Mary's PCOS Treatment FAQ

Depression & Mood Disorder References

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Copyright © 2006 Mary Kate Roget

Updated 10/20/2006


Why did I compile these mood disorder references?

Case Studies
PCOS Treatment Can Improve Depression
Luteinizing Hormone
Quality of Life
Insulin Resistance
Fish Oil

  Why did I compile these mood disorder references?

I have collected the following references to support the claims that, in those with PCOS:

  1. PCOS is associated with mood disorders including depression and bipolar disorder.
  2. The association between PCOS and mood disorders is often a common underlying endocrine disorder.
  3. Treating PCOS can lead to a remission of those mood disorders by correcting the underlying endocrine disorder.
  4. Treating PCOS can be a more effective treatment for depression than antidepressants.

Obviously, mood disorders can have other causes. Whatever the cause, your doctor may indeed want to treat it directly, especially if it's severe.

Too many doctors are ignorant about PCOS. It's frustrating. If you have mentioned to your psychologist or psychiatrist that you suspect you have PCOS, or that you're being treated for PCOS, there's a good chance they have no idea what that means or how important it is to your recovery. These references are here to help you and them appreciate the significance of PCOS in depression and convince them that maybe your treatment for depression should include treatment for PCOS.

Mood disorders are associated with many of the individual features of PCOS including: elevated testosterone, increased luteinizing hormone, insulin resistance, increased TNF-alpha and other inflammatory cytokines, and increased homocysteine.

The first claim that PCOS is associated with mood disorders is fairly well established. notes that symptoms of PCOS include: "Depression or mood swings. Hormonal changes are a known cause of emotional symptoms." According to the American Diabetes Association, "Depression or mood swings also are common in women with PCOS. Although more research is needed to find out about this link, there are studies linking depression to diabetes. Therefore, in PCOS, depression may be related to insulin resistance. It also could be a result of the hormonal imbalances and the cosmetic symptoms of the condition. Acne, hair loss, and other symptoms of PCOS can lead to poor self-esteem. Infertility and miscarriages also can be very stressful. Medications that restore the balance to hormone levels or antidepressants can help these feelings."

These are not all the studies on PCOS and mood, only the ones that support the above claims. There are studies that show that depression and chronic stress can contribute to metabolic disease and PCOS, and I have left those out. There are also several studies showing that fluoxetine, and possibly other antidepressants, can increase insulin sensitivity. Contrary to the abstracts here, birth control pills can cause depression and worsen insulin resistance (depending on the pill). There are many studies on things like exercise, inositol, fish oil, folic acid, magnesium, etc., for depression that I didn't list. Finally, there are many studies that I didn't list related to bipolar disorder showing that some mood stabilizers can make PCOS symptoms worse or cause them.

If I'm missing a good study,

Disclaimer: I am not a doctor. Consult your doctor before using any treatments. Many treatments referenced below are extremely dangerous. Please use this information only as a starting point for doing more research and for topics to discuss with your doctor.

  Case Studies

Common treatment of polycystic ovarian syndrome and major depressive disorder: case report and review.

Rasgon NL, Carter MS, Elman S, Bauer M, Love M, Korenman SG.
Curr Drug Targets Immune Endocr Metabol Disord. 2002 Apr;2(1):97-102.

We present the case of a young woman with treatment-resistant major depression, who presented to the Mood Disorders Clinic with a Hamilton Psychiatric Rating Scale for Depression (HAM-D-21) score of 28, after a year-long treatment with Effexor-XR. The patient also had untreated Polycystic Ovarian Syndrome (PCOS). The resolution of her depressive symptoms resulted from the treatment for PCOS with metformin and spironolactone. The patient remained euthymic 5 months after discontinuation of the antidepressant while continuing therapy for PCOS. We briefly overview of the pertinent literature of the pathophysiology of PCOS and affective disorders, highlighting an overlap in phenotypical presentations between these two disorders. Dysregulation of the hypothalamo-pituitary axis and various end organ systems are implicated in both PCOS and affective disorders. As such, several clinical and biochemical markers are common to both disorders, namely insulin resistance, obesity, and hyperandrogenism. In addition, these metabolic abnormalities are interrelated, causing women with PCOS or affective disorders to get caught in a "vicious cycle" of hormonal dysregulation. The case report presented here illustrates how treatment of symptoms such as insulin resistance and hyperandrogenism can lead to remission of major depressive disorder and PCOS. We suggest that through treatment of underlying metabolic defects, both the mood of the patient and the metabolic condition of PCOS can be assisted.
PMID: 12477299

When not to treat depression in PCOS with antidepressants. (References the study above)

Rasgon NL, Elman S.
Current Psychiatry Online. 2005 Feb;4(2).
Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine.

