Antidepressant augmentation with metyrapone for treatment-resistant depression (the ADD study): a double-blind, randomised, placebo-controlled trial.

BACKGROUND: Many patients with major depressive disorder have treatment-resistant depression, defined as no adequate response to two consecutive courses of antidepressants. Some evidence suggests that antiglucocorticoid augmentation of antidepressants might be efficacious in patients with major depressive disorder. We aimed to test the proof of concept of metyrapone for the augmentation of serotonergic antidepressants in the clinically relevant population of patients with treatment-resistant depression. METHODS: This double-blind, randomised, placebo-controlled trial recruited patients from seven UK National Health Service (NHS) Mental Health Trusts from three areas (northeast England, northwest England, and the Leeds and Bradford area). Eligible patients were aged 18-65 years with treatment-resistant depression (Hamilton Depression Rating Scale 17-item score of ≥18 and a Massachusetts General Hospital Treatment-Resistant Depression staging score of 2-10) and taking a single-agent or combination antidepressant treatment that included a serotonergic drug. Patients were randomly assigned (1:1) through a centralised web-based system to metyrapone (500 mg twice daily) or placebo, in addition to their existing antidepressant regimen, for 21 days. Permuted block randomisation was done with a block size of two or four, stratified by centre and primary or secondary care setting. The primary outcome was improvement in Montgomery-Åsberg Depression Rating Scale (MADRS) score 5 weeks after randomisation, analysed in the modified intention-to-treat population of all randomly assigned patients that completed the MADRS assessment at week 5. The study has an International Standard Randomised Controlled Trial Number (ISRCTN45338259) and is registered with the EU Clinical Trial register, number 2009-015165-31. FINDINGS: Between Feb 8, 2011, and Dec 10, 2012, 165 patients were recruited and randomly assigned (83 to metyrapone and 82 to placebo), with 143 (87%) completing the primary outcome assessment (69 [83%] in the metyrapone and 74 [90%] in the placebo group). At 5 weeks, MADRS score did not significantly differ between groups (21·7 points [95% CI 19·2-24·4] in the metyrapone group vs 22·6 points [20·1-24·8] in the placebo group; adjusted mean difference of -0·51 points [95% CI -3·48 to 2·46]; p=0·74). 12 serious adverse events were reported in four (5%) of 83 patients in the metyrapone group and six (7%) of 82 patients in the placebo group, none of which were related to study treatment. 134 adverse events occurred in 58 (70%) patients in the metyrapone group compared with 95 events in 45 (55%) patients in the placebo group, of which 11 (8%) events in the metyrapone group and four (4%) in the placebo group were judged by principle investigators at the time of occurrence to be probably related to the study drug. INTERPRETATION: Metyrapone augmentation of antidepressants is not efficacious in a broadly representative population of patients with treatment-resistant depression within the NHS and therefore is not an option for patients with treatment-resistant depression in routine clinical practice at this time. Further research is needed to clarify if such augmentation might benefit subpopulations with demonstrable hypothalamic-pituitary-adrenal axis abnormalities. FUNDING: Efficacy and Mechanism Evaluation (EME) programme, a UK Medical Research Council and National Institute for Health Research partnership.

Study protocol for the randomised controlled trial: antiglucocorticoid augmentation of anti-Depressants in Depression (The ADD Study).

BACKGROUND: Some patients with depression do not respond to first and second line conventional antidepressants and are therefore characterised as suffering from treatment refractory depression (TRD). On-going psychosocial stress and dysfunction of the hypothalamic-pituitary-adrenal axis are both associated with an attenuated clinical response to antidepressants. Preclinical data shows that co-administration of corticosteroids leads to a reduction in the ability of selective serotonin reuptake inhibitors to increase forebrain 5-hydroxytryptamine, while co-administration of antiglucocorticoids has the opposite effect. A Cochrane review suggests that antiglucocorticoid augmentation of antidepressants may be effective in treating TRD and includes a pilot study of the cortisol synthesis inhibitor, metyrapone. The Antiglucocorticoid augmentation of anti-Depressants in Depression (The ADD Study) is a multicentre randomised placebo controlled trial of metyrapone augmentation of serotonergic antidepressants in a large population of patients with TRD in the UK National Health Service. METHODS/DESIGN: Patients with moderate to severe treatment refractory Major Depression aged 18 to 65 will be randomised to metyrapone 500 mg twice daily or placebo for three weeks, in addition to on-going conventional serotonergic antidepressants. The primary outcome will be improvement in Montgomery-Åsberg Depression Rating Scale score five weeks after randomisation (i.e. two weeks after trial medication discontinuation). Secondary outcomes will include the degree of persistence of treatment effect for up to 6 months, improvements in quality of life and also safety and tolerability of metyrapone. The ADD Study will also include a range of sub-studies investigating the potential mechanism of action of metyrapone. DISCUSSION: Strengths of the ADD study include broad inclusion criteria meaning that the sample will be representative of patients with TRD treated within the UK National Health Service, longer follow up, which to our knowledge is longer than any previous study of antiglucocorticoid treatments in depression, and the range of mechanistic investigations being carried out. The data set acquired will be a rich resource for a range of research questions relating to both refractory depression and the use of antiglucocorticoid treatments. TRIAL REGISTRATION: Current Controlled Trials: ISRCTN45338259; EudraCT Number: 2009-015165-31.

