Archive for the ‘Bipolar Disorders and Depression’ Category

Brain Problems in Bipolar Disorder: What We Know and How We Know it, circa 2013.

“Is there something wrong with my brain?”  “Does part of my brain not work correctly?”  Each time we make a diagnosis of bipolar disorder in our practice, these questions inevitably and understandably come up.  People want to know about their illness.   This conversation is often an essential part of the treatment.

In 2012, the journal Bipolar Disorders devoted an entire issue to a review and summary of modern neuroimaging research.  It included articles that presented a model of the signature disturbances found in the bipolar brain1-6.  In this longer-than-average blog piece, we will present these findings.  To make this understandable, we’ll begin with a short introduction about neuroimaging and the concept of functional neuroanatomy.


Over the last 20 years, a new series of neuroimaging techniques has been developed that extended and deepened our appreciation of brain structure and function.  Magnetic resonance imaging (MRI) enabled higher resolution snapshots of smaller brain structures than was possible with older computed tomography (CT) scans.  The advent of functional neuroimaging – with functional MRI, positron emission tomography (PET), and single proton emission computed tomography (SPECT) scans – has allowed us to see which areas of the brain are activated when performing specific mental tasks, such as holding something in memory or looking at an emotionally charged picture.   The new techniques also enable us to look beyond single region assessments.  By comparing co-occurring levels of activation in different brain regions during an emotional or cognitive task, fMRI has been used plot out the functional linkage between these separate regions.  We can see how much two areas work together in performing a particular job, thereby generating maps of functional neural connectivity or circuits.   Diffusion tensor imaging (DTI) complements this by analyzing the integrity of the white matter pathways that connect different brain regions.  The result of these new neuroimaging techniques has been the establishment of an early functional architecture of the human brain.  This architecture transcends the earlier ‘brain region A correlates with mental function B’ approach, replacing it with an appreciation of dynamic neural circuits that travel through and utilize multiple brain areas to support our cognitive and affective needs.   So what has this all got to do with bipolar disorder?

Using these new neuroimaging methods, psychiatric researchers have begun constructing functional models of how the brain processes emotion.  Pathways involved in each of the steps of affective behavior – from the initial recognition of the emotional component of a stimulus (e.g., the anger on the face of a mad gunman), through the first emotional response (e.g., fear), the recruitment of cognitive strategies to deal with the situation (e.g., placating the gunman, negotiating, confrontation etc…), selection of the optimal approach (e.g., avoidance of the threat), and the final mobilization of adaptive behavior (e.g., flight/escape) – are being charted and refined.  The result is an emerging map of what parts of the brain (which circuits) do what and how various cognitive, behavioral, and emotional responses are mediated.  This is functional neuroanatomy:  an engineering-like analysis of how the brain works.

With this growing knowledge of how normal human emotion is processed, the stage was set for the study of bipolar patients, to see how and where their responses and underlying neural circuit activation differs from those without this illness.  Over the last 15 to 20 years, a variety of such ‘compare-and-contrast’ neuroimaging experiments have been performed.  In the following sections, we present a brief overview of these findings.  They contain some of the information that we provide when we attempt to answer our patient’s questions about “What is wrong with my brain?”

Brain Abnormalities Associated with Bipolar Disorder

Finding #1:   The brain systems that support normal human emotional response are the ones involved in bipolar disorder.  This has been both a guiding assumption, and an increasingly validated conclusion of research in this area.   In other words, when researchers first began looking for neural abnormalities in bipolar disorder, they had to choose which, among the vast multitude of brain regions, to focus on.  They assumed that the areas that had been found to be associated with ordinary emotional experience would be the ones most likely to show dysfunction in bipolar disorder.  This assumption looks correct.

Finding #2:  A circuit involving the prefrontal cortex, the amygdala, and their connecting pathways is especially implicated in bipolar disorder. The amygdala is an evolutionarily ancient cluster of neurons deep in the temporal lobe.  This primitive structure is responsible for the most basic aspects of emotional experience that occur in all animal species, from reptiles through humans.  This includes the rapid evaluation of emotional stimuli (e.g., is that lion friendly or looking to eat me?) and the mobilization of an initial affective response (e.g., run!).  The prefrontal cortex (PFC), in contrast, is the evolutionarily most-recent, distinctly human part of the brain that sits on top of lower subcortical areas such as the amygdala.  It controls much of our decision-making, planning and organizing.   It has also been found to regulate, through inhibition and other mechanisms, subcortically generated emotional reflexes.  The PFC and amygdala are linked through bundles of white matter fiber tracts that enable communication between the two areas.  Functional neuroimaging has revealed disease-specific disturbance in each of the three areas of this brain system.

