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Women's Mood-Control System May Differ from Men's
Swedish team finds differences in brain systems for handling the 02/14/2008 by Craig Weatherby
Women are significantly more likely to suffer from depression and anxiety, compared with men.

But very few studies focus on gender differences in the brain's mood-regulating system.

While some of the same factors contribute to depression in both sexes, women are subject to unique biological, life-cycle, hormonal and psycho-social influences.

The cyclical rise and fall of estrogen and other hormones may affect the brain chemistry associated with depression and anxiety.

This may be why some women are at increased risk for depression and/or anxiety during the transition into menopause, while others suffer a severe form of premenstrual syndrome (PMS) called premenstrual dysphoric disorder (PMDD).

Now, researchers from Sweden's respected Karolinska Institute report that they may have discovered one reason why rates of depression and chronic anxiety differ between men and women.

Their findings reveal distinctions in each gender's brains, related to regulation of serotonin, which is the neurotransmitter associated with maintenance of good mood.

Prozac-type anti-depressant drugscalled “selective serotonin reuptake inhibitors” (SSRIs)—may work by reducing the rate at which serotonin is re-absorbed by the neurons (brain cells) that secrete it, thereby leaving more serotonin available.
However, more recent evidence suggests that they may work, to the extent they do, by stimulating growth of connections among brain cells (neurons), which is a benefit of omega-3s as well.

Omega-3s and serotonin: possible connections
Harvard University psychiatrist Andrew Stoll, M.D., says that omega-3s keep cell membranes more fluid, making it easier for receptors to respond to neurotransmitters like serotonin (Foreman J 2005).

And studies led by NIH clinical researcher Joseph Hibbeln, M.D., suggest that omega-3s may play a role in regulating serotonin levels.


His team found that low levels of omega-3s in cell membranes were associated with low levels of serotonin in people with aggression and impulse-control problems (Hibbeln JR et al. 1998).

Swedes find sex-based difference in serotonin regulation

Doctoral candidate Hristina Jovanovic and her colleagues at Stockholm's Karolinska Institute used a PET scanner to examine the brains of women and men.

Their results reveal that women have more of the most common serotonin receptors than men, and possess more serotonin receptors in the brain's hippocampus region (Jovanovic H et al. 2008).

As well as being vital to memory formation, the hippocampus is part of the brain's “limbic system,” which is associated with primitive emotional states.

The hippocampus actually shrinks in people with severe depressions, or who suffer from excess stress. (This hippocampal shrinkage can be reversed and perhaps prevented in people with depression and bipolar disorder, with effective treatment.)

Interestingly, the hippocampus is also rich in estrogen and progesterone receptors, so the unusually high number of serotonin receptors in a woman's hippocampus could be connected to the need to deal with hormone-related mood fluctuations. Clearly, we need to know more about this part of the brain.

They also found that women have lower levels of the protein that transports serotonin back into the nerve cells that secrete it: the very same protein (5-HTT) that the most common SSRI-type antidepressants are designed to block.

According to team leader Anna-Lena Nordström, M.D., Ph.D., “We don't know exactly what this means, but the results can help us understand why the occurrence of depression differs between the sexes and why men and women sometimes respond differently to treatment with antidepressant drugs” (Karolinska Institute 2008).

Serotonin system may differ in women with severe PMS

The Karolinska group also found differences between the serotonin system in healthy women, compared with women who suffer from serious premenstrual mental symptoms (Jovanovic H 2008; Jovanovic H et al. 2006).

These findings indicate that the serotonin system in women who suffer from severe PMS may not respond as flexibly to the hormone swings of the menstrual cycle.

As professor Nordström said, “These findings indicate that when developing antidepressants and anti-anxiety drugs, scientists should evaluate their effect on men and women separately, as well as their effects before and after menopause” (Karolinska Institute 2008).

No doubt, every woman will second that emotional health motion.

Prozac-type drugs rest on shaky evidence

Prozac and other SSRI-type drugs are the most commonly prescribed anti-depressants, and rank among the most widely prescribed drugs in America and Europe.

And as we reported recently, the clinical research foundation upon which their approval rests is seriously flawed.

The authors of an evidence review found that some 94 percent of clinical trials with positive outcomes (i.e., effects superior to placebo pills) were published, while only 14 percent of trials with negative or unclear results appeared in any public form.

And the FDA's own study reviewers found that the results of many of the “positive” studies were not as good as their authors claimed (See “Major Heart and Mood Drugs Take Huge Credibility Hits”).



  • Foreman J. Eat fish, be happy. March 8, 2005. Accessed online February 1, 2008 at /articles/2005/03/08/eat_fish_be_happy/
  • Hibbeln JR, Ferguson TA, Blasbalg TL. Omega-3 fatty acid deficiencies in neurodevelopment, aggression and autonomic dysregulation: opportunities for intervention. Int Rev Psychiatry. 2006 Apr;18(2):107-18. Review.
  • Hibbeln JR, Linnoila M, Umhau JC, Rawlings R, George DT, Salem N Jr. Essential fatty acids predict metabolites of serotonin and dopamine in cerebrospinal fluid among healthy control subjects, and early- and late-onset alcoholics. Biol Psychiatry. 1998 Aug 15;44(4):235-42.
  • Hibbeln JR, Umhau JC, Linnoila M, George DT, Ragan PW, Shoaf SE, Vaughan MR, Rawlings R, Salem N Jr. A replication study of violent and nonviolent subjects: cerebrospinal fluid metabolites of serotonin and dopamine are predicted by plasma essential fatty acids. Biol Psychiatry. 1998 Aug 15;44(4):243-9.
  • Jovanovic H, Cerin A, Karlsson P, Lundberg J, Halldin C, Nordström AL. A PET study of 5-HT1A receptors at different phases of the menstrual cycle in women with premenstrual dysphoria. Psychiatry Res. 2006 Dec 1;148(2-3):185-93. Epub 2006 Nov 7.
  • Jovanovic H, Lundberg J, Karlsson P, Cerin A, Saijo T, Varrone A, Halldin C, Nordström AL. Sex differences in the serotonin 1A receptor and serotonin transporter binding in the human brain measured by PET. Neuroimage. 2008 Feb 1;39(3):1408-19. Epub 2007 Oct 25.
  • Jovanovic H. PET evaluation of central serotonergic neurotransmission in women. Accessed online February 13, 2008 at
  • Karolinska Institute. Sex differences in the brain's serotonin system. Accessed online February 13, 2008 at &fromPage=public&lang=1&PRID=9269

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