Author Archive

Understanding Premenstrual Dysphoric Disorder (PMDD)

Imagine a mood disorder in which intense mood swings come predictably every month, wreaking havoc on any idea of calm normalcy. Depressed mood, lethargy, decreased interest and hopelessness occur along with marked irritability, anger, agitation and insomnia.   One has the sense of being overwhelmed and “out of control.” Arguments and heightened tearfulness ensue. Then everything returns to normal for the next week or two, only to be turned upside down by the dreaded monthly roller-coaster.

The intensity of what I have described sounds similar to bipolar disorder in its dramatic presentation. However, it is actually a fairly typical description of Premenstrual Dysphoric Disorder (PMDD), which has recently been recognized as a mood disorder in the DSM-V (1).   The criteria for PMDD is strict in terms of timing, duration, and degree of functional impairment. Symptoms begin during the luteal phase (days 15-28 of the menstrual cycle) and peak around the time of onset of menses. While symptoms can linger into the first few days of menses, there must be a symptom-free period in the follicular phase after the menstrual period begins. The diagnosis needs to be confirmed by prospective charting of at least two symptomatic cycles, and cannot be an exacerbation of symptoms of another disorder (such as depression or bipolar disorder), though PMDD can co-occur with these disorders (1).

PMDD is considered less common than PMS, with an estimated prevalence rate of 3-8% (2) compared with 75% of women for PMS (2,3).   The hormonal fluctuations of the menstrual cycle are themselves not the cause of the mood dysregulation. Rather, certain subpopulations of women have been observed to develop sensitivity to the normal hormonal fluctuations of the menstrual cycle (5). Clinically, we have observed such women to include those who have a personal or family history of mood disorders, or those who seem to have a heightened response to environmental stress.

Multiple mechanisms have been proposed for PMDD. Estrogen (primarily E2, or Estradiol), can affect the serotonin system in ways that are similar to SSRIs. In both rodent and human studies, E2 receptors have been found to be plentiful in the hippocampus and amygdala and modulate the affective response to stress (6). In the normal luteal phase in humans, levels of E2 drop dramatically, which, in some women, could trigger a heightened negative response to stress through several proposed mechansisms. For example, E2 normally decreases MAO (monoamine oxidase) activity, which increases the availability of serotonin (5-HT), dopamine (DA) and norepinephrine (NA). A decrease in E2 could thus trigger a depressive reaction by increasing the breakdown of these neurotransmitters by MAO (2). Attention has also been focused on the role of E2 in the formation of dendritic spines on pyramidal cells in the hippocampus and prefrontal cortex of the brain. Dendritic spine formation is considered to enhance both mood and cognition, with E2 and brain-derived neurotrophic factor (BDNF) working in concert (7). During the follicular phase of the menstrual cycle, when E2 is rising, spines form. During the late luteal phase, however, with E2 falling, the spines become dismantled, resulting in depressed mood and poor concentration (8).

The above mechanism of dendritic spine deterioration is also thought to be promulgated by progesterone, which, like estrogen, rises but then falls during the luteal phase of the menstrual cycle (8). Progesterone is also thought to increase MAO activity, decreasing neurotransmitter activity by causing their breakdown (2). Perhaps for this reason, progesterone has been thought of as a “depressogenic” hormone. However, recent research has highlighted another role for progesterone, in the form of its metabolite, the “neurosteroid” allopregnanolone (Allo-P) (9-11). Neurosteroids are endogenous steroids synthesized in the brain and nervous system from cholesterol that are potent modulators of the two major neurotransmitter systems that govern CNS activity – glutamate, the major excitatory neurotransmitter, and GABA (gamma-aminobutyric acid), the major inhibitory neurotransmitter (10). Too little GABA, too much glutamate (the main “excitatory” neurotransmitter) is considered to be a possible mechanism for depression, anxiety, mania and other disorders. In general, Allo-P is thought to be a GABAa receptor enhancer (10).