Finding #3:   The functioning of the amygdala is often abnormal in bipolar disorder.  This is especially true of manic states where increased activity is found.  The data is less clear in states of depression and euthymia.  Regarding the latter, some studies report disturbed activity during remission, others show normalized functioning.   Some of these mixed results may be due to the type of task used during the fMRI.  A few studies have shown increased recruitment of the amygdala even during cognitive challenges, such as calculating a sum of numbers.  They imply that bipolar individuals may use the emotional part of their brain, even for more objective considerations.

Finding #4:  Bipolar disorder is also associated with disturbed amygdala size.  This is an example of a structure-function correlation.  While less robust than the functional findings, data suggests that early in the course of illness, the amygdala is actually smaller than found in those without bipolar disorder.  Interestingly, this pattern reverses with age, where bipolar adults are found to have larger amygdalae than their unaffected peers.  We do not yet understand how disturbances in function affect the size of a brain area.

Finding #5:  The prefrontal cortex shows reduced activation in bipolar disorder.  This appears to be true across mood states (i.e., whether a person is depressed, manic or euthymic).  It is most prominent during emotional tasks where the PFC fails to adequately modulate the overactive amygdala.  Think of a surge protector that is not working properly:  Instead of controlling and allowing the smooth flow of electricity, the device malfunctions permitting variable and excessive voltage.

Finding #6:  Neuroprogression.  This term refers to the concept that brain abnormalities irreversibly worsen over time similar to what occurs, for example, in Parkinson’s disease.  This is a question of immense prognostic importance.  To determine this, serial neuroimaging is required, i.e., testing a person in adolescence and again in adulthood, or comparing children at risk, to those in the early vs. late stage of the illness.  There is less data here than with the snapshot studies comparing bipolar adults to those without the disorder at a single point in time.  Nonetheless, the early research suggests that the amygdalae of individuals with bipolar disorder increase in size over time and that the PFC, in contrast, shrinks.  We don’t really know what to make of these observations.  Are they caused by the illness itself?  By the medications used to treat the illness (lithium has actually been shown to cause the amygdala to grow)?  Are the changes irreversible?  Given our uncertainty about this, it may be premature to characterize bipolar disorder as neuroprogressive in nature.

Finding #7:  Connectivity problems.  As mentioned earlier, the most implicated circuit in manic depression includes the amygdala, the PFC, and their connections.  These connections consist of white matter tracts that carry signals between these different brain regions.  fMRI and DTI studies have revealed both functional and structural impairments in these white matter connections in bipolar disorder.  These abnormalities have also been found before the onset of the illness (in children-at-risk, for example) and may thus represent vulnerability markers.

Finding #8:  The functional and structural abnormalities mentioned above are not, by and large, found in schizophrenia.  This supports the idea that bipolar disorder is a distinct illness, with its own neural substrate, and that this brain substrate is specific to the system of circuits that mediate emotional experience.

Conclusion and Cautionary Notes

The increasing clarification of the neural abnormalities associated with bipolar disorder is an exciting and potentially promising development for our field.  Being able to visualize the individual structures and integrated operational circuits that underlie both normal and abnormal mood states is an enormous step forward.    Appreciation of this advance, however, should be tempered by two cautionary notes.  First, describing the functional brain underpinnings of a cognitive or emotional process is not synonymous with defining its cause.  It simply lets us know what regions of the brain are doing at that time.  Discernment of the ultimate cause of an extreme mood state may require additional genetic, cellular, epidemiologic, and psychological investigation.

Second, despite its promise, functional neuroimaging is not yet yielding current clinical application.  In other words, there is no current clinical role for the type of brain scans described above in the evaluation and treatment of someone with bipolar disorder.  For the moment, these tests are used exclusively in research studies.  We expect and look forward to this changing in the very near future.



