Archive for the ‘Bipolar Disorders’ Category

Antiepileptic medications have been a mainstay in the treatment of bipolar illness since the use of valproate in the 1980′s. Since that time other anticonvulsants such as carbamazepine, lamotrigine, and oxcarbazepine have been added to the list that help control the mood fluctuations that occur in bipolar disorder. In January 2008, the FDA issued an alert about patients being treated with antiepileptics:

In the FDA’s analysis, patients receiving antiepileptic drugs had approximately twice the risk of suicidal behavior or ideation (0.43%) compared to patients receiving placebo (0.22%).  The increased risk of suicidal behavior and suicidal ideation was observed as early as one week after starting the antiepileptic drug and continued through 24 weeks. The results were generally consistent among the eleven drugs.  Patients who were treated for epilepsy, psychiatric disorders, and other conditions were all at increased risk for suicidality when compared to placebo, and there did not appear to be a specific demographic subgroup of patients to which the increased risk could be attributed. The relative risk for suicidality was higher in the patients with epilepsy compared to patients who were given one of the drugs in the class for psychiatric or other conditions.

The following is a list of antiepileptic drugs included in the analyses:

• Carbamazepine (marketed as Carbatrol, Equetro, Tegretol, Tegretol XR)
• Felbamate (marketed as Felbatol)
• Gabapentin (marketed as Neurontin)
• Lamotrigine (marketed as Lamictal)
• Levetiracetam (marketed as Keppra)
• Oxcarbazepine (marketed as Trileptal)
• Pregabalin (marketed as Lyrica)
• Tiagabine (marketed as Gabitril)
• Topiramate (marketed as Topamax)
• Valproate (marketed as Depakote, Depakote ER, Depakene, Depacon)
• Zonisamide (marketed as Zonegran)

How did the FDA arrive at this conclusion?

According to their documents, the FDA began receiving reports of the increased risk of suicidality with the anticonvulsants and did a preliminary review that confirmed the possibility. So in 2005, the FDA began analyzing 199 placebo controlled trials of eleven different antiepileptic drugs. The conditions studied in these clinical trials included epilepsy, selected psychiatric illnesses, and other indications, including migraine and neuropathic pain syndromes.  The analysis included 27,863 patients in drug treatment groups and 16,029 patients in placebo groups.  Patients included in the analysis were five years of age or older.  There were 4 completed suicides among patients in drug treatment groups and none among the patients in placebo groups.  There were also 105 reports of suicidal symptoms in the drug treatment groups in comparison to 35 reports of suicidal symptoms in the placebo group.

Overall, 0.43% of the patients in drug treatment groups experienced suicidal behavior or ideation versus 0.22% of the patients in placebo groups, corresponding to an estimated 2.1 per 1000 (95% CI: 0.7, 4.2) more patients in the drug treatment groups who experienced suicidal behavior or ideation than in the placebo treatment groups.  In comparison, the overall suicide risk in a treated bipolar population was found to be 3.66% in the STEP-BD study (Marangell, et al. Prospective Predictors of Suicide and Suicide Attempts, Bipolar Disorders 2006, 8: 566-575). In this analysis, the relative risk for suicidal thoughts or behavior was higher for patients with epilepsy compared to those patients with psychiatric or other disorders.  The higher risk for suicidal behavior or suicidal ideation was observed at one week after starting a drug and continued to at least 24 weeks.  The results were generally consistent among the drugs and were seen in all demographic subgroups. Specifically, there was no clear pattern of risk across age groups. (For more information please go to: http://www.fda.gov/cder/drug/InfoSheets/HCP/antiepilepticsHCP.htm)

The Response

The FDA has placed a warning label on all antiepileptic drugs reflecting this increase risk of suicide, but it did not attach the dreaded black box warning. Since then, numerous groups have weighed in on the FDA’s findings. At a December 2008 meeting of the American Epilepsy Society, two researchers presented evidence that the findings are inconsistent and vary greatly by drug, region, and illness. Still other experts felt that this warning will do more harm than good and that it is too early to make such a broad statement without further research to substantiate the FDA’s claims. A noted psychiatrist, Dr. David Kahn of Columbia University, weighed in by commenting that the risk of suicide in bipolar disorder is far higher in an untreated patient than a treated one, and that both doctor and patient should be aware of the risk of suicidality in bipolar disorder.