The drop in progesterone during the late luteal phase of the menstrual cycle causes rapid withdrawal from Allo-P and may be responsible for PMDD symptoms (11). Recent animal studies have shown that low-dose SSRIs such as fluoxetine given during the late luteal phase can stimulate the production of Allo-P, resulting in a rapid improvement in mood symptoms (over hours to days). This is via a separate mechanism from the slower process of selective serotonin reuptake inhibition, in which the patient may not notice a clinical effect for a longer period (at least two weeks). Indeed, the author proposes calling fluoxetine a “selective brain steroidogenic stimulant” (11). The mechanism by which fluoxetine rapidly generates Allo-P production is unclear, but it supports clinical observations of improvement in PMDD symptoms in some patients with intermittent, luteal-phase only dosing of SSRIs (3).

So Allo-P is generally a good thing, correct? Here we run up against seemingly conflicting data – for 3-8% of menstruating women (interestingly, the same prevalence of women who have PMDD), Allo-P causes “paradoxical” effects on the GABAa receptor system (4). The Allo-P-induced negative mood symptoms are dependent on how much Allo-P is present – very low and very high concentrations have less of an effect on mood. However, during endogenous luteal phase levels, negative mood occurs. Women with PMDD are thought to have a “supersensitive” GABAa receptor in which Allo-P actually changes the configuration of the receptor so that it no longer functions as an inhibitory receptor and instead causes “paradoxical” heightened anxiety, depression, and irritability during the luteal phase of the menstrual cycle (4).

So what are the clinical implications of these findings? It appears that for women who have true PMDD, a “less is more” approach applies to treatment, especially use of SSRIs. The trick appears to be how to find and hit the “sweet spot” of just enough Allo-P produced to keep the GABAa receptor working the way it’s supposed to. The desired result – relief from the emotional vicissitudes of PMDD – may be a few steps closer. However, more research must be done to fully clarify the pathophysiology of this elusive illness. Doing so may also shed some light on why some women, but not others, are susceptible to mood shifts in response to the wide ranges of hormone levels found in a typical reproductive lifespan.



  1. Diagnostic and Statistical Manual of Mental Disorders, 5th ed.  Arlington, VA: American Psychiatric Association, 2013.
  2. Spinelli M. Neuroendocrine effects on mood. Reviews in Endocrine and Metabolic Disorders 2005; 6: 109-115.
  3. Steiner M et. al. Expert guidelines for the treatment of severe PMS, PMDD, and comorbidities: the role of SSRIs. Journal of Women’s Health 2006; 15: 57-69.
  4. Backstrom T et. al. Allopregnanolone and mood disorders. Progress in Neurobiology (online) July 5, 2013: 1-7.
  5. Joffe H and Cohen LS. Estrogen, serotonin, and mood disturbance: where is the therapeutic bridge? Biological Psychiatry 1998; 44: 798-811.
  6. Ter Horst GJ. Estrogen in the Limbic System. Vitamins and hormones 2010; 82, 319-338.
  7. Luine V and Frankfurt M. Interactions between estradiol, BNDF and dendritic spines in promoting memory. Neuroscience 2013; 239: 34-45.
  8. Stahl S. Understanding and managing the pieces of major depressive disorder. Carlsbad, CA: Neuroscience Education Institute, 2009, 103-104.
  9. Zorumski CF and Mennerick S. Neurosteroids as therapeutic leads in psychiatry. JAMA Psychiatry 2013; 70: 659-660.
  10. Zorumski et. al. Neurosteroids, stress and depression: potential therapeutic opportunities. Neuroscience and biobehavioral reviews 2013; 37: 109-122.
  11. Lovick TL. SSRIs and the female brain – potential for utilizing steroid-stimulating properties to treat menstrual cycle-linked dysphorias. Journal of Psychopharmacology (online) May 23, 2013: 1-6.


Many of us of a certain age will never forget the sage, one-word piece of occupational advice given to Benjamin Braddock in the movie, The Graduate:   “Plastics.”  In the early 1960’s, plastics were thought to be the next big area of economic growth.  Benjamin, as we all remember, takes in this recommendation with alienated befuddlement.  However from the vantage point of 21st century psychiatric research, this advice may have been unwittingly prescient.

The plasticity of brain structure, or neuroplasticity, has become a major focus of scientific study over the last 10 to 15 years.  Neuroplasticity refers to the degree to which the organization and function of the brain changes through experience.  This article will briefly review the background of this area, some basic findings, and its relevance for understanding and treating bipolar disorders.

