Addressing psychosocial needs in patients with Long-COVID (PsyLoCo-Study): study protocol of a pilot-study of a specialized modular intervention.

Introduction: After an acute infection with the corona virus 10-20% of those affected suffer from ongoing or new symptoms. A causal therapy for the phenomenon known as Long/Post-COVID is still lacking and specific therapies addressing psychosocial needs of these patients are imperatively needed. The aim of the PsyLoCo-study is developing and piloting a psychotherapeutic manual, which addresses Long/Post-COVID-related psychosocial needs and supports in coping with persistent bodily symptoms as well as depressive or anxiety symptoms. Methods and analysis: This pilot trial implements a multi-centre, 2-arm (N=120; allocation ratio: 1:1), parallel group, randomised controlled design. The pilot trial is designed to test the feasibility and estimate the effect of 1) a 12-session psychotherapeutic intervention compared to 2) a wait-list control condition on psychosocial needs as well as bodily and affective symptoms in patients suffering from Long/Post-COVID. The intervention uses an integrative, manualized, psychotherapeutic approach. The primary study outcome is health-related quality of life. Outcome variables will be assessed at three timepoints, pre-intervention (t1), post-intervention (t2) and three months after completed intervention (t3). To determine the primary outcome, changes from t1 to t2 are examined. The analysis will be used for the planning of the RCT to test the efficacy of the developed intervention. Discussion: The pilot study will evaluate a 12-session treatment manual for Long/Post-COVID sufferers and the therapy components it contains. The analysis will provide insights into the extent to which psychotherapeutic treatment approaches improve the symptoms of Long/Post-COVID sufferers. The treatment manual is designed to be carried out by psychotherapists as well as people with basic training in psychotherapeutic techniques. This approach was chosen to enable a larger number of practitioners to provide therapeutic support for Long/Post-COVID patients. After completion of the pilot study, it is planned to follow up with a randomized controlled study and to develop a treatment guideline for general practitioners and interested specialists. Trial registration: The pilot trial has been registered with the German Clinical Trials Register (Deutsches Register Klinischer Studien; Trial-ID: DRKS00030866; URL: https://drks.de/search/de/trial/DRKS00030866) on March 7, 2023.

Clinical effectiveness of patient-targeted feedback following depression screening in general practice (GET.FEEDBACK.GP): an investigator-initiated, prospective, multicentre, three-arm, observer-blinded, randomised controlled trial in Germany.

BACKGROUND: Screening for depression in primary care alone is not sufficient to improve clinical outcomes. However, targeted feedback of the screening results to patients might result in beneficial effects. The GET.FEEDBACK.GP trial investigated whether targeted feedback of the depression screening result to patients, in addition to feedback to general practitioners (GPs), leads to greater reductions in depression severity than GP feedback alone or no feedback. METHODS: The GET.FEEDBACK.GP trial was an investigator-initiated, multicentre, three-arm, observer-blinded, randomised controlled trial. Depression screening was conducted electronically using the Patient Health Questionnaire-9 (PHQ-9) in 64 GP practices across five regions in Germany while patients were waiting to see their GP. Currently undiagnosed patients (aged ≥18 years) who screened positive for depression (PHQ-9 score ≥10), were proficient in the German language, and had a personal consultation with a GP were randomly assigned (1:1:1) into a group that received no feedback on their depression screening result, a group in which only the GP received feedback, or a group in which both GP and patient received feedback. Randomisation was stratified by treating GP and PHQ-9 depression severity. Trial staff were masked to patient enrolment and study group allocation and GPs were masked to the feedback recieved by the patient. Written feedback, including the screening result and information on depression, was provided to the relevant groups before the consultation. The primary outcome was PHQ-9-measured depression severity at 6 months after randomisation. An intention-to-treat analysis was conducted for patients who had at least one follow-up visit. This study is registered at ClinicalTrials.gov (NCT03988985) and is complete. FINDINGS: Between July 17, 2019, and Jan 31, 2022, 25 279 patients were approached for eligibility screening, 17 150 were excluded, and 8129 patients completed screening, of whom 1030 (12·7%) screened positive for depression. 344 patients were randomly assigned to receive no feedback, 344 were assigned to receive GP-targeted feedback, and 339 were assigned to receive GP-targeted plus patient-targeted feedback. 252 (73%) patients in the no feedback group, 252 (73%) in the GP-targeted feedback group, and 256 (76%) in the GP-targeted and patient-targeted feedback group were included in the analysis of the primary outcome at 6 months, which reflected a follow-up rate of 74%. Gender was reported as female by 637 (62·1%) of 1025 participants, male by 384 (37·5%), and diverse by four (0·4%). 169 (16%) of 1026 patients with available migration data had a migration background. Mean age was 39·5 years (SD 15·2). PHQ-9 scores improved for each group between baseline and 6 months by -4·15 (95% CI -4·99 to -3·30) in the no feedback group, -4·19 (-5·04 to -3·33) in the GP feedback group, and -4·91 (-5·76 to -4·07) in the GP plus patient feedback group, with no significant difference between the three groups (global p=0·13). The difference in PHQ-9 scores when comparing the GP plus patient feedback group with the no feedback group was -0·77 (-1·60 to 0·07, d=-0·16) and when comparing with the GP-only feedback group was -0·73 (-1·56 to 0·11, d=-0·15). No increase in suicidality was observed as an adverse event in either group. INTERPRETATION: Providing targeted feedback to patients and GPs after depression screening does not significantly reduce depression severity compared with GP feedback alone or no feedback. Further research is required to investigate the potential specific effectiveness of depression screening with systematic feedback for selected subgroups. FUNDING: German Innovation Fund. TRANSLATION: For the German translation of the abstract see Supplementary Materials section.