What should you take from all of this?

It appears that antiepileptic drugs roughly double the risk of suicidality as compared with placebo. However, the absolute risks are small, and the effect appears more likely in patients treated for epilepsy than for patients with psychiatric illness (although the FDA has yet to publish all the data required to compare these two populations). In our daily practice, we as psychiatrists are always closely monitoring patients for any evidence of suicidality, so any signs and symptoms should be detected early and carefully evaluated. If it appears a medication is contributing to the increased suicidality, it should be discontinued. With this close monitoring of a given patient’s mood state and the small absolute risks found in the FDA’s analysis, we believe the risk associated with prescribing anticonvulsants in bipolar illness is extremely small. That being said, these findings should be discussed with any patient prior to initiating treatment with an antiepileptic medication, and more research is needed to understand the possible link between suicidality and antiepileptics.

Francis Mondimore, M.D. 1999.
Easy-to-understand primer with a nice, basic explanation of normal vs. abnormal mood states and subsequent overview of mania, depression, hypomania and bipolar subtypes. Goes on to review basic pharmacologic and psychotherapeutic treatments although it is now, somewhat dated on both. A good first read.

The Background

The second generation of antipsychotic medications was launched by the arrival of clozapine in1990. Subsequent pharmacologic development produced a handful of similar follow-ups including risperidone, olanzapine, zispradone, aripiprazole and quetiapine. Their novel mechanism of action (increased antagonism at certain dopamine and serotonin receptors) combined with their reduction of certain side effects (movement disorders, especially tardive dyskinesia and hyperprolactinemia) gave these new agents a sense of promise and potential advantage. Later findings that several of these new atypicals might be specifically effective in mood disorders, particularly bipolar states, made their glow even stronger.

The bloom is now off the rose. The first corrective was the uncovering of metabolic problems associated with the use of these second generation antipsychotics. We now know that, as a whole, this group of medications can produce weight gain, increased cholesterol and triglycerides, raised blood sugar and associated diabetes. While these effects vary by particular medication and dose, the idea of a newer, cleaner class of antipsychotics without the burden of troublesome side-effects is no longer tenable.

The Story

It is with additional disappointment then that we report on the article by Ray et al in the January 15^th (2009) issue of the New England Journal Medicine. In a large, retrospective study of Tennessee Medicaid enrollees, the authors compared the rates of sudden cardiac death (SCD) in three groups: those using conventional antipsychotics, those using atypicals and those using neither. They found significantly increased rates of SCD in those groups using either conventional or atypical antipsychotics relative to non-drug-using controls who were matched (in a questionable and novel manner) on a variety of sociodemographic and illness-related variables. (The validity of the matching method is critical to enable genuine drug-related differences to be discerned from patient variables that might predispose to increased rates of cardiovascular mortality, such as tobacco use, obesity or poverty which are all found in higher frequency in patients with persistent, severe mental illness).

More surprisingly, the rates of SCD were essentially similar in those patients using the conventional and the atypical drugs. So, not only were the 2^nd generation agents found to be associated with increased rates of SCD, they did so to a degree comparable to that found with the older, conventional drugs.

Last, the increased risk was found to be dose-dependent with low doses (eg, less than or equal to 75mg/day of quetiapine, or 2 mg/day or risperidone or 7.5 mg/day of aripiprazole) conferring a incidence rate ratio of 1.6, relative to non-users. This incidence rate ratio increased to 2.86 for patients on high doses, which were defined as 3x or more than the maximum lower doses just specified.