Several factors stimulated research on neuroplasticity.  First, shortcomings of the monoamine theory of depression.  Monoamines, like dopamine, norepinephrine, and serotonin are neurotransmitters involved in mood regulation.  In its most simple form, the monoamine theory postulated that deficiencies in monoamine levels caused depression.  We now know that this model has major limitations.  Foremost among them, the several-week lag period between starting an antidepressant and experiencing symptomatic relief.  Given that antidepressants lift monoamine levels almost immediately, there is obviously another mechanism at work that underlies depressed mood states and their response to medication.  Second, we know that the brains of people with bipolar disorder show structural differences from those without the illness.  Affected individuals exhibit overall reductions in gray matter (the part of the brain composed of nerve cells themselves in contrast to white matter which consists of the nerve axons, the long fibers that snake through the brain connecting one cell to another) , increases in amygdala size, and shrinkage or atrophy of specific areas, such as the hippocampus and the dorsolateral prefrontal cortex.  Notably, it has been found that lithium, valproate (Depakote) and certain antidepressants correct these changes.  The last phenomenon shifting attention towards brain structure has been the increased recognition of cognitive impairment occurring in mood disorders.  Roughly correlating with duration of illness and number of episodes, the occurrence of cognitive impairment – especially when independent of mood states – has suggested a chronic, structural problem with the memory-specific areas of the brain.  Together, these three factors shifted research attention away from purely biochemical, neurotransmitter-based models of mood pathology towards a focus on the underlying wiring and arrangement of neural groups in the brain.  This emphasis on brain structure and its malleability has generated several basic ideas that are guiding investigation in this area.

First, the brain is a dynamic organ that responds to new experiences with microscopic changes in its circuitry and functioning.  Read that last sentence again.  The wiring and connections of neurons actually become modified through experience.  This is the first and most significant finding of this new field.  Based initially on animal studies and more recently through MRI and other neuroimaging techniques in humans, researchers are now able to visualize how neurons respond to new experience.  This includes increases in the size and number of dendrites (the part of the nerve cell specialized to receive input from other nerve cells), weakening or strengthening of synaptic connections, and shrinkage or growth of cell groups.   Using a map analogy, we can think of our genetics as providing the layout of the major thoroughfares and neural pathways of our brain.  It is our individual experiences though, which chart out the streets, alleys, and more personally specific wiring that provide our own distinct psychology and physiology.  Hence, we need to give up the outdated view of the brain as a static given and replace it with something much more like a control center muscle that changes its size and abilities based on experience.  This understanding leads to two new questions:  How quickly and when do these structural changes occur?  Additionally, what types of experience are capable of producing these changes?

The initial perspective on neuroplasticity was that it was a phenomenon confined to childhood.  We know that the brains of all mammals expand and develop throughout infancy.  The earlier view was that this potential for change was limited to a critical period of development and that this window closed as the individual matured into adulthood.  The discovery of new brain growth – neurogenesis – in adult mammals was made only recently.  It has been a game-changer.  With more detailed neuroimaging methods, research has shown that many areas of the brain retain the capacity for growth, regeneration, and modification throughout life.  While diminished from its earlier childhood potential, this lifelong capacity is significant and can be activated by a range of experience and interventions.  What types of experience and interventions act on this neuroplastic foundation?  Short answer:  almost everything.

New experiences, new learning, the acquisition of new skills – all these developments result in, and are mediated by microscopic changes in neural circuitry.  This is the second paradigm shift of this young field.  Not only is the brain a dynamic organ, but it changes on a daily basis in response to everything that happens to us.  The new friend we make, the first job we hold, the unexpected storm that hits, the birth of a child, the loss of a parent, the hilarious joke we hear, the new food we try – the experiences of our lives are constantly being processed by, and changing the cellular architecture of our brains.  This realization sets up the final two ideas of this article:  What does neuroplasticity have to do with bipolar disorder?   And what can be done about it?

