One 8-week study showed possible response based on significant improvement in Montgomery-Asberg Depression Rating Scale scores in patients treated for acute bipolar depression when riluzole was added to other antidepressants.1 However, the small, non-randomized, non-blinded nature of the trial limits the conclusions that can be drawn. Of note, there were no instances of mania or hypomania in this trial, indicating that riluzole may not have the mood destabilizing effects of many other antidepressants. Trials with larger sample sizes would be necessary to confirm this result.

A recent study of 14 patients with bipolar disorder given 100-200 mg of riluzole per day showed a relative decrease in glutamate in the brain, as demonstrated by imaging studies.2 This suggests that imaging may play a role in determining response to therapy if further trials support the existing evidence.

Riluzole is being looked at with equal interest in the treatment of major depressive disorder. Another trial with a similar design that looked at response in treatment-resistant patients with major depression taking other antidepressants found a response in some.3 A third trial with high doses of 150-200 mg/day (ALS dose: 50 mg/day) found that riluzole could be effective—even when given without other antidepressants—over a 6-week period.4 However, as in the other two trials, this study was open-label and included fewer than 20 patients. Two randomized trials to be completed over the course of the next 2 years should provide additional evidence regarding the relative efficacy of riluzole in treating mood disorders.

From a safety perspective, the most pressing concern is that the medication may cause liver damage, especially in those already at risk or those who drink excessive amounts of alcohol. Coffee and other caffeinated drinks may increase the effect of riluzole, and smoking may speed its elimination from the body, making higher doses necessary. Riluzole also has to be taken 1 hour before or 2 hours after food, which may be inconvenient for many patients.

Recommendation: Based on preliminary study data, riluzole is a promising therapy that may provide an alternate treatment for bipolar depression and/or major depressive disorder, pending positive results in larger randomized, double-blind trails.

1. Zarate CA Jr, Quiroz JA, Singh JB, et al. An open-label trial of the glutamate-modulating agent riluzole in combination with lithium for the treatment of bipolar depression. Biol Psychiatry. 2005 Feb 15;57(4):430-432.

2. Brennan BP, Hudson JI, Jensen JE, et al. Rapid enhancement of glutamatergic neurotransmission in bipolar depression following treatment with riluzole. Neuropsychopharmacology. 2010 Feb;35(3):834-846.

3. Sanacora G, Kendell SF, Levin Y, et al. Preliminary evidence of riluzole efficacy in antidepressant-treated patients with residual depressive symptoms. Biol Psychiatry. 2007 Mar 15;61(6):822-825.

4. Zarate CA Jr, Payne JL, Quiroz J, et al. An open-label trial of riluzole in patients with treatment-resistant major depression. Am J Psychiatry. 2004 Jan;161(1):171-174.

While its absolute efficacy has not been proven, one randomized controlled trial showed statistically significant improvement in overall depressive symptoms in bipolar patients on long-term therapy with 1g of NAC taken twice daily in a capsule formulation.¹ This is a non-FDA approved version, which is only available as a nutritional supplement. Unlike the liquid and injection available by prescription, only a small percentage of the capsule formulation is active because it is broken down so quickly by the body.²

The study results also have to be interpreted with caution because the trial only involved 75 patients. Another limitation is that the time to next mood episode was the same regardless of whether the patient was taking NAC or placebo. On the positive side, the trial took place over a 24-week period and showed moderate improvement in symptoms. Despite the lack of published evidence, some U.S. psychiatrists are finding a useful place for NAC in clinical practice.

Although NAC is typically described as well tolerated, the side effects may be appreciable. Nausea, abdominal pain, vomiting, constipation, and diarrhea are common with oral treatment.

Recommendation: Because of its sparse efficacy data and at times noxious side effects, this nutritional supplement has a limited place in therapy.

1. Berk M, Copolov DL, Dean O, et al. N-acetyl cysteine for depressive symptoms in bipolar disorder: a double blind randomized placebo-controlled trial. Biol Psychiatry. 2008 Sep 15:64(6):468-475.

2. Sjödin K, Nilsson E, Hallberg A, Tunek A. Metabolism of N-acetyl-L-cysteine: some structural requirements for the deacetylation and consequences for the oral bioavailability. Biochem. Pharmacol. 1989 Nov 15;38(22):3981-3985.