Now, what do these numbers mean in real terms? The Ray study found a rate of SCD in the general population of 143 per 100,000 patient years or 0.0014 per year per single person. This rate increased two to three-fold, with higher doses of medication, to between 0.0029 to 0.0033% per year for a given individual. So, if you were to take an atypical medication for a year, you would have a risk of SCD of between 2 to 3.3 per thousand.

Our Reactions

As usual, we are now left trying to give the appropriate interpretation and attention to these new data. Specifically, to what degree should this new information alter our existing clinical practice? After getting over the initial shock and alarm, we have several reactions and suggestions.

First, though the data is worrisome, this is hardly the last word to be written on atypicals and cardiovascular risk. An earlier study by Liperoti in the 2005 Archives of Internal Medicine found no increased risk of ventricular arrhythmias or cardiac arrest in a case-controlled study of nursing home residents taking atypical antipsychotics (they did, however, confirm an approximately two-fold higher rate of risk in those residents taking first-generation medications). We expect that future studies will refine the emerging picture of risk associated with this class of medications.

Second, if the association between atypicals and SCD is replicated and found to hold water, it does not portend the immediate elimination of this class of medications. Even if this risk is verified, the absolute numbers involved are small enough that judicious use with appropriate cautions will enable ongoing use in those patients where the potential benefits outweigh the associated potential for harm.

A third is to sensitize us to predisposing clinical factors that increase cardiovascular risk in our patients and, thus, make them even greater targets for any rhythm-disrupting properties of antipsychotics. A partial list of such factors includes female sex, older age, the presence of dementia, pre-existing cardiovascular disease, a personal history of syncope, a family history of sudden cardiac death before the age of 40, electrolyte abnormalities, and the use of other drugs which can effect cardiac conduction such as stimulants and tricyclic antidepressants. See Zarate and Patel (Archives of General Psychiatry, 2001, 58, pp 1168-1171) and Abdelmalwa and Mitchell (Advances in Psychiatric Treatment 2006, 12(1), pp 35-44) for thorough reviews of this topic.

The Controversy

Having said all this, the bottom-line question remains: Will we now conduct ourselves differently with this new information? This topic has been the subject of several controversial and conflicting commentaries, each weighing in on the Ray et al study. The accompanying editorial in the New England Journal of Medicine advocated for reduced usage in vulnerable populations (the young and the elderly) and EKG monitoring both before and during treatment with these medications. The Carlat Report (www.thecarlatreport.com, a fantastic source of impartial information on psychiatric research) takes a roughly similar stand. An APA report prepared by Lieberman, Merrill and Parameswaran (www.omh.state.ny.us/omhweb/advisories/adult_antipsychotic_use_attachement.html) takes a stance that is more critical and questioning of the original study and argues that routine EKG monitoring may be premature. We refer readers to these commentaries to obtain a more direct picture of this debate.

Conclusion

Whether EKG monitoring becomes a standard of care or not, I am certainly more cognizant and aggressive in my screening for cardiovascular risk factors in patients in whom I am starting or continuing on antipsychotic medications. The Lieberman et al and NEJM editorial both provide guidelines for assessing risk and managing EKG readings (see also, Abdelmalwa and Mitchell, Advances in Psychiatric Treatment, 2006, 12, pp100-109, for a comprehensive review of monitoring and prevention recommendations).

Given the uncertainty of these findings and the relative ease of getting an EKG, I am trending towards routine monitoring.

How does the Ray et al study affect the status of atypicals? Were the promised benefits and claims of greater safety illusory? The answer, I think, pertains both to this class of medication specifically and to the larger issue of drug development and marketing. Because of the phenomenal costs involved in bringing a psychotropic to market, pharmaceutical companies promote new drug launches with marketing and supporting research designed to maximize usage. This is especially true in the post-approval phase. To a certain extent, we all greet new treatment developments with hope and anticipation. When exaggerated, this optimism can become excessive, leading to the type of irrational exuberance seen in the stock market rise prior to last year. When this type of exuberance takes hold and critical analysis is put aside, this almost ensures a subsequent market correction which will bring a product or a stock back to a more realistic place.

