Bipolar Disorder: Prescription for Omega-3?

A look into the promising benefits of omega-3 in the treatment of Bipolar Disorder…

Omega-3s and BDNF

Omega-3s are polyunsaturated fatty acids that serve many vital functions to the human body- improving cardiac function, decreasing inflammation, and mental health benefits- improving mild depressive symptoms, increasing cognitive function, and reducing the risk of dementia. There are three types of omega-3s: ALA, EPA, and DHA. DHA has the greatest effects on cell membranes, neuronal firing and survival, and nerve impulse transmission. Humans accumulate the most amount of DHA inutero, but the greatest period of synthesizing ALA to DHA is during the young developing years (Balanza-Martinez et al., 2011). Diet is the best source to maintain omega-3 levels throughout adulthood, specifically foods like salmon, sardines, fish oils, walnuts, flaxseeds, and soybeans. Unbalanced intake of omega-3s can exacerbate inflammatory states, chronic diseases, and mental health problems.

Omega-3s play various important roles at the molecular level in the brain. They increase the supply of oxygen and glucose to the brain, protect against oxidative stress, improve neurotransmitter-receptor binding, normalize dopamine levels in the frontal cortex, prevent excessive neuronal apoptosis, and promote BDNF expression. Additionally, adequate intake of omega-3s assists in proper function of the BDNF/tyrosine kinase receptor B (Balanza-Martinez et al., 2011). This receptor is vital in the signaling pathway and expression of BDNF in the brain. Omega-3s have been found to normalize levels of BDNF in the hippocampus (Wu, Ying, & Gomez-Pinilla, 2004). One study demonstrated a correlation between low DHA and reduced BDNF expression in the hippocampus and the PFC (Levant et al., 2008). Likewise, data shows that higher levels of serum omega-3s are associated with greater BDNF expression.

BDNF and Bipolar Disorder

Brain-derived neurotrophic factor (BDNF) is a neuroprotective growth factor protein that plays many vital roles in the human brain. BDNF, which is synthesized from the transcription factor CREB, is involved in neuronal survival, neuron differentiation, dendritic branching, and synaptic plasticity (Balanza-Martinez et al., 2011). Increased BDNF expression is found in the cerebral cortex and hippocampus- areas involved with functions like memory and emotions. BDNF has plays a key role in long term potentiation, which is the process of strengthening the connections between neurons. The expression of adequate BDNF in the brain is a vital component to healthy neurocognitive processes.

There is a vast amount of data implicating BDNF, through various mechanisms, in the pathophysiology of bipolar disorder (BD). Various studies have found an association between low levels of BDNF and BD diagnoses. Levels tend to be lowest in BD patients during acute depressive episodes or acute manic episodes (Tramontina et al., 2009). During remission of symptoms, BDNF levels are higher than they were during the acute episodes of symptoms.  Serum levels of BDNF are negatively correlated with length of illness (Kauer-Sant’Anna et al., 2009), such that the lower the levels of BDNF in BD patients, the longer the course of their illness. Those patients with a  higher frequency of manic episodes present with lower levels of BDNF over time.  One study found a genetic abnormality that occurs at the codon 66 in the BDNF gene (McIntosh et al., 2007). This allele can be found in healthy adults, but in BD patients they display a smaller temporal lobe- important for sensory information processing.

Many of the pharmacological treatments for BD, such as mood stabilizers and antidepressants, increase BDNF levels by increasing the activity of CREB- the transcription factor for BDNF. Interestingly enough, omega-3s play a similar role to that of mood stabilizers and antidepressants, such that omega-3s also increase the activity of CREB (Basselin et al., 2010).

Omega-3s and Bipolar Disorder

Omega-3s offer a wide array of psychiatric benefits: improving stress response, decreasing isolation, reducing aggression, and improving dopamine function. Across studies, patients with depressive symptoms, whether MDD or BD depression, present with lower serum levels of omega-3s, and omega-3s are actually inversely correlated with severity of the mood dysregulation symptoms (Balanza-Martinez et al., 2011). Recent research in the field of BD has been looking at correlations between the illness and  omega-3s in order to advance, not only the knowledge of BD pathophysiology, but also to advance the health maintenance and treatment possibilities for these patients. The data is minimal, but it is promising.