For those of us interested in this area, the source of this rhythm agnosia, apathy and apraxia has been infinitely perplexing. Is it the absence of financial support from Pharma which limits research and clinical work in this area? Is it the absence of insurance reimbursement for therapies that are neither psychotherapeutic nor psychopharmacologic? Is it the lack of cross talk between basic scientists studying human timing and clinicians treating mood disorders? Or is it the lack of sexiness in the ultra low-tech nature of these treatments? Whatever the reason, and I’m sure there are many, this book is an initial attempt to help clinicians in this country understand and better use information about biological rhythms in our clinical work with affective illness.

Having set the stage, my capsule summary: A long-overdue, wonderful first step.

Chronotherapeutics for Affective Disorders is a neat, concise book which provides a very basic review of circadian neurobiology along with a how-to section that explains both the evidence for these treatments and a simple explanation of how they are to be conducted. As per my introduction, it is no surprise that two of the three authors of this little gem are European. Collectively, they represent leaders of the field and they have an unmistakable agenda to promote the use of circadian-modifying interventions.

Chronotherapies (from Greek Mythology, Chronos, for time) are any treatment that manipulates circadian rhythms for symptomatic benefit. While the focus of this book is on their use in the treatment of affective disorders, these strategies are also used for neurologic, sleep, and other conditions. The major forms of chronotherapy used today and the ones with the most empiric validation are sleep deprivation (rechristened Wake Therapy to avoid nasty connotations), light therapy, and sleep phase advance. Each is reviewed in clear and simple language that is enhanced by helpful diagrams and figures. Think Stephen Stahl-type clarity and exposition.

Always starting with the basics, the reader is carried from what is more common knowledge to more rarefied and detailed explanation. For example, information on the use of light therapy for seasonal affective disorder is leavened with practical guidance on what types of light to use, length and timing of administration, potential side-effects and non-seasonal mood indications and contraindications for this treatment. Similarly, though most of us know that keeping our depressed patients up for a full night can effect a rapid but transient remission, this book reviews a substantial body of literature on the use of various augmenting measures (concurrent use of lithium, SSRI antidepressants, sleep phase advance and/or bright light therapy), how these measures cement and preserve the initial antidepressant response, and thus makes the case that these wake therapy packages are some of the fastest, most effective and safest methods currently available. Making their survey complete, the authors include brief sections on dark therapy, melatonin and other chronobiotics, and chronotherapeutic strategies for children and the elderly. An appendix provides valuable diagnostic instruments used to rate and track rhythm-influenced mood disorders and circadian phase status.

Shortcomings? This is a very introductory primer. Those wanting more depth will not be satisfied with this book alone. If this shoe fits you, consider The Principles and Practice of Sleep Medicine, 4^th Edition; the sections on circadian rhythms provide a deeper foundation in the basic sciences.

In sum, this is a small work with a large agenda. It aims to educate mental health clinicians about the basics of circadian timing and how alterations in these intrinsic oscillations can contribute to mood disturbances. It then provides step by step guidance on how to use circadian-modifying strategies to treat depression, mania and mood instability. It’s not easy helping people develop a sense of rhythm. This book provides much-needed and elementary dance lessons for those who haven’t been able to appreciate the beat.

Finally, a book devoted to the other bipolar disorder. Bravo! Gordon Parker, the Australian psychiatrist, researcher and head of the venerable Black Dog Institute in Sydney, deserves credit on this basis alone. But this is far from the only virtue of this monograph. Here we get a rich, quirky wonderful assemblage of opinion from the leading authorities on this prevalent and understudied form of manic depression. The combination of being the first publication out of the gate on this important area together with its quality, diversity and depth make this required reading for all clinicians and those patients and significant others thirsty for knowledge of this bipolar subtype. For this group, here’s the bottom line: Read this book!

