit scores, vitamin D insufficiency remained significantly associated with metabolic syndrome and hypertension. Conclusion-Vitamin D insufficiency was associated with metabolic syndrome and was particularly associated with high blood pressure, although the nature, direction and implications of this association are unclear.

Does Post-traumatic Stress Disorder Impact Treatment Outcomes within a Randomised Controlled Trial of Mitochondrial Agents for Bipolar Depression?

Samantha E. Russell,Anna L. Wrobel,Melanie M. Ashton,Alyna Turner,Mohammadreza Mohebbi,MIchael Berk,Sue Cotton,Seetal Dodd,Chee H. Ng,Gin S. Malhi,Olivia M. Dean 대한정신약물학회 2023 CLINICAL PSYCHOPHARMACOLOGY AND NEUROSCIENCE Vol.21 No.3

Objective: Bipolar disorder often co-occurs with post-traumatic stress disorder, yet few studies have investigated the impact of post-traumatic stress disorder in bipolar disorder on treatment outcomes. The aim of this sub-analysis was to explore symptoms and functioning outcomes between those with bipolar disorder alone and those with comorbid bipolar disorder and post-traumatic stress disorder. Methods: Participants (n = 148) with bipolar depression were randomised to: (i) N-acetylcysteine alone; (ii) a combination of nutraceuticals; (iii) or placebo (in addition to treatment as usual) for 16 weeks (+4 weeks discontinuation). Differences between bipolar disorder and comorbid bipolar disorder and post-traumatic stress disorder on symptoms and functioning at five timepoints, as well as on the rate of change from baseline to week 16 and baseline to week 20, were examined. Results: There were no baseline differences between bipolar disorder alone and comorbid bipolar disorder and post-traumatic stress disorder apart from the bipolar disorder alone group being significantly more likely to be married (p = 0.01). There were also no significant differences between bipolar disorder alone and comorbid bipolar disorder and post-traumatic stress disorder on symptoms and functioning. Conclusion: There were no differences in clinical outcomes over time within the context of an adjunctive randomised controlled trial between those with bipolar disorder alone compared to those with comorbid bipolar disorder and post-traumatic stress disorder. However, differences in psychosocial factors may provide targets for areas of specific support for people with comorbid bipolar disorder and post-traumatic stress disorder.