Postmortem studies of patients with BD have shown decreased serum levels of omega-3s and decreased DHA levels in various brain tissues, specifically the OFC (McNamara et al., 2008). These postmortem brains, with decreased DHA levels, presented with cell membrane abnormalities in the gray and white matter, and we know that omega-3s assist with fatty acid composition of cell membranes.

Various ecological studies have been conducted to zone in on diet and consumption of omega-3s related to BD prevalence. A study conducted across ten countries found that lower per capita fish consumption was correlated with higher rates of BD (Hibbeln, 2002). An inverse relationship was found between high fish intake and rates of MDD and postpartum depression. Additionally, those who consumed fish at least twice per week were less likely to report depressive symptoms.

Knowing the inverse relationship between omega-3s and BD prevalence, a pioneer prophylaxis trial was completed, where over the course of four months some patients received adjunctive therapy with high dose fish oil and others received a placebo (Stoll et al., 1999). The fish oil group had longer remissions and vastly greater improvements in their BD symptoms and overall functioning. Positive effects were largely found for their bipolar depressive symptoms, with no positive effect for their manic symptoms. In another trial, researchers looked at the effects of giving different concentrations of omega-3s (1g/day vs 2g/day) to patients with BD (Frangou, Lewis, & McCrone, 2006). Both doses improved global bipolar symptoms and depressive symptoms, but no decrease in manic symptoms. Also, a dose effect was not observed. In a small study with female BD patients, omega-3s were given as an adjunct, and these patients showed increased neuronal density and integrity, which protected them against excitatory apoptosis (implicated in the pathophysiology of BD) (Frangou, Lewis, Wollard, & Simmons, 2007). Lastly, a study was conducted in youth with BD and they were given omega-3s as adjunctive therapy. Results suggest that omega-3s in youth may in fact reduce bipolar depressive symptoms, bipolar irritability, and bipolar manic symptoms (Clayton et al., 2009). Even more interesting, some youth in this trial were given DHA as a monotherapy, and they too showed modest improvements over eight weeks.

Prescription for Omega-3s?

The role of omega-3s in BD is a growing field of research, and the area does call for larger studies. We know that deficient intake of omega-3s is implicated in BD, even though the exact reason is not clear- whether it is due to its relationship to BDNF expression or not. Omega-3s have been more successful in treating bipolar depressive symptoms in adults, rather than mania symptoms, but some benefits in youth mania have been identified. Of great interest, is the fact that omega-3s share similar mechanisms of actions to drugs used to treat BD.

We mustn’t ignore the valuable information in front of us. Low levels of omega-3s have been associated with a higher prevalence of BD. Diets high in omega-3s and high serum omega-3 levels are associated with decreases in BD symptoms. Omega-3s are proven to increase BDNF expression in the brain, and patients with BD have decreased levels of BDNF. Prophylactic and adjunctive use of omega-3s in patients with BD has shown positive results in symptomology. With this in mind, we as providers working with patients with BD, should counsel our patients on the potential benefits of taking a fish oil supplement or adopting a high Omega-3 diet.

References

Balanza-Martinez, V., Fries, G.R., Colpo, G.D., Silveira, P.P., Portella, A.K. Tabares- Seisdedos, R., et al. (2011). Therapeutic use of omega-3 fatty acids in bipolar disorder. Expert Review of Neurotherapy, 11(7), 1029-1047. doi: 10.1586/ern.11.42.

Basselin, M., Kim, H.W., Chen, M., et al. (2010). Lithium modifies brain arachidonic and    docosahexaenoic metabolism in rat lipopolysaccharide model of neuroinflammation.  J Lipid=Research, 51(5), 1049–1056. doi: 10.1194/jlr.M002469

Clayton, E.H., Hanstock, T.L., Hirneth, S.J., Kable, C.J., Garg, M.L., & Hazell, P.L. (2009). Reduced mania and depression in juvenile bipolar disorder associated with long-chain omega-3 polyunsaturated fatty acid supplementation. European Journal of Clinical Nutrition, 63(8), 1037-1040. doi: 10.1038/ejcn.2008.81.