How is substance use linked to psychosis? A study of the course and patterns of substance dependence in psychosis.

Substance use in mentally ill patients is now a major problem that influences the course and outcome of psychosis. With prevalence ranging up to 60%, several theories were postulated to explain the link. It would be interesting to know if substances have different effects in persons with psychosis than in those without. This study aimed to explore patterns of symptomatology of dependence and comorbid psychiatric illness by comparing and contrasting it with a group suffering from pure substance dependence. Consecutively admitted patients who were matched for age, sex, and tobacco use were divided into 3 groups. These were substance dependence without any comorbid psychiatric disorder (SD; n = 32), schizophrenia with substance dependence (SC; n = 31), and bipolar disorder with substance dependence (BD; n = 31). Patients were administered the Schedules for Clinical Assessment in Neuropsychiatry (SCAN) and Mini International Neuropsychiatric Inventory (MINI) to evaluate the chronology of criterion of International Classification of Diseases (ICD)-10 dependence. Results showed that cannabis was the most common substance used by both the SC (100%) and BD (80%) groups. This was followed by alcohol as the most common substance used, with prevalence of 87% in SC and 77% in BD groups. There was a significant difference in the pattern of use of cannabis in patients with psychosis, who developed tolerance much faster (P = .018) and had longer durations of cannabis use (P = .001) than the SD group. The presence of "loss of control" over drug use criterion seems to be a specific marker predicting development of dependence and psychosis. Cannabis use is more strongly associated with development of psychosis than any other substance.

Perceived reasons for and consequences of substance abuse among patients with psychosis.

BACKGROUND: Substance use is a common comorbidity with psychotic illnesses. Although several theories exist to explain this link, individual reasons for use may differ. The aim of this study was to evaluate patient perceptions of the reasons for and consequences of their substance use in patients with psychosis and compare them with those of an age-, sex-, and tobacco use-matched control sample without psychosis. METHOD: Consecutively admitted patients were divided into 2 groups, those who had substance dependence without psychosis (n = 32), admitted in our addiction unit, and those who had psychotic illness with substance dependence, admitted in our inpatient psychosis unit and referred to as the dual-diagnosis group (n = 62). Patients were administered the Schedules for Clinical Assessment in Neuropsychiatry for ICD-10 Diagnostic Criteria for Research to confirm schizophrenia, bipolar affective disorder, and substance dependence diagnoses and were asked open-ended questions to evaluate the perceived reasons for and consequences of their substance use. The study was conducted from July to September 2006. RESULTS: There were significant differences between the 2 groups in reasons for maintenance and relapse of both cannabis use and alcohol use, the 2 most common substances. While the substance dependence without psychosis group attributed both maintenance and relapse to external factors such as nature of work, social milieu, or peer pressure, the dual-diagnosis group attributed them to internal factors such as enhancement of positive mood and alleviation of withdrawal effects. CONCLUSIONS: Individuals with psychosis have greater vulnerability to internal factors, which may maintain substance use. Targeting perceived internal factors may play a useful role in management and possibly identification and prevention of psychosis in vulnerable individuals in the future.

Delayed-onset delirium tremens - a diagnostic and management challenge.

BACKGROUND: Delirium tremens (DT) is one of the most serious complications of alcohol withdrawal, affecting 5-10% of in-patients with a mortality rate up to 15%. DT, characterised by delirium and tremors, appears within 48-72 h of abstinence and persists for about 5-10 days. CASE PRESENTATION: We report a case of DT in a young man with delayed onset on the 15th day after the cessation of alcohol use, despite an uncomplicated detoxification with benzodiazepine treatment. CONCLUSION: We hypothesise that the intake of country liquor in our patient, which contains higher percentages of alcohol, causes a prolonged imbalance of N-methyl-d-aspartic acid and glutamate receptor activity, leading to the picture of delayed-onset DT and that an atypical presentation at the time of admission and atypicality in early course are clinical pointers to the subsequent development of delayed-onset DT.

Chronology of alcohol dependence: implications in prevention.