SARS-CoV-2 infection is associated with physical but not mental fatigue - Findings from a longitudinal controlled population-based study.

OBJECTIVE: Fatigue has been identified as the core symptom of long-Covid, however, putative pandemic-related influences remain largely unclear. We investigated trajectories of total, physical and mental fatigue and the factors associated with it in previously infected and non-infected individuals up to one year post- infection. METHODS: We used data from a longitudinal cohort study of German adults with two samples: A representative probability sample and a sample of individuals with proven SARS-CoV-2 infection. Surveys were conducted in spring 2020(T1), autumn 2020(T2) and summer 2021(T3). Fatigue was assessed using the FAS, distinguishes between physical and mental fatigue. Depression, anxiety and stress were assessed using PHQ-4 and PSQ. RESULTS: 1990 participants [mean age 47.2 (SD = 17.0), 30.5% previously infected] were included in the survey at T1 (n = 1118 at T2, n = 692 at T3). Total and physical fatigue, but not mental fatigue were significantly higher in the previously infected compared to the non-infected sample at T2, but this group difference disappeared at T3. We identified Covid-infection as a factor associated with transient total and physical fatigue at T2. Depression, anxiety and stress at T1 were associated with total, physical and mental fatigue at both follow-ups. CONCLUSIONS: Our results highlight the importance of considering physical and mental fatigue as separate entities, while suggesting a greater relevance of the physical signs of fatigue in understanding long-Covid. The results further showed that baseline mental health symptoms were the most strongly associated with fatigue trajectories.

Stress and Depressive and Anxiety Symptoms in the General Population and in SARS-CoV-2-Infected Patients-Findings from a Population-Based Three-Wave Study.

Objective: Understanding factors that impaired mental health during the COVID-19 pandemic is extremely relevant in order to mitigate long-term consequences of the pandemic and to promote resilience in future crises. Method: Data were collected in southern Germany in a population-based survey study (CoKoS) with three times of measurement in May 2020, November 2020 and July 2021. Predictors of depressive and anxiety symptoms were measured with a short version of the Patient Health Questionnaire (PHQ-4) in the general population (N = 758) and individuals who were infected with SARS-CoV-2 in the beginning of the pandemic (N = 412). We investigated differences between both samples and how stress components (worry, tension, demands and joy) measured with the Perceived Stress Questionnaire (PSQ) varied with depressive and anxiety symptoms over time. Three linear mixed models (GLMMs) were fitted to predict the PHQ-4 stepwise, including sociodemographic variables and stress (PSQ). Results: Depressive and anxiety symptoms increased from May 2020 to November 2020 and remained stable until July 2021. There were no differences between people with SARS-CoV-2 infection and the general population. Those with a pre-existing disease and lower education reported higher levels of depressive and anxiety symptoms. Stress explained a substantial fraction of variance in depressive and anxiety symptoms. The stress component worry emerged as the strongest predictor of depressive and anxiety symptoms, whereas joy seemed to buffer these symptoms. Conclusions: The results suggest that mitigating people's worry and increasing joy may promote resilience in future crises. Future studies should assess mental health interventions targeted at vulnerable groups, such as those with lower socioeconomic status and poorer health.