Frangou, S., Lewis, M., & McCrone, P. (2006). Efficacy of ethyleicosapentaenoic acid in bipolar depression: randomized double-blind placebo-controlled study. British Journal of Psychiatry,188, 46–50. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/16388069        

Frangou, S., Lewis, M., Wollard, J., & Simmons, A. (2007). Preliminary in vivo evidence of increased Nacetyl-aspartate following eicosapentanoic acid treatment in patients with bipolar disorder. Journal of Psychopharmacology, 21, 435–439. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/16891338

Hibbeln, J.R. (2002). Seafood consumption, the DHA content of mothers’ milk and prevalence rates of postpartum depression: a cross-national, ecological analysis. Journal of Affective Disorders, 69,  15–29. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/12103448

Kauer-Sant’Anna, M., Kapczinski, F., Andreazza, A.C., et al. (2009). Brain-derived neurotrophic factor and inflammatory markers in patients with early-vs. late-stage bipolar disorder. International Journal of Neuropsychopharmacology, 12(4), 447–458. doi: 10.1017/S1461145708009310.

Levant, B., Ozias, M.K., Davis, P.F., et al. (2008). Decreased brain docosahexaenoic acid content produces neurobiological effects associated with depression: interactions with reproductive status in female rats. Psychoneuroendocrinology, 33, 1279–1292. doi: 10.1016/j.psyneuen.2008.06.012

McIntosh, A.M., Moorhead, T.W., McKirdy, J., et al. (2007).Temporal grey matter reductions in bipolar disorder are associated with the BDNF Val66Met polymorphism. Molecular Psychiatry,12(10),   902–903. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/17895927

McNamara, R.K., Jandacek, R., Rider, T., et al. (2008). Deficits in docosahexaenoic acid and associated elevations in the metabolism of arachidonic acid and saturated fatty acids in the postmortem orbitofrontal cortex of patients with bipolar disorder. Psychiatry Research, 160(3), 285–299. doi: 10.1016/j.psychres.2007.08.021

Stoll, A.L., Severus, W.E., Freeman, M.P., et al. (1999). Omega-3 fatty acids in bipolar disorder a preliminary double-blind, placebocontrolled trial.  Arch General Psychiatry, 56, 407–412. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/10232294

Tramontina, J.F.,  Andreazza, A.C., Kauer-Sant’Anna, M.,  et al.  (2009). Brain-derived neurotrophic factor serum levels before and after treatment for acute mania. Neuroscience Letters, 452(2), 111–113. doi: 10.1016/j.neulet.2009.01.028

Wu, A., Ying, Z., & Gomez-Pinilla, F. (2004). Dietary omega-3 fatty acids normalize BDNF levels,  reduce oxidative damage, and counteract learning disability after traumatic brain injury in rats. Journal of Neurotrauma, 21, 1457–1467. Retrieved from    http://www.ncbi.nlm.nih.gov/pubmed/15672635

It Must be Something in the Water: Lithium as a Panacea?

Certain substances have long been added to our drinking water to promote public health, such as chlorine to prevent bacterial growth and fluoride to inhibit tooth decay for example (Centers for Disease Control, 2014).  The prospect of adding a psychotropic medication, however, would seemingly result in public outcry.  Yet this very topic has been gaining attention as the myriad benefits of Lithium, a naturally occurring ion used in the treatment of bipolar disorder, have been explored.

What is Bipolar Disorder?

Bipolar disorder is a mood disorder characterized by distinct vacillations between depressive and manic episodes. Given the emotional basis of the disorder, it is not surprising that the limbic system in the brain has been implicated in its pathophysiology.  Decreased size and function of the medial prefrontal cortex, hippocampus, amygdala, and ventromedial parts of the basal ganglia have been identified in patients with bipolar disorder (Drevets, Price, & Furey, 2008).  Though conflicting studies have suggested increased amygdala volume, it is believed that many of these findings were based on patients already receiving pharmacological intervention.   Overall, it is believed that dysfunction within these structures accounts for many of the emotional and cognitive disturbances found with bipolar disorder (Drevets, Price, & Furey, 2008).