BACKGROUND: Study of the chronology of criteria of dependence in alcohol dependence syndrome (ADS) can enable us design strategies for the prevention for ADS, which aims at reducing the occurrence of ADS. OBJECTIVE: To study the age-wise and order-wise chronologies of ICD-10 (DCR) dependence criteria in individuals with ADS. MATERIALS AND METHODS: Consecutively admitted and consenting inpatients with ICD-10 (DCR) diagnosis of ADS were evaluated in a structured interview after detoxification using Semi-Structured Assessment for the Genetics of Alcoholism (SSAGA)-II. RESULTS: The total sample size was 81. The mean ages at the first onset of alcohol use, development of the first criterion and International Statistical Classification of Diseases and Related Health Problems 10(th) Revision (ICD-10) dependence was 18.72 years (SD, 6.84), 24.33 years (SD, 9.21) and 27.51 years (SD, 9.28), respectively. In age-wise chronology, tolerance, loss of control and craving were present in 97.53%, 80.24% and 79%, respectively, of our study sample. In order-wise chronology, either craving (16%) or tolerance (71.6%) was present as the first criterion and the presence of craving (16%), tolerance (21%) or loss of control (18.5%) was observed in the first criterion in 55.5% of the subjects. CONCLUSIONS: Knowledge of chronology, its frequencies and time duration between various milestones in the development of the dependence criteria may enable the selection of the target population at an early stage. The pattern of development of dependence may provide us with an opportunity for interventions to reduce the incidence of ADS, as a step toward primary prevention. Adequate training of the primary care personnel and early psychiatric referral may help in the reduction in the incidence of ADS.

The role of Gateway drugs and psychosocial factors in substance dependence in Eastern India.

OBJECTIVE: Western studies have identified the gateway patterns of substance use which lead the way from the so called "Soft Drugs" (like nicotine, etc.) to the "Hard Drugs" (like Opioids) [the Gateway hypothesis]. Nicotine and alcohol have been implicated as the most common initiating drugs in studies from different places, however, studies are lacking from this region. This study was designed to find the drugs of initiation and to understand the factors for initiation, maintenance, and relapse of these substances in persons dependent on them in Eastern India. METHOD: Seventy subjects with ICD 10 DCR diagnosis of substance dependence admitted consecutively in Center for Addiction Psychiatry, Central Institute of Psychiatry (CIP), Ranchi, were taken up for the study after taking written informed consent. A semistructured questionnaire including the substance use part of Mini International Neuropsychiatric Inventory (MINI) was administered. RESULTS: Alcohol and opioids were the most common drugs of dependence but nicotine and alcohol were found to be the most common initiating drugs in both alcohol and opioid groups. Persons dependent on opioids presented earlier for treatment, with earlier development of withdrawal symptoms and having completed lesser years of formal education, and had higher monthly incomes as compared to those dependent on alcohol. The most common psychosocial factors determining initiation and maintenance were peer pressure or curiosity. CONCLUSIONS: If adolescents and youth can be motivated to stay away even from the "gateway drugs" by targeting common initiation factors, it may lead to delay in dependence or possibly avoidance of development of dependence.

Effectiveness of continuing nursing education program in child psychiatry.

PROBLEM: Program evaluation of the effectiveness of two continuing nursing education programs (CNE) in child psychiatry in India. METHODS: Pre- and postevaluation of a total of 51 nurses attending a 10-day CNE program, using a 30-item (six-domain) questionnaire according to CNE topics in child psychiatry. FINDINGS: The CNE program resulted in significant increase in the total scores as well as scores in several sub-domains in the field of child psychiatry. CONCLUSIONS: In a country that does not offer degree programs that integrate psychiatric nursing into the curriculum, CNE programs are an important educational option for nurses. The CNE program offered in this study, comprising lectures, discussion, interactive sessions, and case demonstrations totaling 60 hr across 10 days, was effective in improving the level of knowledge of nurses. It was equally beneficial for senior as well as less experienced nurses.

A Comparative Study of Sexual Dysfunction due to Typical and Atypical Antipsychotics in Remitted Bipolar-I Disorder.

In the remitted phase of bipolar I disorder, sexual dysfunction is commonly due to drugs used in the treatment rather than the disease itself. There are very few studies, especially in the Indian population, addressing the frequency of sexual dysfunction due to antipsychotics in bipolar I disorder. Hence this study was done to determine the sexual dysfunction due to antipsychotics and to compare the same among typical and atypical antipsychotics. A cross sectional study with 108 male patients of remitted bipolar I disorder (DSM-IV), chosen by purposive sampling technique was done. Psychopathology was assessed using the Brief Psychiatric Rating Scale, Structured Interview Guide for the Hamilton Depression Rating Scale and Young Mania Rating Scale. Sexual side effects due to antipsychotics were assessed using the Udvalg for Kliniske ndersogelser (UKU) side effect rating scale. The total sample size was divided into two groups of those on typical antipsychotics (n = 53) and atypical antipsychotics (n = 55). The two groups were compared for sexual dysfunction using Chi-square test. Results showed dysfunction in at least one phase of the sexual response cycle, comprising of desire, arousal and orgasm, was present in 66% of the sample population. Erectile dysfunction was present in 42% of the sample population and it was the most common type of sexual dysfunction reported. It was also significantly different across the two groups (p = 0.025). There was no significant difference in other aspects of sexual dysfunction across the two groups. In conclusion patients of Bipolar I disorder experience sexual side effects of antipsychotics frequently. Erectile dysfunction is the most common sexual dysfunction among men and this is significantly higher with typical than atypical antipsychotics.