The recent studies about the metabolic and cardiac toxicities of 2^nd generation antipsychotics are simply bringing these new medications back to the type of more realistic valuation they should have had and maintained from the start. Atypicals will need to take their place with all other psychotropic medications as drugs with distinct risks and potential efficacies. True progress will have been made if, in the future, we are a little more circumspect about the next class of agents that comes our way.

The search for effective treatments for bipolar depression is fully underway. Driven by epidemiologic prevalence, clinical need and financial profit, academic researchers and Pharma are both developing anda testing new compounds at a furious pace. Modafinil (Provigil) is a recent entrant into this mad race. Approved by the FDA for use in Excessive Daytime Sleepiness (EDS) associated with Narcolepsy, Sleep Apnea and Shift Work Sleep disorder, studies over the past five years have assessed the potential of this new drug in treating conditions that range from ADHD, Cocaine Dependence and Mood Disorders.

Modafinil is usually described as a novel compound that affects a variety of neurotransmitter systems in the brain. The purported novelty of this compound is intended to distinguish it from traditional stimulants, such as amphetamine, with which it shares numerous properties. Articles from the past two years though have more carefully examined the mechanism of action of modafinil and found that it appears to facilitate the release of dopamine and act through dopaminergic receptors in a similar fashion to traditional stimulants. A 2007 study from the European Journal of Pharmacology described it as a psychostimulant that is pharmacologically similar to, but much less potent and efficacious than, amphetamine (Dopheide, MM., et al).

Given this profile, it is no wonder that the antidepressant potential of this compound would attract interest. There is a long history of stimulant trials in the treatment of depression.

There are several, mainly indirect, lines of evidence that suggest that modafinil might be of value in the treatment of bipolar depression. First, as an agent with demonstrated wakefulness-promoting activity (it keeps people awake), it makes sense to think that it might benefit the anergia and hypersomnia that so often characterize the depressed phase of this illness. To date, the evidence on this point is mixed and limited. When used in unipolar depression in patients who had only partially responded to SSRI’s and had residual symptoms of depression, fatigue and tiredness one placebo-controlled, double-blind study showed a statistically significant advantage (Fava M, et al., 2005), another study of similar design failed to show any difference between modafinil and placebo (Dunlop, BW, et al., 2007). A third open-label trial by Ninan and colleagues in 2004 showed significant benefit. Notably, these studies focused on modafinil’s effect on residual fatigue and tiredness. To what extent modafinil would be active against other, core features of depression (feelings of guilt, disturbed sleep and eating, hopelessness) is unknown.

A second, indirect line of evidence bearing on this drug’s potential in bipolar depression is a single study of modafinil monotherapy for atypical depression (a syndrome that shares many symptoms with bipolar depression.) Structured somewhat unusually, patients were first treated in an open-label fashion and then randomized to either placebo or active drug for continuation treatment. Relative advantage for the drug was found in the open-label but not the continuation phase of this study. Not definitive but intriguing.

Last is the single and only direct study of modafinil in bipolar depression. Done by Mark Frye and colleagues at UCLA and published in the American Journal of Psychiatry in 2007, this research tested modafinil augmentation in 85 patients with bipolar depression who were inadequately responsive to a mood stabilizer with or without an antidepressant. Performed over 6 weeks, this placebo-controlled, double-blind study showed a rapid, significant and sustained advantage of modafinil on depressive symptoms. So what conclusions can be drawn on the overall efficacy of modafinil for bipolar depression at this time?

