The N-acetylcysteine Story: A New Potential Therapy for Bipolar Illness and Substance Abuse
N-acetylcysteine (NAC), a readily available substance from health food stores, is able to reestablish glutamate homeostasis (regulation and balance) in the reward area of brain (the nucleus accumbens), reported Peter Kalivas of the University of South Carolina at the “Staging neuropsychiatric disorders: Implications for idiopathogenesis and treatment” meeting in Mojacar, Spain this past November. Kalivas reported that NAC appears to be effective across a spectrum of addictions, including cocaine, heroin, alcohol, cigarette smoking, and gambling.
How NAC works in the brain
Even more remarkably, NAC also appears to have positive effects in placebo-controlled studies in the treatment of patients with bipolar illness, report Mike Berk and colleagues, who are studying the same substance in Australia. Compared with placebo, patients taking adjunctive NAC showed improvement in all outcome measures, especially depression, after 3 and 6 months. In another article, also published in Biological Psychiatry in 2008, Berk’s research group demonstrated that NAC improved some negative symptoms of schizophrenia. NAC has also shown positive effects in trichotillomania and on nail-biting, suggesting that it has a variety of potential clinical uses in conditions associated with pathological compulsive behavioral patterns.
More Medical Comorbidities Among Bipolar Population
Goldstein and colleagues interpreted data from the National Epidemiological Survey in 2001-2002 that included 41,682 representative adults in the U.S. population sampled compared with 1,411 found in the community with a diagnosis of bipolar disorder.
Those with bipolar disorder had a 3.86 times higher odds of having coronary heart disease compared with those in the general population. They were also 2.15 times more likely to have hypertension. Most disturbingly, the mean age of those with coronary heart disease in the general population was 62.1 years of age, but in those with bipolar illness, it was 50.4 years of age. This indicates that the markedly increased risk and incidence of coronary artery disease occurred approximately 11 years earlier in those with bipolar illness compared with those without. Most interestingly, the number of prior depressive episodes correlated with the presence of either coronary heart disease or hypertension.
Aspirin for Bipolar Patients?
Bipolar patients treated with acetylsalicylic acid (aspirin) in conjunction with lithium prophylaxis needed fewer other adjunctive treatments, compared to patients treated with lithium alone, reports Stanley Rapoport of the National Institutes of Health. These retrospective epidemiological data are of considerable interest in relationship to evidence of an inflammatory component in the affective disorders, as reviewed in Vol. 13(2), 2009 of the BNN, but because the data is preliminary, more study is required.
EDITOR’S NOTE: Several measures of inflammation are higher in children and adults with bipolar disorder compared with controls. These include the ratio of inflammatory to anti-inflammatory cytokines, higher levels of TNF-alpha, and the inflammatory marker c-reactive protein. These peripheral markers measured in blood have been confirmed with direct measurements in postmortem brain autopsy specimens of people who had a history of bipolar disorder.
It is unclear how this information about inflammation in bipolar disorder may eventually inform treatment. In past BNNs, we have noted the positive effects of the anti-inflammatory antibiotic minocycline on schizophrenia, and stressed the need for studies of this compound in bipolar disorder. TNF-alpha inhibitors have also been associated with improvement in depression when used in the treatment of patients with rheumatoid arthritis and other autoimmune disorders.
rTMS Effective in Major Depression
Mark George from the Medical University of South Carolina presented a sham-controlled, multi-site, randomized trial of repeated transcranial magnetic stimulation (rTMS) in 199 antidepressant-free patients with unipolar non-psychotic major depression. The rTMS was delivered to the left prefrontal cortex for 37.5 minutes at 120% of motor threshold (MT), with a 10 Hz, four-second train duration and 26-second inter-train interval, yielding 3000 pulses/session, with a figure-of-eight solid core coil. Compared with the sham treatment (which plays the same role a placebo would in a drug trial), active rTMS had a significant effect (p = .015), with 14% of patients remitting on the treatment compared with 5% on the sham procedure. Thus, the odds of attaining remission (the primary outcome measure) were several times greater with active rTMS than sham.
The number needed to treat (NNT), a measure of the number of patients who would need to be treated with active rTMS in order to get one more responder compared to the number of responders seen on sham rTMS (the smaller the number, the more effective the treatment) was 12. However, as in other previous studies, most of the remitters had prior low antidepressant-rated degrees of treatment resistance. When the blind study was complete and patients were openly given rTMS treatments (a practice known as open label extension), approximately 30% of the patients from each condition were able to achieve remission.