Women with depression and polycystic ovary syndrome (PCOS) can be trapped in a vicious cycle of hormonal dysregulation. Treating these patients appropriately—with or without antidepressants—requires an understanding of their underlying metabolic disorder. This article presents a case that exemplifies the association between depression and PCOS. Based on our research and clinical experience, we offer recommendations to help you manage depression in patients with PCOS.
Article in Current Psychiatry Online

Organic mood disorder associated with the HAIR-AN syndrome.

Levin TR, Terrell TR, Stoudemire A.
J Neuropsychiatry Clin Neurosci. 1992 Winter;4(1):51-4.
Medical Psychiatric Unit, Emory University Hospital, Atlanta, GA.

The HAIR-AN syndrome is characterized by hyperandrogenism, insulin resistance, and acanthosis nigricans. The authors report the first case of an organic mood disorder associated with this condition that improved markedly in response to ovarian suppression with oral contraceptives. The proposed pathophysiology of this syndrome is also discussed. PIP: Psychiatrists at Emory University Hospital in Atlanta, Georgia examined a 37-year old divorced woman suffering from refractory depression. She reported her 1st bout of depression to be at 9-10 years old (onset of menses). She tried to kill herself at ages 11 and 17. The only time she remembered not being depressed was when she was using oral contraceptives (OCs). She 1st took them for oligomenorrhea at age 14. She suffered from oligomenorrhea off and on ever since then. The next time she took OCs was in her early 20s while she was married. She stopped taking them after she had her son. An outpatient psychiatrist had been treating her for the last 10 years. 3 years before this visit to Emory, psychotic depression and a suicide attempt sent her to a hospital. 5 years before coming to Emory, she gained 40 lbs and developed hirsutism, acne, and a low-pitched voice. 8 months before coming to Emory, a physician diagnosed acanthosis nigricans which is dark hyperpigmentation of the epidermis in body fold areas. 6 months prior to coming to Emory, an endocrinologist evaluated her for oligomenorrhea, obesity, and hirsutism and prescribed 0.25 mg dexamethasone/day to inhibit androgen production, regulate menses, and reduce facial hair. 3 months before admission, she experience severe depression. Her psychiatrist treated her with bupropion, amitriptyline, buspirone, and lithium and continued the same dexamethasone treatment. At Emory, her glucose tolerance tests were abnormal and her insulin levels were elevated. Emory psychiatrist stopped all psychotropic medications and dexamethasone. They and some endocrinologists diagnosed HAIR-AN syndrome (hyperandrogenism, insulin resistance, and acanthosis nigricans). They prescribed OCs and within several weeks her mood improved. 2 months later she was fine and had lost 25 lbs. The primary disturbances of HAIR-AN syndrome are insulin resistance and hyperandrogenism. These 2 disturbances together cause acanthosis nigricans.
PMID: 1627962

Mania in hyperandrogenism, insulin resistance, and nigricans acanthosis syndrome.

Chan YC, Hankins MB, John-Daniel B.
Am J Psychiatry. 2002 Feb;159(2):318.
Columbus, Ohio.

To the Editor: Hyperandrogenism, insulin resistance, and acanthosis nigricans (HAIR-AN) syndrome has been defined only in the past 20 years and may be present in as many as 1%–3% of all women with hyperandrogenism (1). A case of organic mood disorder (depressed type) associated with the HAIR-AN syndrome, which improved markedly in response to ovarian suppression with oral contraceptives, has been documented (2). In this report, we describe a patient with HAIR-AN syndrome who developed her first manic episode after she had stopped taking her birth control pills 2 months earlier.
PMID: 11823285

Polycystic ovary syndrome and psychiatric morbidity.

Bruce-Jones W, Zolese G, White P.
J Psychosom Obstet Gynaecol. 1993 Jun;14(2):111-6.
Department of Psychological Medicine, St Bartholomew's Hospital, London, UK.