First, the layout. Eschewing the standard APA format of blandly compiling the accumulated data in an area and striving for a deadening impartiality, Parker chooses an all together different and creative alternative. Rather than draining the lifeblood out of the subject, he makes room for the full cacophony of opinion, debate, agreement and conflict that constitutes the field of research at this time. He specifically includes authors with differing viewpoints and distinct emphases. Even better, he puts forth his own, unique outlook in living color, warts and all. The result is less a compilation than a real-time, streetfight amongst respected colleagues. very real portrait of how medicine exists and evolves.

The second delightful aspect of the book’s format is who and what Parker has chosen to include. Clinicians and patients are given voice alongside of the more typical research-weighted authorship. Chapters reviewing the data on atypical antipsychotics alternate with vivid, first person accounts of disturbed mood states. Clinical experts are given the chance to present compelling arguments based on their treatment experiences. Models of well-being are described from sufferer, physician and research perspectives. Omega 3 fatty acids receive their fair share of attention. And the psychotherapies get equal billing with other psychoactive interventions. Here again, the result is a blooming circus of opinion stretching out in multiple directions.

The book is divided into two main parts. The first section starts with one of the most vivid first-person accounts of this illness that I have ever read. It is followed by a concise but richly detailed history and evolution of ideas about this disorder and where it fits in relation to other psychopathology. The next twelve chapters present short reviews of various points pertaining to diagnosis and treatment. Clinical expert James Phelps reprises his fascinating argument to reverse the default diagnostic bias of affective disorders, making bipolarity the baseline standard and only identifying unipolar illness in the absence of evidence for cyclicity or mixity. Parker then suggests an isomeric model that differentiates bipolar I from bipolar II exclusively on the basis of psychotic symptoms. The reader then gets the chance to see radically different viewpoints on the role of antidepressants in this mood subtype authored by Parker and Joseph Goldberg. Overall, this first section is well-written and the editing gives it a smooth, coherent feel.

The second section, however, is outstanding. Taking the lead, Parker describes a multidimensional treatment package for bipolar type II that emphasizes antidepressants, psychoeducation and well-being plans. And he’s not just talking SSRI’s for bipolar depression; they’re his first line choice for mood-stabilizing agents as well! With this as the set-up, the next twelve chapters allow the leading experts in the field to wrestle with the editor’s contentions.  Among the best responses are those of Post, Ghaemi, Goldberg and Ketter who emphasize the intrinsic recurrence and mixity of bipolarity and the corresponding indication for mood stabilizers over antidepressants. It is here in the noisy and well-reasoned squabbling that the book’s strengths truly shine. Not content to serve up the standard pablum, Parker forces the reader to weigh alternatives, consider the evidence and decide where they stand.

Kudos to this Aussie who has the wherewithal to show our field in all its messy beauty.

One sentence opinion: A necessary but typically uninspiring review of an important subject.

Is there a need to devote a book specifically to the depressed phase of bipolar disorder? Absolutely. Should it present data from each of the important research areas on this subject? Of course. Does it need to do so in a formulaic and bland fashion? Judging from the products of the major psychiatric publishers, the unfortunate answer appears to be yes. With a few rare exceptions, such as the stellar Manic Depressive Illness by Goodwin and Jamison or A Mood Apart by Peter Whybrow, review books on psychiatric topics are all too often poorly written, uncreative amalgams of multi-authored chapters without a coherent editorial voice or viewpoint. The result is reading that becomes as dutiful as the writing.

Ok. Now that that’s out of my system, let me return to some specifics about this book.

Despite my overall take on this work, several chapters rise above the tepid baseline. Ghaemi’s pleasure in challenging the prevailing nosology of mood disorders in American psychiatry is evident in the introductory chapter. It is fun and informative. Likewise, the sections on suicide, mood stabilizers and antidepressants show similar signs of life while conveying important information.

The rest of the book is a painful slog. Data is presented in dense and rote fashion. Too many of the references are dated, even for the 2006 publication date.

The chapter on neurobiology is the most disappointing. The emphasis is on neurotransmitter studies of bipolar illness, many dating back to the 1970’s. More recent research on 2^nd messenger systems, functional neuroimaging, and kindling are paid token attention in single paragraphs that feel like afterthoughts.

While this book is indeed, so much less than it could have been, it did have one significant stealth asset: at the time of it’s writing, it was the first work published specifically on bipolar depression. Readers interested in this subject are, fortunately, no longer constrained by this former exclusive status.