EDITOR’S NOTE: This large study, sponsored by NIMH rather than the pharmaceutical industry, confirms previous industry-related findings that active rTMS is more effective than sham in the treatment of major depressive disorder. These data also conform to recent meta-analyses of many smaller studies indicating that high intensity rTMS treatment is clinically effective for major depression. In prior rTMS studies, those with bipolar depression appeared to respond at about the same rate as those with unipolar illness, suggesting the possibility that these findings might also generalize to those with bipolar disorder, although this remains to be studied more systematically.
This study showed that patients with greater degrees of initial treatment resistance had less optimal outcomes to active rTMS. Some studies also show that electro-convulsive therapy (ECT) decreases in effectiveness in those with greater degrees of treatment-resistance. Response rates to ECT are approximately 40-50% in those with high degrees of treatment-resistance compared with 60-80% in those without. The rTMS data suggest that the treatment as studied may be a useful alternative to antidepressants for some patients with major depression, but it may not be an optimal approach for those with the highest degrees of treatment resistance. Further studies are warranted in patients with high treatment resistance in order to define optimal stimulation parameters that may be more successful for them.
Aripiprazole (Abilify) Now FDA-Approved to Decrease Irritability in Children with Autism
In a recent study, children 6-12 years old with autism were treated with aripiprazole and showed improvement in irritability. The study lasted 52 weeks and had an open-label flexible-dose design (ranging from 2-15 mg/day) with an average dose of 9.6 mg/day. Few discontinuations occurred due to adverse effects, suggesting that aripiprazole is generally safe for use in this patient cohort. Increase in weight gain was the reason seven subjects (2%) discontinued the drug, although weight gain appeared to plateau with continued treatment.
Aripiprazole is already FDA-approved for the treatment and prevention of mania in adults and children (10-17 years). It is also approved as an adjunct (add-on) to poorly effective antidepressants in adults with unipolar (non-psychotic) major depression.
EDITOR’S NOTE: The general safety and tolerability of aripiprazole for the treatment of irritability in children with autistic disorder in this study means the drug can be added to the list of potential treatments for patients with autism. Previously, only risperidone had shown strong placebo-controlled data for efficacy in autism. A study by Hollander published in Neuropsychopharmacology this year indicated that valproate was also significantly better than placebo in treating irritability in children with autism spectrum disorders.
A Positive Placebo-Controlled Trial of Valproate (Depakote) in Autism
A recent issue of the Journal of Neuropsychopharmacology reported that a placebo-controlled trial of valproate (Depakote) showed the drug is effective in treating irritability in those with autism. Approximately 50% of the participants were less irritable on valproate compared with only about 15% on placebo. Valproate was also generally well-tolerated.
EDITOR’S NOTE: This is a particularly important finding, both for clinical treatment and for its potential theoretical implications. Valproate, in addition to its properties as a mood-stabilizing anticonvulsant that increases brain GABA levels and exerts a variety of other neurobiological effects, is also a histone deacetylase inhibitor.
Anticonvulsant Zonisamide (Zonegran) May Treat Alcohol Abuse
Albert Arias and collaborators from the University of Connecticut Health Center presented a study of zonisamide in which the drug provided significant benefits over placebo in patients with primary alcoholism (i.e., not with comorbid bipolar illness). Treatments began at 100 mg/day and increased to a maximum of 500 mg/day.
EDITOR’S NOTE: If replicated, this study would place zonisamide in a category with topiramate (Topamax), which has also been shown to decrease alcohol intake and craving. Both drugs also share the ability to cause minor weight loss as a potentially positive side effect, and both drugs have also proven effective in double-blind studies in the treatment of bulimia.
However, four double-blind, placebo-controlled studies found that topiramate did not have acute antimanic efficacy. Zonisamide has not been studied in a systematic fashion, but open studies suggest its potential utility in mania and, to a lesser degree, in depression.
Since zonisamide may have positive effects on mood in patients with bipolar disorder, and there is now placebo-controlled documentation of its efficacy in primary alcohol abuse disorders, its ultimate potential utility in patients with bipolar disorder and comorbid alcoholism deserves consideration.
Welcome to the new BNN site!
We just launched this new site to keep you informed about the latest bipolar research and treatment. We apologize for our BNN archives being temporarily unavailable during the site re-design. They are back now!
We also have restored the NIMH-LCM life charts for adults and children, which you can download to chart your moods and medications in order to evaluate how treatment is going.
Keep checking back for more features and articles about the latest research!