Post-Traumatic Distress in Adults With Congenital Heart Disease: an Under-Recognized Complication?

The stressful and potentially traumatic perception of repeated hospitalization, outpatient check-ups, and medical interventions places a high stress burden on patients with congenital heart disease (CHD). These experiences can lead to post-traumatic stress symptoms (PTSSs). This study aimed to estimate the prevalence of PTSSs in adults with CHD (ACHDs) and to identify the associated risk factors. In this cross-sectional study, 234 ACHDs were recruited from November 2021 to August 2022 at a dedicated tertiary care center. Data were collected on general health, anxiety and depression, PTSSs, and on quality of life using validated and standardized questionnaires. In addition, the reasons for PTSSs were assessed using free-text responses. Overall, 17.1% to 20.5% (mean age: 35.2 ± 10.8 [18 to 66] years, 46.6% women) of the enrolled patients met the criteria for clinically relevant PTSSs related to their CHD or treatment. The associated risk factors (p <0.05) included preexisting mental distress (odds ratio [OR] 4.86), depression (OR 5.565) and anxiety (OR 3.36,), level of perceived mental distress during the traumatic event (OR 1.46), and number of medical procedures (OR 1.17). In addition, a worse clinical state was associated with more PTSSs (p = 0.018). Using free-text responses, the various reasons for PTSSs were identified, ranging from cardiac procedures to social stigma. In conclusion, the high prevalence of PTSSs calls for increased awareness of PTSSs in ACHDs in cardiovascular care. PTSSs and their associated disorder can adversely affect the manifestation and progression of cardiac disease. Thus, it is necessary to reflect upon psychocardiac prevention and intervention as an integral part of multidisciplinary cardiac care.

COVID-19 Vaccines: Fear of Side Effects among German Health Care Workers.

(1) Background: Health care workers (HCWs) play a key role in increasing anti-COVID vaccination rates. Fear of potential side effects is one of the main reasons for vaccine hesitancy. We investigated which side effects are of concern to HCWs and how these are associated with vaccine hesitancy. (2) Methods: Data were collected in an online survey in February 2021 among HCWs from across Germany with 4500 included participants. Free-text comments on previously experienced vaccination side effects, and fear of short- and long-term side effects of the COVID-19 vaccination were categorized and analyzed. (3) Results: Most feared short-term side effects were vaccination reactions, allergic reactions, and limitations in daily life. Most feared long-term side effects were (auto-) immune reactions, neurological side effects, and currently unknown long-term consequences. Concerns about serious vaccination side effects were associated with vaccination refusal. There was a clear association between refusal of COVID-19 vaccination in one's personal environment and fear of side effects. (4) Conclusions: Transparent information about vaccine side effects is needed, especially for HCW. Especially when the participants' acquaintances advised against vaccination, they were significantly more likely to fear side effects. Thus, further education of HCW is necessary to achieve good information transfer in clusters as well.

COVID-19 Vaccination Acceptance and Hesitancy among Healthcare Workers in Germany.