Current thought holds that impaired neuroplasticity contributes to the abnormal mood states, impaired cognition, structural changes, and delayed antidepressant response found in bipolar disorders.   In times of health, our brains and minds retain the ability to learn, grow, forget, strengthen, and prioritize certain information.  When depressed though, one might only focus on negative events and memories.  One might forget that his or her depressions are always brief and quickly respond to therapy, and feel instead that their black state will go on forever.  In contrast, in mania it may be difficult to appreciate the risks and difficulties of unrestrained plans and ambitions.  From a neuroplasticity perspective, these moods reflect a condition of cognitive and emotional constraint, and an underlying impairment in learning and brain malleability.  Here too, this theory makes intuitive sense to anyone that has experienced or dealt with the above mood states.   It is often difficult to help a person get perspective (i.e., think differently, remember other times, etc…) on their emotional condition.  Neuroplasticity theory would also suggest that the subtle cognitive impairment and structural changes found in the brains of bipolar individuals reflect the same type of reduced potential for experience-based brain circuit modification.  Through this lens, manic depressive illness is seen as a disorder of structural, cognitive and emotional unresponsiveness, constriction, and shrinkage.  Things get locked in a narrow groove from which one cannot easily escape.  So what’s to be done about this?

Neuroplasticity models suggest a role for therapy, medications, and a host of adjunctive interventions to restore the free-flowing dynamism of a healthy brain.  As a new form of experience, psychotherapy is uniquely suited to challenge, unlock, and expand the cognitive and structural constrictions of extreme mood states.  Psychotherapy is designed to provide new experiences for patients.  Its effectiveness may lie in its ability to do this.  Interestingly, antidepressant medications have also been found to restore the reshaping potential of mammalian brains.  The neuroplasticity model arguesthat it is this mechanism which mediates antidepressant response and accounts for the delay between rising monoamine levels and improvement.  Last, animal research has demonstrated the effects of environmental and behavioral changes on brain structure.  Rats caged in enriched environments show increased brain growth, enhanced neuronal resilience in response to stress and greater dendritic arborization (branching) than their peers housed in standard, barren cages.  This line of research has been extended to exercise, video games, and may also apply to environmental exposure to adequate sunlight, level of socializing, and intellectual stimulation.   This model argues that all effective therapeutic modalities will act by directly or indirectly restoring the mind’s ability to freely process information and the brain’s capacity for experience-guided fine-tuning.

Research on neuroplasticity presents a new way of thinking about the brain and bipolar illness.   It moves us away from a more fixed model of the central nervous system to one that is intrinsically reactive and evolving.  It elaborates on simple ideas about excess or reduced neurotransmitter levels to more complex models that include attention to the scaffolding, layout, and modifiability of the surrounding cellular matrix and nerve pathways.  In so doing, it encourages a wider range of therapeutic interventions for the difficult mood states that characterize this challenging disorder.

Plastics.  Indeed.

In future pieces, we will describe some of important mechanisms and major molecular players involved in mediating neuroplasticity.


  1. Carlson, P. J., J. B. Singh, et al. (2006). Neural circuitry and neuroplasticity in mood disorders: insights for novel therapeutic targets. NeuroRx 3(1): 22-41.
  2. Kapczinski F, Frey BN, Kauer-Sant’Anna M, Grassi-Oliveira R. (2008). Brain-derived neurotrophic factor and neuroplasticity in bipolar disorder. Expert Rev Neurother. 2008 Jul;8(7):1101-13.
  3. Krishnan, V. and E. J. Nestler (2010). Linking molecules to mood: new insight into the biology of depression. American Journal of Psychiatry 167(11): 1305-1320
  4. Bavelier, D., D. M. Levi, et al. (2010). Removing brakes on adult brain plasticity: from molecular to behavioral interventions. Journal of Neuroscience 30(45): 14964-14971.
  5. Castren, E. (2013). Neuronal network plasticity and recovery from depression. JAMA Psychiatry 70(9): 983-989.

Bipolar Disorders and the Case of the Missing Self

Every few years, a new author comes along who is uniquely capable of giving voice to the ineffable aspects of their experience with serious mood problems:  Kay Jamison with her (An) Unquiet Mind, William Styron who perceived Darkness Visible, and Sylvia Plath’s The Bell Jar are the more modern prototypes.    Recently, a freelance journalist, Linda Logan, published a brief piece in the New York Times:  The Problem With How We Treat Bipolar Disorder 1.   This mini-memoir is second-to-none in capturing the roller-coaster ride that is far-too-often the case with this illness.

In prose that is simple, direct, and blunt, Ms. Logan describes her 25 year journey through missed diagnosis, misdiagnosis, and a cavalcade of treatments that alternately helped and worsened her underlying condition.  This is a sobering read; it is not for the faint-of-heart.

