Posted by Berk on May 14, 2013, at 4:38:32
In reply to Re: Lamictal and lithium carbonate » Berk, posted by tensor on May 13, 2013, at 18:11:36
No no it was just a mistake because i am beginner for this site. :(
Sorry for disturbing..I think i m bipolar-2.because i didnt switch to mania never.maybe 1 hypo-mania but it is not exact.Maybe unipolar depression.
It is very hard to answer an antidepressant alone for me.
My treatment now :
efexor 300 mg
lamictal 300 mg
solian 200 mg (amisulpride)now, i didnt answer this coctail. i think that's why my thyroid hormone level is very low and my tsh is very high.i didnt do blood tsh test.that's my old pdoc's hypothesis.he is sure that i m bipolar-2.
in the past i used lithium in a succesful way.but lamictal is better than lithium in bipolar-2 i think.
what is the problem inside my brain?
i will add t3 and t4 combination.also today i will try NAC 600 (N-acetylcysteine) .
Abstract
BackgroundEvidence 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.
MethodThis 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 1 g BID of NAC that examined the use of NAC as a maintenance treatment for bipolar disorder.
ResultsIn 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.
ConclusionThese open label data demonstrate a robust decrement in depression scores with NAC treatment. Large placebo controlled trials of acute bipolar depression are warranted.
KeywordsN-acetyl cysteine;
Depression;
Mania;
Bipolar disorder;
Maintenance;
Treatment1. Introduction
Individuals with bipolar disorder spend three times longer in the depressive phase of the illness than in mania (Judd and Akiskal, 2003). Consequently, bipolar depression is highly disabling and confers marked occupational and social impairment. Together with depressive mixed states, the depressive phase of bipolar disorder is its most lethal period, as it is associated with substantial suicide risk. Hence its management is complicated and made more difficult by the absence of a range of established effective treatments. Indeed the efficacy of antidepressants in the treatment of bipolar depression remains unclear and extrapolation from unipolar depression data provides little assistance (Ghaemi, 2008). For instance, contemporary, large and methodologically rigorous trials of antidepressants in bipolar disorder have been largely negative (Tohen et al., 2009) and in practise the administration of antidepressants can precipitate mania and shorten the inter-episode window of euthymia. Similar to the paucity of evidence for pharmacotherapy there is a limited evidence base for psychological interventions for acute bipolar depression (Scott and Colom, 2005), however on the basis of efficacy in unipolar depression and in bipolar maintenance treatment, psychological treatments are frequently used. Even lithium is less effective in addressing acute depression than mania (Malhi et al., 2010), and the evidence for the deployment of valproate in bipolar depression is equivocal (Bond et al., 2010). Lamotrigine (van der Loos et al., 2009) and some atypical antipsychotics demonstrate efficacy in bipolar depression but have substantial pragmatic or tolerability issues (Ng et al., 2009). Thus the consensus in the bipolar field is that the unmet clinical need is greatest in bipolar depression (Malhi et al., 2009 and Malhi et al., 2010).
Data confirming the role of redox dysregulation in bipolar disorder derives from five main areas: i) evidence of dysregulated oxidative defences; ii) data on effects of oxidative stress on cellular constituents, particularly lipids, proteins and DNA; iii) evidence that known bipolar treatments have profound influences on oxidative processes; iv) association studies of polymorphisms of key genes in the glutathione pathway (Fullerton et al., 2010); and v) structural evidence of a neuroprogressive process. These data have been reviewed in detail elsewhere (Berk et al., 2008c, Dean et al., 2009 and Ng et al., 2008).
Glutathione, the primary endogenous antioxidant in the brain, is synthesised from the precursor amino acids, l-glutamate, l-cysteine and l-glycine, in two enzymatic steps. In oxidative stress states, glutathione is vulnerable to depletion. Enhancing l-cysteine supply, the rate limiting factor in glutathione synthesis via a precursor, N-acetylcysteine (NAC), leads to a rise in brain glutathione (Dean et al., 2004).
The aim of this study was to investigate the efficacy of adjunctive NAC in the treatment of major depressive episodes (MDE) in bipolar disorder in the initial open label phase of a randomised, double blind placebo-controlled maintenance trial. It was hypothesised that NAC would improve symptoms of depression in the open label phase of the trial.