First, with the exception of the one well-controlled study by Frye on patients with bipolar depression, most of the evidence to date comes from open-label, non-blinded studies, often addressing other forms of depression. Second, all of the research has evaluated short-term efficacy; whether longer-term and prophylactic benefit will be demonstrated is anybody’s guess. Third, while modafinil was not associated with any serious side-effects, including hypomanic/manic switching, its long-term safety profile requires documentation. Last, under closer inspection, modafinil appears to have considerable similarity to traditional stimulants. An article by P.J. Carlson in 2004 in the journal Bipolar Disorders showed that methylphenidate (Ritalin) and amphetamine (Adderall or Desoxsyn) effectively treated residual symptoms of depression and fatigue in patients with bipolar depression. How this new drug compares to stimulants and other antidepressant and mood stabilizing drugs used in bipolar depression is unknown. The answers to these questions will help determine whether modafinil represents a truly novel agent with a distinctive mechanism of action or is simply old wine in a new bottle. In the meantime, I’ll use it sparingly and give some reconsideration to old-fashioned stimulants.

The use of antipsychotic medications in the treatment of bipolar disorder is hardly new.

The effectiveness of the original, first generation antipsychotic agents was obvious from the start. They reduced the excitement, agitation, psychosis and other symptoms of the manic syndrome. And this made sense. Drugs defined as neuroleptics should produce an acute calming action. Recent pharmaceutical developments and new research has complicated this early, simple state of affairs and forced a reevaluation of the role of this class of medications in the treatment of manic-depressive illness.

Starting with clozapine (Clozaril) in the late 1980′s and followed by a series of pharmacological cousins such as risperidone (Risperdal), ziprasidone (Geodon), quetiapine (Seroquel) and aripiprazole (Abilify), second generation of antipsychotic agents have shown effectiveness against an increased range of symptomatology. While both the old and new agents were equally active in treating the positive symptoms of schizophrenia (such as hallucinations, delusions and formal thought disorder), the new medications were found to be significantly superior in reducing the disabling negative or deficit symptoms of apathy, amotivation and blunted affect. In addition, the frequency of certain side-effects was dramatically lower with this second generation class. The distinct mechanism of action responsible for their enhanced therapeutic scope combined with this reduced side-effect profile resulted in our designation of them as atypical.

Starting with the recognition of their action on the negative/deficit (they are similar but not synonymous) syndrome of psychotic disorders, research has been exploring the boundaries of effectiveness of these second generation agents. Initial case reports described an enhancement of antidepressant action in treatment-resistant depression. This was followed by exploration of their potential as monotherapy for depression.

This trend has culminated in a handful of recent articles assessing the role of atypical agents in the acute treatment of bipolar depression. Of these, there are two recent studies examining the effectiveness of one particular drug, quetiapine, that were well-controlled and generated impressive findings. I’ll briefly review these studies, their findings and the implications they have for clinical practice. Before doing so, it will be worthwhile to mention several facts about bipolar depression that provide context for any new research in this area.

First, bipolar depression is common and disabling. Depressive symptoms far outweigh manic symptoms in the overall course of both Bipolar I and Bipolar II subtypes (BP II much more so than BPI).

Second, depressive symptoms often fail to respond to treatment with mood stabilizers alone. Residual problems with energy, amotivation, hypersomnia and cognitive impairment are all too common.

Third, there is significant scientific controversy about the role of antidepressants in the treatment of bipolar depression. The controversy involves questions of efficacy and questions of potential side-effects. A recent article by Sachs in the New England Journal of Medicine (2007) demonstrated no significant benefit in duration of or recovery from bipolar depression when antidepressants were added to mood stabilizers compared to mood stabilizer monotherapy. Other articles document increased recovery rates with antidepressants and increased rates of relapse when antidepressants are withdrawn.

Adding to this complexity, there is an even greater controversy about whether antidepressants aggravate the course of bipolar illness, either by precipitating mania/hypomanic or mixed episodes and/or inducing mood cycling. Here, too, camps exist within the psychiatric field with one highlighting the dangers of antidepressant use and the other emphasizing the frequent benefit of these drugs.