Beyond her gift for describing these diagnostic and treatment experiences, Ms. Logan focuses on a grossly neglected aspect of this illness:  what it does to one’s sense of self.  Starting from her early experiences with depression, moving through a kaleidoscope of hypomanic and psychotic states, including the psychological impact of various medications, she describes how the experience of intense mood states and their treatment challenge our most basic knowledge of ourselves.  As clinicians working in this area, we find that questions about self-identity almost inevitably arise in the course of this illness.   When a diagnosis of bipolar disorder is made, for example, people who knew of themselves as outgoing, upbeat, and irreverent are forced to consider whether their fast-paced levity was who they truly were or part of an illness.  Or the person who has spent so long in a depressed state that it comes to define both how they know themselves and how others know them.  This person too will have to consider the same questions if and when their depression is effectively treated.  Illness or identity?   Helping patients with mood disorders address and resolve these almost existential uncertainties is an often necessary part of their therapy.

In her article, Ms. Logan describes her long journey through bipolar disorder and her experiences with losing, questioning, despairing about, and ultimately finding a new sense of herself.  The final version incorporates some of her old and healthy qualities, while acknowledging the ravaging effects of the illness, and ultimately spins out a fresh original that combines bits of old and new, disturbed and undeterred, lost and found.

Bipolar disorder presents many challenges to those it afflicts.  Linda Logan’s writing brightly illuminates one such trial – that of her ‘vanishing self’ – and the torturous path towards recovered and reconstructed identity.   If you or someone you know has this illness, read this work, hold on tight, and gain inspiration from this brave author’s courage.

The Problem With How We Treat Bipolar Disorder.  Linda Logan.  New York Times.  April 26, 2013.

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.

The Treatment of ADHD: ADDenda

The Treatment of ADHD:  ADDenda

I can’t resist adding some extra ideas to Dr. Plyler’s review of Amy Arnsten’s article, Catecholamine Influences on Dorsolateral Prefrontal Networks 1.  As he indicated, ADHD is one of the conditions on which we focus in this practice.   Dr. Arnsten’s paper made several points that deserve special emphasis.

1. The neurochemical control of the DLPFC (that part of the frontal cortex mediating control of attention, response inhibition, and working memory – the neuropsychological capacities whose impairment generates the classic symptoms of ADHD) under normal conditions is exquisitely calibrated to environmental demands and internal reserves.  Put differently, the regulatory actions of our DLPFC are adjusted on an almost second to second basis, depending on the immediate cognitive tasks confronting us and our level of stress and fatigue.  This dynamic reality contrasts with the more popular but almost cartoonish view of certain brain regions monolithically carrying out set functions.

2. With this understanding of how the brain (the DLPFC in particular) operates under normal circumstances, a realization is inevitable:  our pharmacotherapeutic efforts at treating ADHD are laughably clumsy and primitive by comparison.  In contrast to the immediate neurochemical changes that cause fine-grained temporal adjustments in DLPFC functioning, our use of medication is bulky and nonspecific.  We do not have the capacity to alter our medications on a second to second basis, nor make quick adjustments in doses depending on the particular challenges facing the individual.  This realization should humble all of us engaged in the therapy of this challenging disorder.  We need a brain-based version of the insulin pump:  a delivery method that can more finely titrate dosing according to environmental demands.

3. This realization has a practical implication for the pharmacotherapy of ADHD:  Customize!  We should tailor our medication efforts to the specifics of each patient’s daily needs and the variability of their needs.   For those with regular daily schedules such as full-time businessmen, stay-at-home moms, or college students, using set doses of long acting stimulants may be the easiest and most effective treatment strategy.  For those with more erratic schedules though, such as part-time students, project-based workers, or parents whose demands ramp up in the morning and the evenings when their kids are home – these patients may benefit from more flexible dosing strategies of their stimulants.  They may also benefit from shorter-acting agents that allow greater therapeutic fine-tuning.  Whichever route is optimal, it should be carefully worked out together as part of the treatment process.

4. Last, ADHD is not only about dopamine.  Arnsten emphasizes the critical and overlooked role of norepinephrine in DLPFC function and impairment.  This leads to a second clinical implication:  Don’t forget about noradrenergic agents in treating ADHD.  Yes, stimulants will hit both dopamine and norepinephrine, but for those who cannot tolerate or those who fail to respond optimally to these agents, we must give more serious consideration to atomoxetine and guanfacine.  In our experience, these noradrenergic medications are under-utilized.