2. MethodsThe open label treatment phase of a double blind placebo controlled randomised controlled trial of the efficacy and tolerability of NAC 1 g BID in the maintenance phase of bipolar disorder is presented here. Depressive symptomatic severity, using the Bipolar Depression Rating Scale (BDRS) (Berk et al., 2007) was the primary outcome measure of this component of the study. Secondary outcomes included the Montgomery-Åsberg Depression Rating Scale (MADRS) (Montgomery and Asberg, 1979), the Clinical Global Impression (Spearing et al., 1997), and measures of, functioning and quality of life (QoL). Participants were recruited drawing upon a variety of sources that included patient databases, the participants' case clinicians, and advertisement or via private clinicians (e.g. family physicians or specialists). All participants received NAC in an open label manner for a period of two months, following which; they were assigned randomly and consecutively to treatment with NAC or placebo in a double blind fashion for a further six months. Data from the placebo-controlled component of the study will be published separately. All participants remained on treatment as usual (TAU) for the duration of the trial. With research and ethics committee approval, the trial was conducted according to GCP guidelines (ICH Expert Working Group, 2006) and registered on the Australian Clinical Trials Registry ACTRN12607000074493.
2.1. Inclusion and exclusion criteriaTo be included in the study participants: had to meet DSM-IV criteria for bipolar I, bipolar II and bipolar NOS; have current symptoms of depression, with a MADRS score of ≥ 12 at baseline; have the capacity to consent to the study and comply with study procedures; be using effective contraception if female, sexually active and of childbearing age; and have been on stable therapy for at least 1 month prior to randomisation. Exclusion criteria included: participants with a known or suspected clinically relevant systemic medical disorder; elderly subjects with respiratory insufficiency; individuals who were pregnant or lactating; participants taking greater than 500 mg of NAC/day, 200 μg of selenium/day or 500 IU of Vitamin E/day or who have had an allergic reaction to NAC or any component of the preparation; and/or who were assessed as being unable to comply with either the requirements of informed consent or the treatment protocol. Withdrawal criteria included individuals who ceased taking their trial medication for seven consecutive days or who ceased effective contraception or became pregnant. Dose changes to existing medications (either increases or decreases in dose), or addition or removal of an agent was accepted and participants were allowed to continue with the trial. This was an outcome measure of the primary study. Additionally, participants were withdrawn from the study if they withdrew consent or developed serious adverse events associated with the study drug. Discontinuation due to adverse events occurred either at the request of the patient or the discretion of the investigator.
2.2. MeasurementsParticipants were assessed at baseline using a structured clinical interview, the MINI-plus. Change in the participants' clinical status was assessed using the Bipolar Depression Rating Scale (BDRS) (Berk et al., 2004 and Berk et al., 2007), MADRS, Young Mania Rating Scale (YMRS) (Young et al., 1978), Clinical Global Impression (CGI) improvement and severity scales (Guy, 1976), and CGI modified for substance use and bipolar disorder (CGI BP) (Spearing et al., 1997), Global Assessment of Functioning Scale (GAF) (Endicott et al., 1976), Social and Occupational Functioning Assessment Scale (SOFAS) (Goldman et al., 1992), Streamed Longitudinal Interview Clinical Evaluation from the Longitudinal Interview Follow-up Evaluation (SLICE/LIFE) (Keller et al., 1987) and Range of Impaired Functioning Tool (LIFE RIFT) (Leon et al., 1999), and the Quality of Life Enjoyment and Satisfaction Questionnaire (Q-LES-Q) (Endicott et al., 1993). Adherence was monitored using pill counts of returned clinical trial material. In the open label phase, scales were repeated fortnightly for eight weeks or on the day of study termination if the patient withdrew prior to the final scheduled visit. Adverse events were tabulated.
2.3. Data analysisData analysis was performed by a consultant biostatistician (SMC), who was blind to treatment assignment, using IBM® SPSS® Statistics 18. Data were screened to determine the presence of outliers and whether data conformed to a normal Gaussian distribution. Data that were not normally distributed were transformed using logarithmic transformation (plus constant when zero was a valid data point). For ease of interpretation, untransformed data are presented in tables.
To determine differences between completers and non-completers of the 8-week open label phase, a series of independent samples t-tests and chi-square analyses was conducted on demographic and baseline variables.