Vaccination hesitancy is a threat to herd immunity. Healthcare workers (HCWs) play a key role in promoting Coronavirus disease 2019 (COVID-19) vaccination in the general population. We therefore aimed to provide data on COVID-19 vaccination acceptance/hesitancy among German HCWs. For this exploratory, cross-sectional study, an online survey was conducted in February 2021. The survey included 54 items on demographics; previous vaccination behavior; trust in vaccines, physicians, the pharmaceutical industry and health politics; fear of adverse effects; assumptions regarding the consequences of COVID-19; knowledge about vaccines; and information seeking behavior. Odds ratios with 95% confidence intervals were calculated and chi-square tests were performed. Four thousand five hundred surveys were analyzed. The overall vaccination acceptance was 91.7%. The age group ≤20 years showed the lowest vaccination acceptance. Factors associated with vaccination hesitancy were lack of trust in authorities and pharmaceutical companies. Attitudes among acquaintances were associated with vaccination hesitancy too. Participants with vaccination hesitancy more often obtained information about COVID-19 vaccines via messenger services or online video platforms and underperformed in the knowledge test. We found high acceptance amongst German HCWs. Several factors associated with vaccination hesitancy were identified which could be targeted in HCW vaccination campaigns.

Effectiveness of a Brief Psychotherapeutic Intervention for Employees With Psychosomatic and Psychosocial Complaints-Pilot Study of a Consultation Off the Workplace.

Employees' mental health impairments are a leading reason for sickness-leave and early retirement. This is why a large number of different intervention programmes have evolved in recent years with the aim of counteracting this development. Our study evaluates a short-term cognitive-behavioral psychotherapeutic intervention off the workplace. We investigated improvement of mental and physical health in psychologically strained employees of a white collar company. Depressive symptoms (PHQ-9), anxiety symptoms (GAD-7), somatic symptoms (PHQ-15), and perceived stress (PSQ-20) were assessed at the beginning and after the intervention. Patient satisfaction (recommendation - likeliness) was also measured after the intervention. In a second step, we have looked at potential determinants of therapy outcome. Changes in the symptom measures were assessed using t-tests, MANOVA, and Chi²-tests. Cohen's d was computed as effect size measure. One-hundred twenty-seven participants completed the assessment before, and 66 participants post intervention. Mean age of the participants was 44.6 (SD = 9.8) years, 54% were men. 89.7% of the patients attended one to five sessions. Depressive, anxiety, somatic symptoms, and perceived stress significantly declined from baseline to end of intervention. Effect sizes ranged from d = 0.49 (perceived stress) to d = 0.72 (depressive symptoms). Moreover, 93% of the patients stated that they were satisfied with the intervention and would recommend it to a friend. Previous uptake of psychiatric/psychotherapeutic treatment moderated the effect of the intervention on depressive symptoms, i.e., patients without previous experience showed a stronger reduction in symptoms of depression. The results tentatively suggest that the intervention is effective in reducing a broad range of psychological symptoms. Future research could investigate preferences and different outcomes of on-site and off-site work place interventions.

Depression screening using patient-targeted feedback in general practices: study protocol of the German multicentre GET.FEEDBACK.GP randomised controlled trial.

INTRODUCTION: Approximately one out of six patients in primary care suffers from depression, which often remains undetected. Evidence regarding the efficacy of depression screening in primary care, however, is inconsistent. A previous single-centre randomised controlled trial (RCT) in cardiac patients, the DEPSCREEN-INFO trial, provided the first evidence that written feedback to patients following a positive depression screening reduces depression severity and leads to more comprehensive patient engagement in mental healthcare. To amplify these effects, the feedback should be tailored according to patients' needs and preferences. The GET.FEEDBACK.GP RCT will test the efficacy of this patient-targeted feedback intervention in primary care. METHODS AND ANALYSIS: The multicentre three-arm GET.FEEDBACK.GP RCT aims to recruit a total of 1074 primary care patients from North, East and South Germany. Patients will be screened for depression using the Patient Health Questionnaire-9 (PHQ-9). In the case of a positive depression screening result (PHQ-9 score ≥10), the participant will be randomised into one of three groups to either receive (a) patient-targeted and general practitioner (GP)-targeted feedback regarding the depression screening results, (b) only GP-targeted feedback or (c) no feedback. Patients will be followed over a period of 12 months. The primary outcome is depression severity (PHQ-9) 6 months after screening. Secondary outcomes include patient engagement in mental healthcare, professional depression care and cost-effectiveness. According to a statistical analysis plan, the primary endpoint of all randomised patients will be analysed regarding the intention-to-treat principle. ETHICS AND DISSEMINATION: The Ethics Committee of the Hamburg Medical Association approved the study. A clinical trial company will ensure data safety, monitoring and supervision. The multicentre GET.FEEDBACK.GP RCT is the first trial in primary care that tests the efficacy of a patient-targeted feedback intervention as an adjunct to depression screening. Its results have the potential to influence future depression guidelines and will be disseminated in scientific as well as patient-friendly language. TRIAL REGISTRATION NUMBER: NCT03988985.