  1. Blond, B. N., C. A. Fredericks, et al. (2012). “Functional neuroanatomy of bipolar disorder: structure, function, and connectivity in an amygdala–anterior paralimbic neural system.” Bipolar Disorders 14(4): 340-355.
  2. Hafeman, D. M., K. D. Chang, et al. (2012). “Effects of medication on neuroimaging findings in bipolar disorder: an updated review.” Bipolar Disorders 14(4): 375-410.
  3. Schneider, M. R., M. P. DelBello, et al. (2012). “Neuroprogression in bipolar disorder.” Bipolar Disorders 14(4): 356-374.
  4. Strakowski, S. M., C. M. Adler, et al. (2012). “The functional neuroanatomy of bipolar disorder: a consensus model.” Bipolar Disorders 14(4): 313-325
  5. Townsend, J. and L. L. Altshuler (2012). “Emotion processing and regulation in bipolar disorder: a review.” Bipolar Disorders 14(4): 326-339.
  6. Whalley, H. C., M. Papmeyer, et al. (2012). “Review of functional magnetic resonance imaging studies comparing bipolar disorder and schizophrenia.” Bipolar Disorders 14(4): 411-431.

Postpartum Troubles Point to Increased Risk of Future Bipolarity

In our clinical work, we are always striving to determine who is at high risk of developing bipolar disorder.   Our patients come to us with a variety of mood and anxiety problems.  Often, those who are ultimately diagnosed with bipolar disorder have experienced a long period of misdiagnosis and incorrect treatment.

Women in the immediate postpartum period are a particularly vulnerable group.   According to at least one expert, there is no other period in a woman’s life when the risk of onset or exacerbation of bipolar disorder is as high, likely due to a combination of sleep deprivation and hormonal factors (1).  Despite this, postpartum depression is generally assumed to be of the non-bipolar type.   Recently, however, there is mounting evidence that postpartum depression heralds the onset of bipolar disorder in some women (2-4).   This is of considerable concern because the standard treatment for postpartum depression includes the use of an antidepressant.   In postpartum women predisposed to bipolar disorder, antidepressant treatment in the absence of mood stabilizers can result in the rapid onset of mania and psychosis (2), often resulting in hospitalization in order to protect both mother and infant.

Are there certain characteristics of patients suffering from first episode postpartum depression that can hint at a heightened risk of bipolar disorder?   One study found that these patients had a more first degree relatives with a history of hypomania/mania and a higher rate of hypomania/mania while treated with antidepressants (3).   However, these patients were not followed over time to see if they actually developed bipolar disorder.

All of which makes a recent study by Munk-Olsen and colleagues more compelling (4).  The authors, based in Denmark, Wales and the U.S., considered the possibility that a significant proportion of postpartum episodes that receive other diagnoses do in fact occur in women with underlying bipolar illness.   They hypothesized that the triggering of illness by childbirth is a marker for bipolar illness, even though the patient ‘s presentation appears non-bipolar at time (i.e. depressed or anxious mood, without the obvious presence of hypomanic or manic symptoms).

Munk-Olsen’s group analyzed a large Danish database of 120,378 women with a first-time psychiatric contact (inpatient or outpatient) between 1970 to 2006.  Excluded from the study were women who were diagnosed with bipolar disorder at the time of that contact.   During follow-up, 3062 of these women received diagnoses of bipolar disorder at a subsequent psychiatric contact, of which 132 had had their initial psychiatric contact 0 to 12 months following the birth of their first live-born child.    Conversions rates to bipolar disorder were significantly predicted by the timing of initial contact.  Women having a first-ever psychiatric contact within the first month postpartum showed an increased probability of converting to bipolar disorder at a later stage: initial contact 0 to 14 days postpartum, relative risk (RR) = 4.26 and initial contact 15-30 days postpartum, relative risk (RR) = 2.65.  Fifteen years after initial contact, 13.87% of women with onset in the immediate postpartum period (0-30 days after delivery) had converted to bipolar disorder compared with 4.69% of women with later postpartum onset (31-365 days after delivery) and 4.04% at other points (women having their initial psychiatric episode before or over 365 days after giving birth) (4).

The bottom line:  Women who first develop significant emotional problems soon after childbirth (especially in the first 30 days) should be carefully screened for evidence of bipolarity.   Extreme caution is warranted when utilizing antidepressants in these women (2).  A family history of bipolar disorder and/or a history of hypomania or mania on antidepressants confers further risk (3).