From this inventory, the qualities of an ideal agent for the acute treatment of bipolar depression begin to emerge. It would act quickly, within several days. It would have strong, phase-specific activity. It would not aggravate the overall course of illness and would not precipitate manic or hypomanic episodes. Its acute antidepressant action would be complemented by an ability to prevent future episodes of depression. And last, it would treat and prevent manic and hypomanic symptoms and episodes. A tall order.

The two recent studies on quetiapine should be evaluated against this backdrop.

Known as BOLDER I and II (for BipOLar DEpRession), the two studies employed identical designs using double blind, randomized assignment and placebo controls to ensure maximum objectivity. The first publication came out in 2005, the replication study appeared the following year. The sample cohort was large, over 500 patients per study, consisting of both Bipolar I and Bipolar II patients experiencing a current depressive episode. After a washout period to eliminate any prior psychoactive medication, patients were randomized to receive either placebo, 300 or 600 mg/day of quetiapine. Over the next 8 weeks, subject’s moods were assessed with standard rating instruments. The findings were dramatic and consistent between both studies.

A broad and rapid antidepressant response, that was significantly greater than that found with placebo, was evident from the first week onward. Whether measured by response (usually defined as a 50% reduction in preexisting depression score) or the more complete elimination of symptoms seen in a remission, both doses of quetiapine outperformed the inactive comparator. In the first report, the two drug doses yielded virtually identical results. In the second, the lower dose produced a non-significantly greater effect size (a measure of effectiveness) than the larger dose.

One last point. There was no exacerbation of disease course with quetiapine: no induction of mania, hypomania, or mixed episodes nor any worsening of cycle frequency compared to placebo.

So, where do these results leave us? Should quetiapine be considered a first line drug for the acute treatment of bipolar depression? My answer: it’s getting close. Perhaps even very close. This position reflects a significant change in my viewpoint. Several years ago, I would have scoffed at the idea that atypical antipsychotics might have specific, as opposed to a more general, tranquilizing effect on the depressive symptoms of bipolar conditions. Similar to most of my colleagues, I viewed the use of these medications as a somewhat messy, nonspecific, symptomatic treatment reserved for manic and mixed syndromes. As good science should, these studies force a reconsideration of practice patterns and clinical outlook. So, having my mind pried open, does quetiapine meet the criteria for the ideal drug in this condition? Some remaining questions and concerns follow.

First, questions about the study methodology. This was a drug-washout design in which patients with bipolar depression, not responsive to their current regimen of medication, were taken off all psychoactive medication over a one to four week period. They were then randomized to placebo or quetiapine. The ensuing treatment arms thus examined not just the treatment of bipolar depression but also the presence of potentially confounding discontinuation of prior mood stabilizing medication. What effect does this twist have on the outcome and interpretation of the studies? Not clear. How much of the noted improvement was related to amelioration of any discontinuation effects vs. resolution of the depressive syndrome per se? A study using a drug augmentation format could provide reinforcement for, and clarification of these initial results. Such a design would add quetiapine or placebo to the ongoing drug regimens of patients experiencing a bipolar depressive episode. Tohen and colleagues have conducted such studies examining the benefit of the atypical antipsychotic, olanzapine (Zyprexa), when used alone or in conjunction with fluoxetine (Prozac) in the treatment of bipolar depressions and found significantly improved outcomes with combination vs monotherapy.

Two other significant reservations exist. First, the BOLDER studies extended over an 8 week period. Hence, they have demonstrated acute antidepressant effectiveness of quetiapine only. Whether quetiapine will be shown active in longer term maintenance or prophylaxis/prevention formats is unknown.

Second, like other atypical antipsychotics, quetiapine has it’s share of side-effects ranging from acute sedative and cognitive reactions to more serious, longer term metabolic changes in weight, lipid and glucose regulation.