Cognitive Behaviour Therapy Complemented with Emotion Regulation Training for Patients with Persistent Physical Symptoms: A Randomised Clinical Trial.

INTRODUCTION: Persistent medically unexplained symptoms (MUS) are a major burden for health care. Cognitive behaviour therapy (CBT) is efficacious for patients with MUS, with small to medium effects. The current study investigates whether therapy outcomes of a CBT for MUS patients can be improved by complementing it with emotion regulation training. METHODS: In a multicentre trial 255 patients with at least three persisting MUS were randomised to 20 sessions of either conventional CBT (n = 128) or CBT complemented with emotion regulation training (ENCERT; n = 127). Somatic symptom severity and secondary outcomes were assessed at pre-treatment, therapy session 8, end of therapy, and 6-month follow-up. RESULTS: Linear mixed-effect models revealed medium to large effects in both study arms for almost all outcomes at the end of therapy and 6-month follow-up. ENCERT and CBT did not differ in their effect on the primary outcome (d = 0.20, 95% CI: -0.04 to 0.44). Significant time × group cross-level interactions suggested ENCERT to be of more benefit than conventional CBT for a few secondary outcomes. Moderator analyses revealed higher effects of ENCERT in patients with co-morbid mental disorders. DISCUSSION/CONCLUSIONS: Current findings are based on a representative sample. Results demonstrate that both CBT and ENCERT can achieve strong effects on primary and secondary outcomes in MUS patients. Our results do not indicate that adding a training in emotion regulation skills generally improves the effect of CBT across all patients with MUS. Large effect sizes of both treatments and potential specific benefits of ENCERT for patients with co-morbid mental disorders are discussed.

Is a delay in the diagnosis of bipolar disorder inevitable?

OBJECTIVE: A diagnosis of bipolar disorder (BD) is often preceded by an initial diagnosis of depression, creating a delay in the accurate diagnosis and treatment of BD. Although previous research has focused on predictors of a diagnosis change from depression to BD, the research on this delay in diagnosis is sparse. Therefore, the present study examined the time taken to make a BD diagnosis following an initial diagnosis of major depressive disorder in order to further understand the patient characteristics and psychological factors that may explain this delay. METHOD: A total of 382 patients underwent a clinical evaluation by a psychiatrist and completed a series of questionnaires. RESULTS: Ninety patients were initially diagnosed with depression with a later diagnosis of BD, with a mean delay in diagnostic conversion of 8.74 years. These patients who were later diagnosed with BD were, on average, diagnosed with depression at a younger age, experienced more manic symptoms, and had a more open personality style and better coping skills. Cox regressions showed that depressed patients with diagnoses that eventually converted to BD had been diagnosed with depression earlier and that this was related to a longer delay to conversion and greater likelihood of dysfunctional attitudes. CONCLUSION: The findings from the present study suggested that an earlier diagnosis of depression is related to experiencing a longer delay in conversion to BD. The clinical implications of this are briefly discussed, with a view to reducing the seemingly inevitable delay in the diagnosis of BD.

Are manic symptoms that 'dip' into depression the essence of mixed features?