1.  Sharma V. and Mazmanian D. (2003).  Sleep loss and postpartum psychosis.  Bipolar Disord 5 (2): 98-105.

2.  Sharma V.  (2006).  A cautionary note on the use of antidepressants in postpartum depression.  Bipolar Disord  8 (4): 411-414.

3.  Azorin JM et. al. (2012).  Identifying features of bipolarity in patients with first-episode postpartum depression: findings from the international BRIDGE study.  J Affect Disord 136 (3): 710-715.

4.  Munk-Olsen, T. et. al. (2012).  Psychiatric disorders with postpartum onset: possible early manifestations of bipolar affective disorders.  Arch Gen Psychiatry 69 (4): 428-434.

IPSRT as monotherapy in bipolar II disorder: can psychotherapy be more than an ‘adjunct’ in the treatment of bipolar disorder?

Clinicians who work with patients suffering from bipolar disorder have known this for quite some time: medication alone, while helpful in controlling many of the acute symptoms of bipolar disorder, is not enough to help patients manage this complex illness.   Patients often feel overwhelmed by the diagnosis and need support to adjust to the realities of fluctuating mood states, which frequently result in interpersonal and occupational dysfunction.   For these and other reasons, psychotherapy is an important component of bipolar disorder treatment.

In recent years, multiple studies have been published which support this view, including randomized, controlled trials.  Taken together, they indicate that various psychotherapeutic approaches, such as individual and group CBT (cognitive behavioral therapy), family focused therapy, psychoeducation, and IPSRT (interpersonal and social rhythm therapy), can be helpful adjuncts in the management of bipolar disorder (1,2).   While these studies vary widely in terms of interventions given, patients selected and controls utilized, what they have in common is the idea that psychotherapy is effective as an “add-on,” to pharmacotherapy.  There is little, if any, indication that such treatments can be used as monotherapy in any phase of bipolar disorder.

This may be changing.

We happened to take notice of a small pilot study by Holly Swartz, M.D. and Ellen Frank, Ph.D. and their group in Pittsburgh (3).  Published in 2009, this study evaluates the effect of psychotherapy as monotherapy in patients with bipolar II depression.  Unmedicated individuals (n=17) meeting DSM-IV criteria for bipolar II depression received weekly IPSRT (interpersonal and social rhythm therapy) for 12 weeks.  After 12 weeks of acute treatment, individuals received an additional 8 weeks of follow-up treatment with continued IPSRT (with supplementary lamotrigine for IPSRT nonresponders).  By week 12, 41% (n=7) of the sample responded to IPSRT monotherapy; 53% (n=9) had responded by week 20 (by this time, one subject was receiving lamotrigine in addition to IPSRT while the other was receiving IPSRT alone).

While small and limited by the lack of a control group, this study is significant in that it demonstrates that psychotherapy – even without medication – can help those who suffer from bipolar II depression.  It puts psychotherapy back on the radar, not as a mere adjunct to treatment, but as THE treatment for this condition. 

Some caveats: the population consisted of bipolar II patients.  Thus, patients with a history of mania were excluded.   Mood stabilizing medication such as lithium, valproic acid, and neuroleptics remain the “gold standard” in managing acute mania.  However, bipolar depression is often resistant to medication treatment.  Antidepressants have been shown to cause worsening of mood cycling.  Not everyone can tolerate side effects.  This population, therefore, of depressed bipolar II patients, might be specifically amenable to psychotherapy as monotherapy.

So what can we conclude from the results?  Obviously, more research is needed, but there are clues that psychotherapy, specifically IPSRT, can play an important role even in bipolar I patients taking medication.  Dr. Frank’s group in 2005 published a randomized trial of IPSRT vs. ICM (intensive clinical management), in which 175 patients were included (4).  This study showed that participants with bipolar I disorder assigned to IPSRT in the acute phase of treatment were able to stay in remission longer (during the maintenance phase) than those assigned to ICM.  This was especially true for individuals without serious medical illnesses or anxiety.