Arnsten, A. F. T. (2011). “Catecholamine influences on dorsolateral prefrontal cortical networks.” Biological Psychiatry 69(12): e89-99.

Fine-Tuning our Understanding of the ADHD Brain

The greater our understanding of an illness state, the better we are able to treat it.  As one of the core disorders in our practice, we constantly review and update our knowledge on ADHD. In the course of a recent review, I came across a wonderful compilation issue on ADHD in Biological Psychiatry (Biol Psychiatry June 15 2011, vol. 69).  The review issue covers a wide range of topics from psychostimulants as cognitive enhancers to the molecular genetics of ADHD.  The most relevant and clinically applicable article, however, was Amy Arnsten’s paper on “Catecholamine Influences on Dorsolateral Prefrontal Cortical Networks” (Biol Psychiatry. 2011 June 15;69(12):e89-99).  She does a masterful job of presenting complex material in a clear and elegant manner.  Dr. Arnsten is able to capture the fluidity and dynamics of cortical functions associated with ADHD while still giving the reader anchor points that are useful in everyday clinical practice.

Dr. Arnsten’s article focuses on the effects of dopamine (DA) and norepinephrine (NE) on the dorsolateral prefrontal cortex (PFC).  This area of the brain has long been associated with executive function and working memory – the two primary problem areas associated with ADHD.  Executive functions are the neuropsychological capacities involved in planning, prioritizing and organizing tasks.  Working memory is the mind’s ability to keep and utilize information in short term storage, like the random access memory on a computer.  Though dopamine was held to be the primary neurotransmitter involved with ADHD, recent evidence has demonstrated that norepinephrine plays a significant role as well.  Working backwards from the evidence that medications used to treat ADHD such as methylphenidate and atomoxetine affect catecholamine (NE and DA) transmission in the PFC, Arnsten honed in on the specific receptors affected by these medications.  In her investigation, she found that the α2A receptor and D1 receptor had particular relevance to ADHD.

Recent studies found that norepinephrine strengthens PFC signaling through post- synaptic stimulation of α2A receptors on PFC neurons.   Conversely, dopamine acts at D1 receptors to decrease the signal to noise ratio by inhibiting stimulation from non-relevant external cues.  They also found that there is a “sweet spot” in the amount of norepinephrine and dopamine being released in the system, i.e. too much or too little markedly impairs PFC function. To break it down to a clinical level – medications such as methylphenidate or atomoxetine affect both norepinephrine and dopamine levels.  Appropriately increased levels of these neurochemicals then cause two actions to treat the symptoms of ADHD.  First, the norepinephrine ramps up signal strength for relevant stimuli through effects on α2A receptors, and second, the dopamine reduces the signal strength of non-relevant stimuli.

How do these ideas translate into the clinical realm?  Let’s imagine a person with ADHD working on a report on the computer.  Suddenly, an email pops up or the phone rings.  Untreated, his/her attention is immediately diverted to the new stimuli and a cascade of distractions ensues.  The report is left half -finished and the person doesn’t get back to it for hours.  Treated with methylphenidate, the non-relevant stimuli of an email pop up or phone call is now recognized but the dopamine working on the D1 receptor keeps that signal strength low, and the norepinephrine targeting the α2A receptor keeps the signal strength high for the report in front of him/her that needs to be finished.  This is referred to as “sculpting” or “spatial tuning” as the signal to noise ratio is kept appropriately calibrated to the task in front of the person that needs to be completed. This flow of dynamic signaling management is one of the hallmarks of executive function that can be so affected by ADHD.

Returning to the theme that greater understanding leads to better treatment, appreciation of the two component nature of attentional “sculpting” or “spatial tuning” enhances our ability to fine tune the treatment of our patient’s ADHD.   Clarifying whether our patient is having trouble with target signal emphasis and/or reducing distractor stimuli enables us to customize and more precisely adjust our medication interventions.  This insight is also useful for patients to better understand their specific challenges with this disorder.

We will continue to stay on top of advances like these in our practice areas of specialization so that we can better educate ourselves and you.


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.