How Does Lithium Work?

Lithium is a mood-stabilizing agent that has been considered a standard treatment for bipolar disorder for more than 50 years.  Despite potentially serious side effects, lithium has been proven effective in managing and preventing manic episodes.  While lithium’s efficacy has been established, its mechanism of action in the brain remains uncertain.  Theories include affecting signal transduction through inhibition of second messenger enzymes, modulation of G proteins, and interaction within downstream signal transduction cascades (Stahl, 2013).  What is clear, however, is that lithium works by restoring the stability of several anomalous signaling pathways in the brain, resulting in a more balanced mood (Lenox & Hahn, 2006).

Lithium has been shown to support the function of the amygdala, hippocampus, and prefrontal cortex, all of which are brain regions associated with emotion regulation (Higgins & George, 2013).  A 2011 study conducted by Hallahan et al. utilized MRIs to compare the relative sizes of these brain regions in individuals with bipolar disorder, those with bipolar disorder taking lithium, and healthy controls.  Interestingly, treatment with lithium was found to increase hippocampal volume even when compared with healthy subjects.  It is thought that lithium’s neuroprotective effects, such as increased brain derived neurotrophic factor (BDNF) synthesis, mediate this increase in volume (Hallahan et al., 2011).  BDNF plays a vital role in the brain by promoting the survival of existing neurons as well as encouraging proliferation of new neuronal pathways.  This upregulation of BDNF provided by lithium treatment could explain its many benefits.

Hallahan

(Hallahan et al., 2011)

Lithium has also been shown to dampen excitatory neurotransmitters, such as dopamine and glutamate, and enhance the inhibitory neurotransmitter GABA (Malhi, Tanious, Das, Coulston, & Berk, 2013).  One study examined post-mortem brain tissue of the dorsolateral prefrontal cortex of individuals with a history of bipolar disorder.  Researchers found increased glutamate levels in the un-medicated bipolar brain and increased GABA levels in those treated with lithium (Lan et al., 2008).  These findings suggest that lithium provides a balance to the aberrant neurotransmission levels propagated by the disorder.

How Would Adding Lithium to Drinking Water be Beneficial?

The benefits of lithium expand beyond stabilizing the extreme moods characteristic of bipolar disorder.  Studies have proven the powerful capacity of lithium to decrease both aggressive behavior and suicide (Higgins & George, 2013).  Still, these findings have only been demonstrated in psychiatric populations.  So what does lithium have to do with the general populace?

As mentioned previously, lithium is a naturally occurring element that is found in groundwater across the globe.  Concentrations vary from undetectable to .170 mg depending on geographic location (Fels, 2014).  It is pertinent to note that even at the highest concentration, this amount constitutes less than one thousandth of a minimum therapeutic dose for bipolar treatment (Fels, 2014).

Numerous studies have explored the effects of these trace amounts of lithium in drinking water.  Research conducted in Texas found significantly higher rates of homicide, suicide, rape, and burglary in counties with little or no lithium in their water supply (Schrauzer & Shrestha, 1990).   The authors of this study boldly suggest, “lithium at low dosage levels has a generally beneficial effect on human behavior” (p. 110). Taken alone, this data could be considered interesting at best and coincidental at worst.  Yet in 2011, a similar study of over 6400 lithium samples in Austria found an inverse association between lithium levels in drinking water and overall suicide rates, including mortality rates (Kapusta et al., 2011).  Lastly and perhaps most astounding of all is a study conducted in Japan.  Comparisons of lithium intake and mortality were conducted on over one million Japanese residents.  Zarse (2011) and his colleagues claim that their findings provide evidence that low dose lithium has anti-aging effects and increases the overall lifespan!