The above reservations notwithstanding, and taking into account the current status of bipolar depression and the available options for its treatment, the acute antidepressant potential of quetiapine is looking quite strong.

Epidemiological and observational studies have suggested that consumption of fish and omega-3 fatty acids has a protective role against several illnesses, including depression. Some clinical data support the hypothesis that omega-3 fatty acids are a potential treatment option for mood disorders. Cold-water fish, including cod, salmon, and mackerel, contain the essential omega-3 fatty acids Eicosapentaenoic Acid (EPA) and Docosahexaenoic Acid (DHA). Flaxseed, canola oil, and walnuts are also potential dietary sources of these omega-3 fatty acids. Dietary supplements containing fish oil are also widely available. Omega-3 fatty acids help regulate everyday cellular functions in the body that are necessary for good health. DHA is important as a major structural component of cell membranes, while EPA is thought to play an important role in neuronal signal transduction. DHA and EPA are not produced in the body and people can only get these fatty acids through their diet or from nutritional supplements. Published studies indicate that EPA has some efficacy as an adjunct treatment for mood disorders, particularly for the control of symptoms of depression. However, large-scale, randomized clinical trials are lacking. Several recent review articles and meta-analyses agree that adjunctive treatment with omega-3 fatty acids carries a low risk of side effects and has a beneficial effect on physical health. However, the efficacy on treating mood disorders is not conclusive. Two clinical trials showed positive outcomes as adjunct treatment for patients with depression that had been refractory to treatment. One study showed longer duration in remission in patients with bipolar disorder. Whether omega-3 fatty acid will prove more useful for acute, long-term or prophylactic purposes has yet to be determined. The mechanism by which omega-3 fatty acids can exert a positive effect on mental health is unknown. Hypotheses include an anti-inflammation effect, by enhancing cell membrane integrity, or by altering signal transduction in nerve cells. The dosage of omega-3 fatty acids used in clinical trials varied widely, from 1 gram to 9.6 grams combined EPA and DHA daily. These studies show that omega-3 fatty acid supplements are generally well-tolerated even at higher doses without significant adverse effects. Trials using pure DHA or EPA alone produced conflicting results. One study, using pure DHA (2 grams daily) alone, produced no effect. Another study suggested that 1 to 2 grams daily of EPA was equally effective as higher dosages. The optimal doses of EPA and DHA have not yet been determined through clinical trials. Although omega-3 fatty acids are generally well-tolerated, they do have potential side-effects. Omega-3 fatty acids exert a dose-related effect on bleeding time, which may cause a risk of bleeding. Other potential side effects of omega-3 fatty acids include a fishy aftertaste and gastrointestinal disturbances, all of which appear to be mild and dose-dependent. Some fish contain high levels of heavy metals such as mercury, nickel, lead and other toxins when not processed properly. The FDA and the U.S. Environmental Protection Agency (EPA) have issued statements advising women who may become pregnant, women who are pregnant, breastfeeding mothers, and young children to avoid eating some types of fish. However, fish oil supplements satisfy safety standards for potential contaminants, e.g., heavy metals or other toxins. The United States Food and Drug Administration (FDA) recommends consumption of 3 grams of EPA and DHA omega-3 fatty acids each day, with no more than 2 grams per day coming from dietary supplements. Thus, a daily dosage of 1 to 2 grams EPA is considered safe and possibly beneficial as an adjunct treatment in mood disorders, particular in unipolar or bipolar depression. As with any treatment, this therapy should be monitored by a physician. Many products are available over-the-counter or from the internet in a wide range of prices, from as low as 10 dollars to 50 dollars a bottle, usually for a one-month supply. Variation in prices is mainly due to differences in the distillation process (concentration, purity), higher ratio EPA/DHA (from 1.5:1 to 7:1), and efforts to reduce oxidation (adding small amount of Vitamin E, packaging in an oxygen free environment). Three grades exist: health food grade, pharmaceutical grade, and International Fish Oils Standard (IFOS). The products with 5-star IFOS ratings are the most expensive. However, no existing data suggest that differences in grade correspond to differences in efficacy. In general, people should choose a product from a known or reputable source, such as a trusted brand, with at least 60% combined EPA and DHA per capsule. Capsules with an added antioxidant to reduce lipid peroxidation are recommended. Besides being active oxidation products, peroxidation leads to a fishy after taste, a side effect which becomes particularly intolerable for some people. Side Effects.