Ten cases are reported of polycystic ovary syndrome (PCOS) in association with psychiatric illness presenting to a liaison psychiatry service. This association is critically reviewed paying attention to explanatory factors such as selection bias and steroid treatments. Monoamine imbalances may be involved in the etiology of both PCOS and the accompanying psychiatric illness.
PMID: 8102925

HAIR-AN syndrome and mental disorders.

Morales-Rosello J.
J Neuropsychiatry Clin Neurosci. 1995 Fall;7(4):538-9.

A case study is reported of organic mood disorder in association with HAIR-AN syndrome. Depression responded to treatment with oral contraceptives.
PMID: 8555759

  PCOS Treatment Can Improve Depression

Metformin treatment of polycystic ovary syndrome improves health-related quality-of-life, emotional distress and sexuality.

Hahn S, Benson S, Elsenbruch S, Pleger K, Tan S, Mann K, Schedlowski M,van Halteren WB, Kimmig R, Janssen OE.
Hum Reprod. 2006 Jul;21(7):1925-34. Epub 2006 Mar 20.
Division of Endocrinology, Department of Medicine, Institute of Medical Psychology, University of Duisburg-Essen, Germany.

BACKGROUND: In polycystic ovary syndrome (PCOS), changes in physical appearance, menstrual disturbances and infertility result in psychological distress and reduced quality-of-life. Metformin improves biochemical, clinical and reproductive parameters in PCOS women. In a prospective, observational study, we analysed the effects of metformin treatment on health-related quality-of-life (HRQL), emotional well-being and sexuality in PCOS. No placebo-treated control group was included. METHODS: Before, during and after 6 months of treatment, changes in clinical and endocrine parameters, quality-of-life, psychological disturbances and sexuality were assessed in 64 PCOS patients using validated questionnaires (SF-36, SCL-90-R) and visual analogue scales. Patients were also compared with published normative data for the validated questionnaires. RESULTS: During treatment, HRQL, particularly the psychosocial aspects (indicated by significant increases in SF-36 scales Vitality, Social Function, Emotional Role Function, Mental Health, Psychological Sum scale) and emotional well-being (reflected by significant lowering of SCL-90-R scales) improved. These improvements in HRQL were significantly correlated with a reduction in body weight and significantly more pronounced in patients with normalized menstrual cycles. In addition, PCOS women were significantly more satisfied with their sex life and reported higher frequencies of sexual intercourse following treatment. CONCLUSION: Treatment can improve the psychosocial, emotional and psychosexual situation of PCOS patients. Although at least some of these effects may be related to the reduction of individual clinical symptoms (i.e. weight loss, normalization of menstrual disturbances, improvement of acne), this observational study does not allow us to clearly discern the role of symptom constellation and does not preclude non-specific and/or placebo effects. Nevertheless, emotional distress and reduced quality-of-life are clearly not an inevitable consequence of PCOS and should be considered as adjunct treatment goals in future studies.
PMID: 16549423

Major depression associated with endocrine disease.

Fava GA, Sonino N, Morphy MA.
Psychiatr Dev. 1987 Winter;5(4):321-48.
Division of Psychosomatic Medicine, University of Bologna, Italy.

The discovery of specific behavioral effects of several neuropeptides and the expanded appreciation of a wide range of endocrine disturbances in depressive illness have recently renewed interest in the nature of the relationship between mood and endocrine changes. Major depressive disorders are a major and life-threatening complication of Cushing's syndrome, Addison's disease, hyperthyroidism, hypothyroidism and hyperprolactinemic amenorrhea. A treatment primarily directed to the physical condition may be more effective than antidepressant drugs in such organic affective syndromes. The influence of hormonal disturbances in the development of depression in Conn's disease, pheochromocytoma, parathyroid disturbances, SIADH, acromegaly, hirsutism and other endocrine diseases should be individually evaluated. Antidepressant drugs remain the most specific and readily available treatment of major depressive disorders in the setting of endocrine illness.
PMID: 3328199

Depression in women with polycystic ovary syndrome: clinical and biochemical correlates.

Rasgon NL, Rao RC, Hwang S, Altshuler LL, Elman S, Zuckerbrow-Miller J, Korenman SG.
J Affect Disord. 2003 May;74(3):299-304.
Department of Psychiatry and Biobehavioral Sciences, University of California Los Angeles School of Medicine, Mood Disorders Research Program.