IPSRT is unique for multiple reasons:  it focuses on interpersonal relationships and how closely related these are to mood episodes.    A special emphasis is placed on how bipolar disorder has impacted one’s life, causing role transition, fractured relationships, career derailment and “grief for the lost self.”  In addition, sleep, wake, and social interactions are tracked closely.   Why?   Because of the “social zeitgeber hypothesis”: unstable or disrupted daily routines lead to circadian rhythm and mood instability (4,5).  This is certainly in keeping with our clinical observations that changes in sleep/wake patterns (i.e. pulling an all-nighter) and overstimulation can bring on a manic episode.

We applaud Drs. Frank and Swartz for showing us that psychotherapy can have a powerful effect on a patient’s overall response to treatment.  IPSRT has lent itself well to clinical trials, as it follows a fairly structured and manualized format, and we look forward to larger, controlled studies of IPSRT as monotherapy in bipolar II depression.   A more challenging, but no less important, endeavor would be to examine the efficacy of psychodynamic psychotherapy in the treatment of bipolar disorder.   While manualized treatments (such as IPSRT or CBT, cognitive behavioral therapy) address key symptoms in bipolar disorder, we should not lose sight of the importance of understanding the meaning and overall implications of such symptoms in the context of a person’s life.


(1)  Jones S.  Psychotherapy of bipolar disorder: a review.  J Affective Disorders 2004; 80: 101-114.

(2)  Schottle D et. al.  Psychotherapy for bipolar disorder: a review of the most recent studies.  Curr Opin Psychiatry 2011; 24: 549-555.

(3)  Swartz H, E et. al.  Psychotherapy as monotherapy for the treatment of bipolar II depression: a proof of concept studyBipolar Disord 2009; 11: 89-94.

(4)  Frank E, Kupfer DJ et. al.  Two-year outcomes for interpersonal and social rhythm therapy in individuals with bipolar I disorderArch Gen Psychiatry 2005; 62: 996-1004.

(5)  Frank E.  Treating bipolar disorder.  New York: The Guilford Press, 2005.

New Wonder Drug Remarkably Effective in Bipolar Disorder: Lithium (Yes, Lithium).

The single most important research study in the past year in the area of clinical therapeutics of bipolar disorder was conducted  by Geddes and colleagues at Oxford University in England[1].  Using a randomized open-label design (no placebo control group and subjects knew which medications they were receiving), the BALANCE study sorted 330 subjects with bipolar disorder type I into three treatment groups: lithium alone, valproate (Depakote) alone, or combination treatment with both lithium and valproate.  The outcome measures were time to recurrence of a major mood episode, either mania or depression.  The study design allowed for an extended, two year follow-up on these subjects.  This time frame allows for meaningful assessment of genuine prophylactic effects.  The results found that combination therapy was most effective, marginally more so that lithium alone, but significantly greater than valproate monotherapy.  The interpretation of the data supports the unique efficacy of lithium as the single-most effective mood stabilizer available.

In recognition of the singular importance of this study, the journal Bipolar Disorders devoted an issue for commentaries from major luminaries in the field including  Ross Baldessarini[2], Rasmus Licht[3], and S. Nassir Ghaemi[4] and others.  The commentary by Ghaemi, a researcher and analytic thinker whose work I respect enormously, was forthright, pointed, and compelling.  In this commentary, he challenges the pharmaceutically-inspired practice habits of American psychiatrists and their seduction by the next, newest, sexiest drug brought to market.  His writing deserves to be read by patients and clinicians alike.  I include portions of his commentary below:

Clinical conclusions about lithium

“Clinicians can, and should, draw some conclusions, if we have the courage. We need to avoid being mugwumps, refusing to commit to using lithium out of vague fears, despite clear benefits that outweigh the real risks. With the results of BALANCE, in the setting of forty years of lithium research, it seems to me that one clinical conclusion is hard to avoid: Lithium is, by far, the first-line treatment for bipolar disorder. There should be very good reasons not to give lithium to the majority of patients with bipolar disorder as initial treatment. Patient preference, by itself, is not a good enough reason to avoid lithium; the hassles of being a doctor (checking blood levels, assessing kidney function long term) are not good enough reasons either. Patients need to be educated about the many benefits of lithium, including two other major areas, besides mood prophylaxis: mortality reduction, both by suicide and by cardiovascular death, and neuroprotective effects, especially probable reduction of dementia risk and potential protection against the cognitive impairment that is a long-term consequence of multiple mood episodes (1). The drawbacks of lithium are well known, though exaggerated: long-term chronic renal insufficiency, in the best prospective studies with decades of follow-up, is not more than 5% (8); other kidney effects, like decreased urinary concentration capacity, are more common but reversible and not medically dangerous; hypothyroidism is more common but treatable and reversible; nuisance side effects are less frequent than many believe; weight gain is less than with valproate and much less than most neuroleptics; cognitive side effects are problematic in some, but not most persons, and counteracted by long-term cognitive benefits; toxicity in overdose is a risk but this is the only drug that is proven to prevent suicide by a huge effect size (estimated to be nine-fold decreased risk) (1).