Frank starts with a review of existing theories and empirically-validated treatments of bipolar disorder, In so doing, both this book and her treatment model include a healthy serving of psychoeducational information about this illness. Given that this is one of the most potent and, perhaps, a common element of all psychotherapies for bipolar conditions, this inclusion makes good sense.

The model of IPSRT is presented next. In formulating this model, Frank essentially connects two different research areas into a single causal pathway of affective relapse: the association of interpersonal conflicts with unipolar depression and the literature emphasizing circadian disruption in affective relapse of bipolar disorder. Rather than viewing these as separate contributory factors, she proposes that changes in social routine lead to altered biological rhythms (especially sleep) which form the final common pathway to the onset of new mood episodes. Using this model of relapse, IPSRT intervenes both at the level of social discord and circadian disruption to stabilize disordered rhythms.

The remainder of the book details these two fundamental components of IPSRT.

Beginning with a history-taking that seeks to demonstrate the relationship between social and biological rhythm havoc and episode onset, Frank walks the reader through the treatment process and its different modules. The IP component identifies and then addresses the most salient relationship problems the individual is experiencing. The SRT module, however, is what’s new and most interesting here.

Using a standardized tool, the Social Rhythm Metric, patients are asked to note and record the time of a host of daily activities such as sleep onset, awakening, meals, when one leaves home, physical exercise, exposure to sunlight, level of socializing, etc With the initial data as a baseline, therapists and patients work together to increasingly standardize fluctuations in these behavioral indices. Research studies are presented documenting the effectiveness of this approach in reducing relapse in patients with Bipolar Disorder Type I.

This book is readable, engaging and encouraging. The IPSRT model gives patients a new perspective and sense of empowerment in confronting their illness. No longer a disease which strikes randomly and without warning, IPSRT provides patients with a strategy to monitor, anticipate and modify social and biobehavioral rhythms and thereby exert better control over their lives. Not a bad thing.

Postscript: An article from February, 2009, published in the Journal, Bipolar Disorders, by Holly Swartz, Ellen Frank and colleagues at the University of

Pittsburgh, examined the efficacy of IPSRT as a monotherapy for Bipolar II depression. Yes, monotherapy, meaning only IPSRT and no psychoactive medications. Though the study was small, had a high number of drop-outs and no control group, about 40% of the treatment cohort experienced significant improvement.  Is it possible that a subset of bipolar patients can be managed through biologically-stabilizing psychotherapeutic interventions alone??? Stay tuned.

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.

The organization of this text adheres to the same basic layout as the original version.  Chapters are organized sensibly with clinical description and clinical studies preceding and setting the stage for subsequent sections on pathophysiology and treatment. A tribute to its editors, this work does not suffer from the redundancy that is typical of other comprehensive texts.  Summaries of each chapter distill the major points into bite-sized manageable conclusions.  The references are exhaustive and thoroughly up-to-date.

There are, I think, two potential uses for this book.  The easier of the two is as an authoritative reference work.  Used in this fashion, the text provides an accessible place to gain an initial foothold, quickly review a body of literature, or mount a more thorough exploration of virtually any topic in this arena.  When serving this function, the book is a delight:  the right place to go, the best place to start, equally good for both a glancing refresher as an in-depth review.

The second, more challenging role for this work is as an advanced textbook for psychiatrists and psychologists seeking to gain an extensive grounding in the field of recurrent affective disorders.  In this role, both graduate and post-graduate classes could be designed around a complete reading of this book.

The editors strive for an impartial tone in the presentation and summarization of the research findings.  I did not get the sense that they are ideologues nor that they champion certain positions on various controversies in the field.  Their allegiance to disease-specific empiricism (ie, data derived from randomized, controlled trials) is, however, obvious.  This allegiance contributes to an unfortunate constriction in the scope of this work resulting in a failure to include some very relevant psychoanalytic literature on affect and affect regulation, attachment theory and development research on affect.  But perhaps this is too much to expect from any single work.

Concluding summary:  it doesn’t get any better than this.  In terms of modern psychiatric textbooks, this writing sets a new standard for our field.  It will be the new definitive work in this area for years to come.