Zarse

(Zarse et al., 2011)

Without a doubt, the addition of even barely recognizable amounts of lithium to the public water supply would be controversial.  Yet the net benefits are certainly intriguing.  Whether it is the extra BDNF, the homeostatic effect on our neurotransmitters, or something else entirely, it seems that low dose lithium could potentially benefit just about everyone.

References

Centers for Disease Control (2014).  Water Fluoridation Additives Fact Sheet. Retrieved February 12, 2015, from http://www.cdc.gov/fluoridation/factsheets/engineering/wfadditives.htm

Drevets, W., Price, J., & Furey, M. (2008). Brain structural and functional abnormalities in mood disorders: Implications for neurocircuitry models of depression. Brain Structure and Function, 213(2), 93-118. Retrieved from http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2522333/

Fels, A. (2014, September 13). Should We All Take A Bit of Lithium? New York Times. Retrieved from http://www.nytimes.com/2014/09/14/opinion/sunday/should-we-all-take-a-bit-of-lithium.html?_r=0

Hallahan, B., Soares, J., Newell, J., Brambilla, P., Strakowski, S., Fleck, D.,…McDonald, C. (2011). Structural Magnetic Resonance Imaging in Bipolar Disorder: An International Collaborative Mega-Analysis of Individual Adult Patient Data. Biological Psychology, 69(4), 326-335. Retrieved from http://www.sciencedirect.com/science/article/pii/S0006322310009133

Higgins, E., George, M., (2013). The Neuroscience of Clinical Psychiatry (2nd ed.). Philadelphia, PA. Lippincott Williams & Wilkins. p. 260-262.

Kapusta, N. D., Mossaheb, N., Etzersdorfer, E., Hlavin, G., Thau, K., Willeit, M., Praschak-Rieder, N., et al. (2011). Lithium in drinking water and suicide mortality. The British Journal of Psychiatry, 198(5), 346–350. Retrieved from http://bjp.rcpsych.org/content/198/5/346

Lan, M., McLoughlin, G., Griffin, J., Tsang, T., Huang, J., & Yuan, P. (2008). Metabonomic analysis identifies molecular changes associated with the pathophysiology and drug treatment of bipolar disorder. Molecular Psychiatry, 14, 269-279. Retrieved from http://www.nature.com/mp/journal/v14/n3/abs/4002130a.html

Lenox, R., & Hahn, C. (2006). Overview of the mechanism of action of lithium in the brain: Fifty-year update. Journal of Clinical Psychiatry, 61(9), 5-15. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/10826655

Malhi, G., Tanious, M., Das, P., Coulston, C., & Berk, M. (2013). Potential Mechanisms of Action of Lithium in Bipolar Disorder. CNS Drugs, 27(2), 135–153. doi:10.1007/s40263-013-0039-0

Schrauzer, G., & Shrestha, K. (1990). Lithium in drinking water and the incidences of crimes, suicides, and arrests related to drug addictions. Biological Trace Element Research, 25(2), 105–113. doi:10.1007/BF02990271

Stahl, S. (2014). Stahl’s Essential Psychopharmacology (4th ed). San Diego, CA: Cambridge University Press.

Zarse, K., Terao, T., Tian, J., Iwata, N., Ishii, N., & Ristow, M. (2011). Low-dose lithium uptake promotes longevity in humans and metazoans. European Journal of Nutrition, 50(5), 387–389. doi:10.1007/s00394-011-0171-x

Depression, Inflammation, Pregnancy, and SSRI as a modulator.

http://well.blogs.nytimes.com/2014/09/01/possible-risks-of-s-s-r-i-antidepressants-to-newborns/?_r=0

http://www.newyorker.com/tech/elements/depression-and-pregnancy-dilemma

The above two articles are posts on popular news outlets, each weighing and arguing differing points on the use of SSRIs to treat depression during pregnancy. This is a complex and culturally sensitive issue and not one easily reconciled. Both articles address the concerns for adverse post-natal outcomes caused by depression during pregnancy. One argues that SSRIs are responsible for adverse outcomes; the other that women with untreated depression have equally detrimental outcomes. In reading these two articles, one can glean a general understanding of two stances on the issue and form his or her own opinion. This piece will serve not to belabor either of their arguments but rather to look at the inflammation that may be playing a role in outcomes for mother’s who are depressed during pregnancy, and what role SSRIs may play in modulating these factors.