Potential Risks

- May cause prolonged bleeding time and increased bleeding risk especially in patients on anticoagulation therapy, use of NSAID; possibility of increase the risk of GI bleeding when used in combination with SSRI’s.

- Oxidation of omega-3 FA forming biologically active oxidation products.

- Possible alters glucose metabolism in diabetics, requires close monitoring and possible adjusting diabetic medications.

· One case report of hypomania associated with omega-3 fatty acid. B. Question of Heavy Metals and Contaminants

· Accumulation of traces of heavy metals (mercury, head, nickel, arsenic and cadmium) and other contaminants (PCBs) in the food chains; potentially might be found in less-refined fish oil supplement.

·  From www.consumerlab.com, an independent test in 2006 of fish oils on the US market found that all of the products satisfy safety standards for potential contaminants.

· IFOS, International Fish Oils Standard, the most stringent current standard fish oils that are molecularly distilled under vacuum, virtually no measurable level of contaminants could be found. C. Other Considerations

· Some patients unable to tolerate fishy aftertaste.

· Not acceptable to people who follow vegetarian diet (unfortunately, omega-3 fatty acids from vegetable source convert inefficiently, about 5 to 15%, to EPA and DHA).

A press release in January 2007 generated excitement among

Chicago researchers and clinicians studying and treating bipolar disorder.

Dr. Alan Kozikowski and his group in the Department of Medicinal Chemistry and Pharmacognosy at the University of Illinois in Chicago were awarded a three-year, $2.1 million grant from the National Institute of Mental Health (NIMH). The grant was awarded for research toward the development a new drug, a safe and selective glycogen synthase kinase-3 (GSK-3) inhibitor, to treat bipolar disorder.

Glycogen synthase kinase was initially identified as a key enzyme involved in glycogen metabolism. Later, GSK was implicated in a variety of cell functions. When GSK-3 is active, it rapidly destroys downstream transcription factors that are essential for cell survival. A survey of current medical literature shows that GSK-3 inhibition is a hot topic in many fields. Investigators are looking into new drugs for treating type II diabetes, cancer, inflammation, and shock.

Interest in GSK-3 in psychiatry started in late 1990′s and early 2000′s. Researchers found that the therapeutic effects of lithium and valproic acid on bipolar disorder were mediated through pathways involving GSK-3. Lithium is identified as a specific inhibitor of GSK-3 beta, among its other functions.

Drs. Husseini Manji and Todd Gould at NIMH are the leading investigators on GSK-3 beta and bipolar disorder. Their work suggests that GSK-3 beta plays an important role in regulating synaptic plasticity, cell survival, and circadian rhythms in the CNS. The neuroprotective effect of inhibiting GSK-3 beta is also being tested for other neurological diseases such as Alzheimer, Parkinson,

Huntington, and stroke.

Dr. Kozikowski and his colleagues, using a mouse model for mania, are testing new chemicals that specifically inhibit GSK-3 beta. By mimicking the therapeutic action of mood stabilizers, designer drugs may be developed for treating patients with bipolar disorder and other neurodegenerative disorders. However, it will take years for a new product to be brought into clinical trials.  Whether newly-developed synthetic agents will have any clinical superiority over lithium and existing mood stabilizers is not known. In the mean time, we are all eagerly anticipating the outcome.