BACKGROUND: We assessed the prevalence of mood disturbance among women with prospectively documented polycystic ovary syndrome (PCOS). METHODS: Thirty-two women with PCOS completed the Center for Epidemiological Studies-Depression Rating Scale (CES-D). Clinical and biochemical characteristics were assessed. RESULTS: Sixteen women had CES-D scores indicative of depression. Depression was associated with greater insulin resistance (P=0.02) and higher body mass index (P=0.05). Women receiving oral contraceptives for the treatment of PCOS were less depressed than patients not receiving treatment (P=0.03). LIMITATIONS: Possible selection bias, use of a screening tool alone without further diagnostic evaluation of depression, small samples size and lack of direct comparison with an age matched control group, should be considered in interpretation of these results. CONCLUSION: Findings suggest a high prevalence of depression among women with PCOS, and an association between depression and PCOS markers.
PMID: 12738050


Androgens and mood dysfunction in women: comparison of women with polycystic ovarian syndrome to healthy controls.

Weiner CL, Primeau M, Ehrmann DA.
Psychosom Med. 2004 May-Jun;66(3):356-62.
Behavioral and Neuropsychological Consultants, LLP, New York, USA.

OBJECTIVE: Our understanding of the organizational and activational effects of human gonadal hormones on behavior has depended on the study of endocrine disorders. Polycystic ovarian syndrome (PCOS) is a hormonal disorder that begins in puberty and is characterized by chronically augmented free testosterone (FT) levels. The purposes of this study were 1) to compare negative mood states of women with PCOS to those of women with normal hormonal levels and 2) to examine the relationship between negative moods and androgens. METHODS: Twenty-seven women with PCOS were case-matched to 27 normal menstruating women on body mass index since being overweight is a common symptom of PCOS and could affect mood states. Serum levels of FT, total testosterone, sex hormone binding globulin, estradiol, and progesterone were determined. Self-reported depression, anger, anxiety, and aggression were analyzed between groups, and individual scores were compared across groups to hormone values. RESULTS: Depression was significantly increased in the PCOS group and remained so after considering the variance related to physical symptomatology and other mood states. Furthermore, a curvilinear relationship between FT and negative affect across groups was suggested: the most elevated negative mood-scale scores were associated with FT values just beyond the upper limits of normal, while lower negative mood levels corresponded to both normal and extremely high values of FT. CONCLUSIONS: These results are consistent with a model of activational influences of testosterone on adult female behavior. Implications are discussed for future research and for treatment of PCOS and other menstrual-cycle mood disorders.
PMID: 15184695

Serum androgens and depression in women with facial hirsutism.

Shulman LH, DeRogatis L, Spielvogel R, Miller JL, Rose LI.
J Am Acad Dermatol. 1992 Aug;27(2 Pt 1):178-81.
Department of Medicine, Hahnemann University School of Medicine, Philadelphia, PA.

BACKGROUND: Studies on the psychopathologic aspects of hirsutism are sparse. Attempts to correlate these aspects with either the extent of the facial hirsutism and/or circulating serum androgens are virtually nonexistent. This study evaluates the psychopathologic aspects of hirsutism and correlates these findings with the extent of the facial hirsutism as well as with the circulating serum androgens. OBJECTIVE: Our purpose was to assess the psychopathologic aspects of facial hirsutism and to determine whether any correlation exists between these findings and either the extent of the facial hirsutism or the circulating serum androgens. METHODS: Twenty consecutive women with facial hirsutism were studied by administration of psychologic tests (DeRogatis Symptom Inventory and the Affects Balance Scale). The results of these tests were correlated with the grade of facial hirsutism as well as serum levels of total testosterone (T), biologically active testosterone (BT), free testosterone (FT), dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate (DHEA-S), and androstenedione (A-dione). RESULTS: Significant levels of depression were found. No correlation was found between the psychopathologic measurements and the extent of facial hirsutism or serum levels of T, DHEA, DHEA-S, and A-dione. Significant correlations were found between depression and serum levels of FT and BT. CONCLUSION: There is an increased incidence of depression in facially hirsute women and this correlates with their circulating active testosterone levels and not with the extent of their facial hirsutism.
PMID: 1430353

Serum androgens and psychopathology in hirsute women.