The most often researched major components relating to depression and inflammation includes circulating cytokines, specifically:  tumor necrosis factors, c-reactive proteins, and Interleukin-6 (Walker, 2013).  Another factor in depression is the Hypothalamus- pituitary- axis (HPA), and its aberrance in depression causing increased circulating cortisol. The release of cortisol is often linked with the adverse health problems seen in those affected by depression (Rohleder, Wolf & Wolf, 2010). Cortisol levels and inflammatory markers vary by types of depression, as well as chronic depression (Lamers et. al, 2013). If these factors are common in depression in the general population, what might these factors imply for pregnant women and their children?

Inflammation, pregnancy, depression

In trials testing the immune response of depressed pregnant women, Christian et al. (2010) found that women who scored highest on a depression inventory had a much more aberrant immune response, specifically higher levels of macrophage migration inhibitory factor (an inflammatory cytokine). In another study, researchers compared pregnant women in comparably stressful psychosocial environments: unmarried, high school education or less, annual family income less than $15,000. Women with high scores on a depression screening tool were compared with women scoring high on a “perceived stress” scale. It was then concluded that women with depressive symptoms had much higher IL-6 and higher TNF levels. Notably, women experiencing lower social support and increased negative social interaction had the greatest depressive symptoms (Christian, Franco, Glase & Iams, 2009). This data suggests that even when compared to women who perceive high stress, there is a biological inflammatory response to the pathology of having depression.

Childhood outcomes

Christian et al. 2010 summarizes many of recent finding about adverse outcomes of inflammation during pregnancy. These include, but are not limited to, higher cortisol levels as adults, poor immune function related to pre term birth and transfer of maternal inflammatory markers, and preeclampsia. Animal studies have demonstrated that maternal infection during pregnancy elicits an immune response where inflammatory cytokines (IL-6) activate c-reactive proteins (the same processes as in depression), which may then cross the placenta and alter brain development in utero. Study of their offsprings’ brain and behavior show similar patterns to symptoms of autism (Brown, 2014). Women with higher cortisol levels during pregnancy had a higher chance of premature delivery. Their children displayed increased crying, fussing, and negative facial expressions. They also had higher scores for more difficult temperament in emotion and activity (Weeth, van Hees, Burelaar, 2003). Women with elevated TNF-α and maternal infection during the third trimester were at a greater risk for schizophrenia in their offspring (Cannon, Clarke & Cotter, 2014). Other studies have shown that increased C-reactive protein level protein in during pregnancy is linked to a 60% increased chance for later diagnoses of schizophrenia, a 28% increase for every unit of c-reactive protein increased (Canetta et al as cited in Cannon, 2014). While some of these results are related to maternal infection, similar inflammatory markers are elicited in depression.  This suggests a correlation between inflammatory responses in depressed mothers and an increased risk for developing psychiatric disorders in their offspring.

Interventions

Given how stress and depression can increase these inflammatory markers, could an SSRI treat the depression, and effectively reduce these adverse outcomes? Some studies find that drugs such as escitalopram (Lexapro) do not significantly reduce circulating cytokines after 4 weeks of treatment (Haastrup, Knorr, Erikstrup, Kessing & Ullum, 2012). However, Walker (2013) describes many more studies for the past twenty years suggesting that SSRIs reduce the amount of TNF-α, interleukin 1 β, and other cytokines. The mechanism for why this happens is still unclear, however mediation of serotonin and its effects on cytokine pathways and other inflammatory responses may be the key.  Some use of conventional anti-inflammatories has also shown promising research as an adjunct for treating depressive symptoms (Walker, 2013).

Like most literature on psychotropic medication the long term risk and benefits are unclear. Understanding the inflammatory markers and pathology of depression is important in making a sound decision with each mother-to-be. Ultimately, it is that mother’s choice to weigh the risks and benefits of seeking treatment with an SSRI against facing the symptomatology and biological responses of depression. Psychotherapy may modulate some of these factors, but it is a provider’s responsibility to inform women of their options, and provide sound data for treatment.

