Responding to the general absence of information for the lay public on the less acute forms of manic depressive illness, this book provides a helpful overview of the symptoms, course and diagnosis of these less well-known bipolar subtypes.  Written in ultra-basic, simple language, by Dr. Jim Phelps, the Corvallis, OR psychiatrist behind the incredibly useful website psycheducation.org, this work is designed to familiarize readers with the characteristics of Bipolar Disorder Type II.  But there is another, larger agenda here:  to present a different diagnostic viewpoint on bipolarity itself, one that emphasizes illness course, and specifically recurrence, as the hallmark of the illness.  This, in contrast to the current American schema, exemplified in DSM IV TR that sees episode polarity, specifically mania/hypomania, as the defining essence of the condition. Dr. Phelps explains in a clear, pain-staking and repetitive fashion the rationale for using recurrence as the defining standard, the implications this has for diagnosis (it vastly broadens the scope of the condition to include all other recurrent mood disorders such as recurrent depression, SAD, PMDD, etc…) and for treatment.  With regard to treatment, Dr. Phelps repeatedly emphasizes the hazards that can occur from both antidepressant monotherapy (using antidepressants alone without a mood stabilizer) and using antidepressants in combination with mood stabilizers.  My only quibble here is that this is presented as fact rather than the actual, active controversy that surrounds this issue today.  In my opinion, we are far from agreement on the appropriate role of antidepressants in the treatment of the bipolar depression.  This aside, Dr. Phelps should be commended for authoring a much-needed and easily understood treatise on the spectrum concept in manic depression.

This book is directed at a lay audience and devotes itself to defining and explaining this most common subtype of bipolar illness. This book is very informative for any patient with bipolar II but also has some serious problems. So, first with the good. Dr. Fieve’s writing is clear and concise, and his patient examples are both interesting and appropriate. He differentiates Bipolar II from Bipolar I quite well and explores all of the aspects of bipolar II. He covers the range from genetics to the critical importance of sleep/biological rhythms to the behavioral disturbances (e.g. substance abuse, hypersexuality) associated with bipolar illness. The second half of the text details the diagnostic and treatment modalities and prepares the patient as to what to expect in that process. Comorbid illnesses, such as ADHD and panic disorder, are also discussed.

My problems with this book come largely from Dr Fieve’s idea that this illness is somehow beneficial to patients. He has even created his own subtype – Bipolar IIB -wherein the “B” stands for beneficial. He makes numerous comments about his patients being the “movers and shakers” in New York City and associates their bipolar II illness with their level of success. I will admit that I have seen some very successful patients in my practice with bipolar II but I believe they succeed despite all of the problems that the illness brings. The second problem occurs in his treatment parameters. He places little importance on psychotherapy and it is depicted as only an adjunct to the appropriate medications. My belief is that the appropriate medications are only the start of treatment, and psychotherapy teaches the patient how to cope with their illness and try to achieve some balance in their life.

I would recommend this book because it is one of the few devoted entirely to Bipolar II, but I have some serious reservations as noted above.

Both literary and scientific, presents info mainly on BPI D/O (but also prodromal and softer forms of illness and their relationship to acute episodes) in accessible form. Beautifully depicts relationship between person’s environment and illness, contextualizes illness in personal history and psychology.

Kay Jamison, 1996.
Mainly biographically based review of the link between artistic genius and creativity and Bipolar Disorder.

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.

Quarterly magazine containing scientific and legislative news and
describing people, both famous and otherwise, with bipolar disorder.
1-866-672-3038 and website: http://www.bphope.com/

by Michael Otto, Noreen Reilly-Harringoton, Robert O. Knauz, Aude Henin, and Jane N. Kogan.  The book  contains information about bipolar disorder and its treatment, and also includes information on managing stress, poor communication, sleep, dysfunctional cognitions, and other psychosocial factors associated with increased risk of relapse. This workbook culminates in a treatment contract that helps patients and their support network identify symptoms and early action strategies for helping manage bipolar disorder; this contract is to be signed in collaboration with the treating clinician.

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.

ADHD is an increasingly recognized disorder and pharmaceutical companies are regularly developing new drugs and new formulations of older drugs in an attempt to gain an increasing share of this lucrative market. Whether the new pharmaceuticals bring actual therapeutic advantage or simply represent new ‘brands’ with similar effectiveness is an ongoing question. Vyvanse (Lisdexamfetamine dimesylate) is the newest arrival on this competitive turf. It was shown to be effective compared to placebo in two clinical trials of children ages 6-12 and in one trial in adults.

Vyvanse is a prodrug formulation of dextroamphetamine. A prodrug is a pharmacological substance (drug) that is administered in an inactive (or significantly less active) form. Once administered, the prodrug is metabolized into an active metabolite. In the case of Vyvanse, this process takes place in the gastrointestinal tract, thus releasing active dextroamphetamine. The active metabolite dextroamphetamine then mediates the therapeutic effect in a fashion similar to other stimulants. Though the mode of therapeutic action in Attention-Deficit/Hyperactivity Disorder (ADHD) is not known, the amphetamines are thought to block the reuptake of norepinephrine and dopamine into the presynaptic neuron and increase the release of these substances in the brain.

Lisdexamfetamine does not produce high dextroamphetamine levels when injected or snorted, and thus may have lower abuse potential compared to conventional stimulants. Vyvanse was developed specifically in this prodrug formulation with the goal of providing an extended duration of effect that is consistent throughout the day, with a reduced potential for abuse, overdose toxicity, and drug tampering. Side effects were consistent with other psychostimulants, and long term monitoring demonstrated no significant changes in blood pressure or electrocardiographic parameters. There have been no comparative studies between Vyvanse and other stimulants, and it’s duration of effectiveness is similar to other long acting stimulant formulations (8-10 hours). The only circumstances that Vyvanse seems to be more useful in treatment over other stimulants are those in which there is a significant abuse potential. With the possibility of this rather slender exception, our verdict on Vyvanse is that it is more of the same: another long-acting stimulant in a field that is growing in size but not diversity. We look forward to different drug development strategies, perhaps those which derive from a more precise molecular genetic understanding of the neurobiology of ADHD, that will one day generate truly novel and improved therapeutic agents for this disorder.