BACKGROUND: Three symptoms of (hypo)mania that clinically represent mood disorders mixed states have been omitted from the DSM-5 mixed features specifier because 'they fail to discriminate between manic and depressive syndromes'. Therefore, the present study examined the role of distractibility, irritability and psychomotor agitation (DIP) in characterising mixed depressive states. METHODS: Fifty in-patients at a specialist mood disorders unit underwent a detailed longitudinal clinical evaluation (3-6 weeks) and were assessed on a range of standardized measures to characterise their illness according to depression subtype, duration of illness and clinical features-including specifically depressive and manic symptoms and the context in which these occur. RESULTS: 49 patients met criteria for major depressive episode, and of these, 34 experienced at least one dip symptom. Patients who endorsed distractibility were more likely to be diagnosed with Bipolar Disorder than Major Depressive Disorder; patients who endorsed irritable mood were more likely to have non-melancholic depression (admixture of depressive and anxiety symptoms), and patients who reported psychomotor agitation experienced a significantly greater number of distinct periods of (hypo)manic symptoms compared with those who did not. LIMITATIONS: The present study used a modest sample size and did not control for medication or comorbid illness. Although this is inevitable when examining real-world patients in a naturalistic setting, future research needs to allow for comorbidity and its impact, specifically anxiety. CONCLUSIONS: The present findings suggest that all 3 symptoms that have been excluded from DSM-5 may be cardinal features of mixed states, as they 'dip' into depressive symptoms to create a mixed state.

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.

Maintenance N-acetyl cysteine treatment for bipolar disorder: a double-blind randomized placebo controlled trial.

BACKGROUND: N-acetyl cysteine (NAC) is a glutathione precursor that has been shown to have antidepressant efficacy in a placebo-controlled trial. The current study aimed to investigate the maintenance effects of NAC following eight weeks of open-label treatment for bipolar disorder. METHOD: The efficacy of a double blind randomized placebo controlled trial of 2 g/day NAC as adjunct maintenance treatment for bipolar disorder was examined. Participants (n = 149) had a Montgomery Asberg Depression Rating Score of ≥12 at trial entry and, after eight weeks of open-label NAC treatment, were randomized to adjunctive NAC or placebo, in addition to treatment as usual. Participants (primarily outpatients) were recruited through public and private services and through newspaper advertisements. Time to intervention for a mood episode was the primary endpoint of the study, and changes in mood symptoms, functionality and quality of life measures were secondary outcomes. RESULTS: There was a substantial decrease in symptoms during the eight-week open-label NAC treatment phase. During the subsequent double-blind phase, there was minimal further change in outcome measures with scores remaining low. Consequently, from this low plateau, between-group differences did not emerge on recurrence, clinical functioning or quality of life measures. CONCLUSIONS: There were no significant between-group differences in recurrence or symptomatic outcomes during the maintenance phase of the trial; however, these findings may be confounded by limitations. TRIAL REGISTRATION: The trial was registered with the Australian New Zealand Clinical Trials Registry (ACTRN12607000074493).

The efficacy of N-acetylcysteine as an adjunctive treatment in bipolar depression: an open label trial.

BACKGROUND: Evidence is accumulating to support the presence of redox dysregulation in a number of psychiatric disorders, including bipolar disorder. This dysregulation may be amenable to therapeutic intervention. Glutathione is the predominant non-enzymatic intracellular free radical scavenger in the brain, and the most generic of all endogenous antioxidants in terms of action. N-acetylcysteine (NAC) is a glutathione precursor that effectively replenishes brain glutathione. Given the failure of almost all modern trials of antidepressants in bipolar disorder to demonstrate efficacy, and the limited efficacy of mood stabilisers in the depressive phase of the disorder, this is a major unmet need. METHOD: This study reports data on the treatment of 149 individuals with moderate depression during the 2 month open label phase of a randomised placebo controlled clinical trial of the efficacy of 1g BID of NAC that examined the use of NAC as a maintenance treatment for bipolar disorder. RESULTS: In this trial, the estimated mean baseline Bipolar Depression Rating Scale (BDRS) score was 19.7 (SE=0.8), and the mean BDRS score at the end of the 8 week open label treatment phase was 11.1 (SE=0.8). This reduction was statistically significant (p<0.001). Improvements in functioning and quality of life were similarly evident. CONCLUSION: These open label data demonstrate a robust decrement in depression scores with NAC treatment. Large placebo controlled trials of acute bipolar depression are warranted.