Some people cannot take lithium. But everyone should be offered it, most should try it, and a minority can then stop it if it is intolerable. If we take this approach, we find that many persons tolerate it, do well, and do not need the common current rigamarole of antidepressants plus neuroleptics, which leaves patients partially treated at best, and hardly treated at worst.

Lithium is unique because it actually treats an entire disease—manic-depressive illness. It is not merely a treatment for a symptom—like neuroleptics for mania or antidepressants for depression. Studies indicate that about one-third of patients get completely well long term with lithium monotherapy (10). This figure is not minor, and compares favorably with the long-term remission seen with antidepressants in major depressive disorder in the STAR*D study (11). BALANCE is another source of evidence for the notable benefit of lithium monotherapy in a substantial minority of persons with bipolar disorder. The makers of our DSM-IV nosology have assumed that all our pills are mere symptom treatments; they do not think our diagnoses reflect diseases in any meaningful way, and they do not believe that any of our treatments cure diseases. Hence, the claim that we should only make pragmatic judgments, compensating for the follies of practitioners and the manipulations of pharmaceutical companies. Lithium is their refutation, and BALANCE is a modern proof that, though they are hard to conduct and require a great deal of labor, we can clarify clinical controversies with rigorous studies. We researchers need to do the studies, perpend on their importance, teach clinicians to implement the results in practice, and educate our nosologist colleagues, especially now as DSM-5 is in process, as to what they mean.”


We listen in full agreement to this elegant and rigorous analysis.  Lithium really is the closest thing we have to a wonder drug.  It is our first choice for the great majority of bipolar patients that we treat in our practice.


1.            BALANCE investigators and collaborators, G.J., Goodwin GM et al, Lithium plus valproate combination therapy versus monotherapy for relapse prevention in bipolar I disorder (BALANCE): a randomised open-label trial. The Lancet, 2010. 375(9712): p. 385-395.

2.            Baldessarini, R.J., Commentary: The Bipolar Affective Disorder: Lithium/Anticonvulsant Evaluation (BALANCE) Study. Bipolar Disorders, 2010. 12(7): p. 669-672.

3.            Licht, R.W., A new BALANCE in bipolar I disorder. The Lancet, 2010. 375(9712): p. 350-352.

4.            Ghaemi, S.N., From BALANCE to DSM-5: taking lithium seriously. Bipolar Disorders, 2010. 12(7): p. 673-677.


Acute Antidepressant Effects of Lamotrigine: More and More Disappointing.

In the past several years, two new studies have been published examining the efficacy (in pristine, experimental conditions; rigorous selection criteria, minimal comorbid conditions) and effectiveness (real world variability) of lamotrigine (Lamictal) in the treatment of acute bipolar depression [1, 2].  These and other studies were recently summarized in a review paper by Amann and colleagues in the Journal of Psychopharmacology[3].  Attempting to synthesize disparate findings, Amann concludes that “…the antidepressant effect of LTG in acute bipolar depression, if it exists, is small.


These data support our own clinical work with this anticonvulsant, where we consistently find its acute antidepressant effects quite limited.  In our practice, we now reserve lamotrigine for use with residual depressive symptoms, which either fail to respond to primary mood stabilizers or other antidepressant treatment, or that fail to clear with the remission of the depressive episode.  We are less pessimistic but still uncertain about lamotrigine’s efficacy in the long-term prevention of depressive episodes.


This emerging profile of lamotrigine as a marginal antidepressant stands in stark contrast to the fanfare announcing its arrival in the late 1990’s when it was viewed as the Holy Grail for the treatment and prevention of bipolar depression.  This recalibration parallels our growing recognition of the limited potential of standard antidepressants, in general, in the therapy of the depressed phase of this illness[4].