Treatment response was determined at week 8 (end of open label) using absolute mean change in the primary (BDRS) and secondary (MADRS, functioning, and QoL) outcome variables. Mixed effects Models Repeated Measures analysis of variance (MMRM) was employed to determine whether there was significant change in the outcome measures with Toeplitiz covariance structure was used to model the relations between observations on different occasions. MMRM differs from traditional repeated measures models analysis of variance and analysis of covariance in that all existing data comprise the model and it does not require the imputation or substitution of missing data with estimated or hypothetical values (Gueorguieva and Krystal, 2004). It is therefore the preferred method of analysing longitudinal data in psychiatry and is considered superior to techniques such as last observation carried forward (Gueorguieva and Krystal, 2004). Planned comparisons using MMRM were conducted to examine mean change on the outcome measures from baseline to week 8.
3. Results
3.1. Sample characteristicsOne hundred and forty nine individuals meeting DSM-IV-TR criteria for bipolar disorder on a structured clinical interview (MINI-plus) were randomised. Participants were aged between 22 and 70 years of age and approximately two-thirds (67.8%) were female. Bipolar I disorder was the main diagnosis and the average length of illness since time of diagnosis was 10.0 years (see Table 1).
Table 1. Demographic and illness characteristics at baseline (Week 0).
VariableTest statisticsValue
Age at entry to studyM (SD)45.8 (11.4)
Gender % Female% (n)67.8 (101)
Diagnosis
Bipolar I disorder% (n)69.6 (103)
Bipolar II disorder% (n)29.7 (44)
Bipolar NOS% (n)0.7 (1)
Suicidality %Yes% (n)70.9 (105)
Age of first symptomsM (SD)22.0 (10.6)
Age of diagnosisM (SD)35.9 (11.6)
Duration of illness since diagnosis (years)M (SD)10.0 (9.4)
Mdn7
Number of psychiatric hospitalisations (years)M (SD)3.0 (4.4)
Mdn1
Number of manic episodes > 10% (n)53.5 (76)
Number of depressive episodes > 10% (n)78.3 (112)
Smoker %Yes% (n)33.6 (50)
Alcohol use %Yes% (n)46.3 (69)
Alcohol dependence/abuse% (n)14.2 (21)
Substance use %Yes% (n)4.0 (6)
Substance dependence/abuse% (n)14.3 (21)
Table optionsPrecisely one third (33.6%) of the sample were current smokers. Almost half (46.3%) of the participants consumed alcohol, but only one in 7 (14.2%) met criteria for alcohol abuse/dependence. On the MINI, abuse/dependence of substances occurred in 14.3% of participants.
3.2. Participant flowRetention in the study was high with 132 participants completing the 8-week open label treatment phase (88.6%). There were no differences between completers and non-completers with respect to demographic characteristics, onset of illness (age of first symptoms, age at diagnosis), suicidality, substance use, psychopathology and functioning. The two groups did however, differ significantly (χ2 = 4.61, p = .032) with respect to diagnostic grouping with 72.5% of completers having bipolar I disorder and 47.1% of non-completers having bipolar II disorder.
3.3. Primary and secondary outcome measuresThe results from the MMRM models for primary and secondary outcome measures are shown in Fig. 1. There was a statistically significant change in BDRS scores from baseline to week 8 (p < .001) with an estimated average change of 8.7 (SE = 0.9). Similarly, there was significant improvement from baseline to week 8 on most clinical measures, with the exception of the CGI-BP Severity Mania scores (p = .078). The average CGI-BP Improvement scores at week 8 was 3.8 (SD = 0.7) for mania, 2.5 (SD = 1.2) for depression, and 2.6 (SD = 1.2) for overall symptom severity. Significant improvements were similarly seen on all measures of functioning and for the Q-LES-Q.
Full-size image (55 K)
Fig. 1. Symptomatology and functioning from Week 0 (baseline) to Week 8 (end of open label). (YMRS, Young Mania Rating Scale; MADRS, Montgomery-Åsberg Depression Rating Scale; BDRS, Bipolar Depression Rating Scale; CGI-BP Clinical Global Impressions-Bipolar Disorder; GAF, Global Assessment of Functioning; SOFAS, Social and Occupational Assessment Scale; LIFE-RIFT, Range of Impaired Functioning Tool; SLICE-LIFE, Streamed Longitudinal Interval Clinical Evaluation for the Longitudinal Interview Follow-Up Evaluation; Q-LES-Q, Quality of Life Enjoyment and Satisfaction Questionnaire). *p < 0.05 for change from baseline to week 8.