 

References

Brown. (2014). Elevated maternal C-reactive protein and autism in a national birth cohort. Molecular Psychiatry, 19, 259; 259-264; 264. Retrieved from psyc11 database.

Buka, S. (2001). Maternal cytokine levels during pregnancy and adult psychosis. Brain, Behavior, and Immunity, 15, 411; 411-420; 420. Retrieved from psyc3 database.

Cannon. (2014). Priming the brain for psychosis: Maternal inflammation during fetal development and the risk of later psychiatric disorder. The American Journal of Psychiatry, 171, 901; 901-905; 905. Retrieved from psyc11 database.

Christian, L. M. (2009). Depressive symptoms are associated with elevated serum proinflammatory cytokines among pregnant women. Brain, Behavior, and Immunity, 23, 750; 750-754; 754. Retrieved from psyc6 database.

Christian, L. M. (2010). Depressive symptoms predict exaggerated inflammatory responses to an in vivo immune challenge among pregnant women. Brain, Behavior, and Immunity, 24, 49; 49-53; 53. Retrieved from psyc7 database.

Christian, L. M. (2012). Psychoneuroimmunology in pregnancy: Immune pathways linking stress with maternal health, adverse birth outcomes, and fetal development. Neuroscience & Biobehavioral Reviews, 36, 350-361. doi:http://dx.doi.org/10.1016/j.neubiorev.2011.07.005

Christian, L. M., Franco, A., Glaser, R., & Iams, J. D. (2009). Depressive symptoms are associated with elevated serum proinflammatory cytokines among pregnant women. Brain, Behavior, and Immunity, 23, 750-754. doi:http://dx.doi.org/10.1016/j.bbi.2009.02.012

de Weerth, C. (2003). Prenatal maternal cortisol levels and infant behavior during the first 5 months. Early Human Development, 74, 139; 139-151; 151. Retrieved from psyc4 database.

Haastrup, E. (2012). No evidence for an anti-inflammatory effect of escitalopram intervention in healthy individuals with a family history of depression. Journal of Neuroimmunology, 243, 69; 69-72; 72. Retrieved from psyc9 database.

La Marca-Ghaemmaghami, P. (2013). The association between perceived emotional support, maternal mood, salivary cortisol, salivary cortisone, and the ratio between the two compounds in response to acute stress in second trimester pregnant women. Journal of Psychosomatic Research, 75, 314; 314-320; 320. Retrieved from psyc10 database.

Lamers. (2013). Evidence for a differential role of HPA-axis function, inflammation and metabolic syndrome in melancholic versus atypical depression. Molecular Psychiatry, 18, 692; 692-699; 699. Retrieved from psyc10 database.

Miller, V. M. (2013). Gestational flu exposure induces changes in neurochemicals, affiliative hormones and brainstem inflammation, in addition to autism-like behaviors in mice. Brain, Behavior, and Immunity, 33, 153; 153-163; 163. Retrieved from psyc10 database.

Rohleder, N. (2010). Glucocorticoid sensitivity of cognitive and inflammatory processes in depression and posttraumatic stress disorder. Neuroscience and Biobehavioral Reviews, 35, 104; 104-114; 114. Retrieved from psyc7 database.

Villanueva, R. (2013). Neurobiology of major depressive disorder. Neural Plasticity, 5, 1; 1-7; 7. Retrieved from psyc10 database.

Walker, F. R. (2013). A critical review of the mechanism of action for the selective serotonin reuptake inhibitors: Do these drugs possess anti-inflammatory properties and how relevant is this in the treatment of depression? Neuropharmacology, 67, 304-317. doi:http://dx.doi.org/10.1016/j.neuropharm.2012.10.002

Zuckerman, L. (2003). Immune activation during pregnancy in rats leads to a PostPubertal

emergence of disrupted latent inhibition, dopaminergic hyperfunction, and altered limbic morphology in the offspring: A novel neurodevelopmental model of schizophrenia. Neuropsychopharmacology (New Yo