1.            Calabrese, J.R., et al., Lamotrigine in the acute treatment of bipolar depression: results of five double-blind, placebo-controlled clinical trials. Bipolar Disorders, 2008. 10(2): p. 323-33.

2.            Geddes, J.R., J.R. Calabrese, and G.M. Goodwin, Lamotrigine for treatment of bipolar depression: independent meta-analysis and meta-regression of individual patient data from five randomised trials. British Journal of Psychiatry, 2009. 194(1): p. 4-9.

3.            Amann, B., et al., Lamotrigine: when and where does it act in affective disorders? A systematic review, in J Psychopharmacol OnlineFirst 2010. p. 1-6.

4.            Sachs, G.S., et al., Effectiveness of Adjunctive Antidepressant Treatment for Bipolar Depression, in NEJM 2007. p. 1711-1722.


Not the SAMe Old Story: New Antidepressant Data on Popular Nutritional Supplement.

May 13th, 2011

Evidence is building for the use of SAMe (S-adenosyl methionine) as adjunctive therapy in major depressive disorder. Just this past August, a landmark study by Papakostas, et al, demonstrated the superior efficacy of SAMe when combined with other antidepressant agents (e.g., fluoxetine, venlafaxine, duloxetine) over antidepressant monotherapy.1 Although SAMe has been reported to induce mania in some case reports, there may be a potential role in treatment for bipolar depression as well.2

Previous to this double-blind, randomized controlled trial, SAMe had been shown to have similar efficacy to tricyclic antidepressants such as imipramine in small trials.3 Based on results from the most recent trial, in a group of patients with an incomplete response to conventional antidepressants, six would need to be treated to experience one response and seven would need to be treated to achieve one remission (also known as number needed to treat).1 On the flip side, few adverse effects were reported. However, caution should be used because of the theoretical risk of serotonin syndrome.

In addition, the study results were only analyzed for patients who took the drug exactly as prescribed, which tends to favor the study medication and does not reflect real-life practice.1 Caution is also warranted because exact percent improvements for each group were not reported and only 73 patients were included in the study. The study participants were only tracked for a period of six weeks, making long-term conclusions impossible.

Typical treatment doses are in the 400-1600 mg/day range.

Recommendation: Because SAMe is an affordable nutritional supplement with few side effects, it is a suitable option for patients with major depressive disorder and suboptimal response to standard antidepressant therapy. The jury is still out on a potential role in bipolar depression.


1. Papakostas GI, Mischoulon D, Shyu I, Alpert JE, Fava M. S-adenosyl methionine (SAMe) augmentation of serotonin reuptake inhibitors for antidepressant nonresponders with major depressive disorder: a double-blind, randomized clinical trial. Am J Psychiatry. 2010 Aug;167(8):942-8.

2. Nelson JC. S-adenosyl methionine (SAMe) augmentation in major depressive disorder. Am J Psychiatry. 2010 Aug;167(8):889-91.

3. Delle Chiaie R, Pancheri P, Scapicchio P. Efficacy and tolerability of oral and intramuscular S-adenosyl-L-methionine 1,4-butanedisulfonate (SAMe) in the treatment of major depression: comparison with imipramine in 2 multicenter studies. Am J Clin Nutr. 2002 Nov;76(5):1172S-6S.

Riluzole: Promising Therapy for Treatment-Resistant Mood Disorders.

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.

N-Acetyl Cysteine for Bipolar Depression: Novel Approach, Limited Data.

Always looking for novel ways to treat bipolar disorder, researchers have turned to an old standby for Tylenol overdose: n-acetyl cysteine (NAC). Among other causes, mood disorders may be a result of oxidative or metabolic imbalances in the brain caused by low levels of the biochemical glutathoine. NAC works to restore these imbalances, which are possibly at the root bipolar depression, by working as an antioxidant.

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.


Atypical Antipsychotics and Sudden Cardiac Death: More Trouble in the Promised Land.

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 15th (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 2nd 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 (, a fantastic source of impartial information on psychiatric research) takes a roughly similar stand. An APA report prepared by Lieberman, Merrill and Parameswaran ( 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.


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 2nd 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.

Modafinil in Bipolar Depression: Treatment Advance or Back to the Future?

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.