Figure options4. Discussion
The reduction in depressive symptomatology in this trial suggests that NAC may have efficacy in acute bipolar depression. Of note, there was a comparable reduction in measures of quality of life and functioning. These data are concordant with the only previous data examining NAC in bipolar disorder. In that 6-month bipolar disorder placebo controlled trial (N = 75), adjunctive NAC in participants with either bipolar I or II disorder significantly improved clinical outcomes, particularly depression, quality of life and measures of functioning, with large effect sizes in almost all domains (Berk et al., 2008b and Magalhaes et al., 2011). In addition, the utility of NAC in other psychiatric disorders, including a large clinical trial of schizophrenia (Berk et al., 2008a and Berk et al., 2010), and small scale clinical papers in obsessivecompulsive disorder (Lafleur et al., 2006) and compulsive and grooming disorders (Grant et al., 2009 and Odlaug and Grant, 2007), pathological gambling (Grant et al., 2007), nailbiting (Berk et al., 2009) and cocaine dependence (Larowe et al., 2006 and Larowe et al., 2007) have been reported (Dodd et al., 2008).
NAC crosses the blood brain barrier and replenishes brain glutathione in a rat model (Dean et al., 2004) and protects against markers of oxidative stress in the striatum, in both an exercise induction oxidative stress model (Aguiar et al., 2008) and a haloperidol treatment model (Harvey et al., 2008). Further, NAC enhances neurogenesis of neuronal stem cells and promotes neuronal survival (Dean et al., 2004) after injury, a point that is particularly relevant given the reduction in neurogenesis reported in depression and the ability of antidepressants to enhance neurogenesis (Qian and Yang, 2009). This potential neuroprotective effect of NAC (Farr et al., 2003) has been demonstrated in a variety of neurodegenerative disease models (Andreassen et al., 2000, Ferrari et al., 1995, Koppal et al., 1999, Louwerse et al., 1995, Mayer and Noble, 1994, Rothstein et al., 1994 and Staal et al., 1995).
Interestingly, glutamate has been implicated in mood disorders (Lavoie et al., 2008 and Skolnick et al., 2009) and can be modulated by NAC by its effects on cystine glutamate exchange. Additionally, NAC has putative anti-inflammatory effects that are again concordant with an emerging role of inflammatory processes in depression. Finally, and in keeping with the actions of almost all accepted antidepressants, NAC administration in the forced swim test results in a significant decrease in the immobility time in male Wistar rats (Ferreira et al., 2008). All of these factors in conjunction with the findings of our study suggest an acute antidepressant action for NAC.
The principal limitation of this study is the absence of a placebo arm, which is essential to make definitive conclusions regarding efficacy. However, the sample size is ample for a study of this design. The absence of significant restrictions on comorbid therapy enhances the generalisability of the data, as does the inclusion of bipolar I, II and NOS participants but may at the same time have contributed to a dilution of demonstrable efficacy. However, despite these limitations, the data overall clearly signal the potential efficacy of NAC in acute bipolar depression, and further support the imperative for acquiring placebo controlled data to better evaluate its effects in clinical practise.
Role of funding sourceThis study received funding from grant 06TGF-996 from the Stanley Medical Research Institute for the expenses of the trial. Heidi Cobb benefited from support from NHMRC Program Grant ID 510135. The funding sources had no role in study design, management, data analysis or manuscript preparation.
Conflict of interestBerk and Bush are co-inventors on two provisional patents regarding the use of NAC and related compounds for psychiatric indications, which, whilst assigned to the Mental Health Research Institute, could lead to personal remuneration upon a commercialisation event. Bush is a stock shareholder of Eucalyptus Biosciences and Prana Biotechnologies. Berk has served on advisory boards and received funds and/or honoraria from Astra Zeneca, Eli Lilly, Janssen Cilag, Lundbeck, Servier, Glaxo Smith Kline, Organon, Novartis, Pfizer, Bristol Myers Squibb, Sanofi Synthelabo and Solvay. Malhi has served on advisory boards and received funds and/or honoraria from Astra Zeneca, Eli Lilly, Janssen Cilag, Lundbeck, Servier, Pfizer, Organon and Wyeth. Dodd has received funds and honoraria from Servier and Eli Lilly All other authors declare that they have no conflicts of interest.
wcan i use lamictal and nac together, these two together act on glutamate level.?Sorry for long writing.(copy paste)
http://www.sciencedirect.com/science/article/pii/S0165032711003247
poster:Berk
thread:1043571
URL: http://www.dr-bob.org/babble/20130501/msgs/1043611.html