Derogatis LR, Rose LI, Shulman LH, Lazarus LA.
J Psychosom Obstet Gynaecol. 1993 Dec;14(4):269-82.
Department of Mental Health Sciences, Hahnemann University School of Medicine, Philadelphia, PA.

Twenty consecutive women referred for evaluation and treatment of idiopathic hirsutism were evaluated with regard to levels of serum androgens, degree of hirsutism, nature and prevalence of psychological symptoms, and mood and affects. Androgens measured were total testosterone, free testosterone, biologically active testosterone, dehydroepiandrosterone, dehydroepiandrosterone sulfate and androstenedione. Psychological symptoms were quantified via the Derogatis Symptom Inventory, and mood and affects were measured by the Affects Balance Scale. Results revealed very significant correlations between unbound fractions of testosterone (i.e. free and biologically active testosterone) and both symptom and mood measures of depression (r = 0.60; p < 0.01). Significant inverse correlations were also observed between unbound fractions of testosterone and positive affects measures (e.g. 'contentment' r = -0.51; p < 0.05). Correlations between total testosterone and psychological variables were non-significant in all instances. Measures of degree of hirsutism correlated approximately zero (o) with psychological symptom and mood measures in this sample. When psychiatric 'caseness' criteria were applied to the cohort, seven of the 20 women (35%) were found to be positive. Results are interpreted to suggest that depression among hirsute women appears more likely to have its basis in a deranged neuroendocrine mechanism than in psychosocial causes.
PMID: 8142981

The impact of testosterone imbalance on depression and women's health.

Rohr UD.
Maturitas. 2002 Apr 15;41 Suppl 1:S25-46.
Department of Gynecology and Obstetrics, Gynecological Oncology, University Hospital, Essen, Germany.

Women suffer more often from depression than males, indicating that hormones might be involved in the etiology of this disease. Low as well as high testosterone (T) levels are related to depression and well-being in women, T plasma levels correlate to depression in a parabolic curve: at about 0.4-0.6 ng/ml plasma free T a minimum of depression is detected. Lower levels are related to depression, osteoporosis, declining libido, dyspareunia and an increase in total body fat mass. Androgen levels in women decrease continuously to about 50% before menopause compared to a 20-year-old women. Androgen levels even decline 70% within 24 h when women undergo surgical removal of the ovaries. Conventional oral contraception or HRT cause a decline in androgens because of higher levels of SHBG. Hyperandrogenic states exist, like hirsutism, acne and polycystic ovary syndrome. Social research suggests high androgen levels cause aggressive behavior in men and women and as a consequence may cause depression. Higher androgen values are more pronounced at young ages and before and after delivery of a baby and might be responsible for the "baby blues". It was found that depression in pubertal girls correlated best with an increase in T levels in contrast to the common belief that "environmental factors" during the time of growing up might be responsible for emotional "up and downs". T replacement therapy might be useful in perimenopausal women suffering from hip obesity, also named gynoid obesity. Abdominal obesity in men and women is linked to type 2 diabetes and coronary heart diseases. Testosterone replacement therapy in hypoandrogenic postmenopausal women might not only protect against obesity but also reduce the risk of developing these diseases. Antiandrogenic progestins might be useful for women suffering from hyperandrogenic state in peri- and postmenopause. Individual dosing schemes balancing side effects and beneficial effects are absolutely necessary. Substantial interindividual variability in T plasma values exists, making it difficult to utilize them for diagnostic purposes. Therefore a "four-level-hormone classification scheme" was developed identifying when estradiol (E) and T levels are out of balance. (1) Low E-low T levels are correlated with osteoporosis, depression, and obesity; (2) high E-low T with obesity, decreased libido; (3) high T-low E levels with aggression, depression, increased libido, and substance abuse; (4) high E-high T with type II diabetes risk, breast cancer and cardiovascular risk. Testosterone delivery systems are needed where beneficial and negative effects can be balanced. Any woman diagnosed for osteoporosis should be questioned for symptoms of depression.
PMID: 11955793

The stress system in the human brain in depression and neurodegeneration.

Swaab DF, Bao AM, Lucassen PJ.
Ageing Res Rev. 2005 May;4(2):141-94.
Netherlands Institute for Brain Research, Amsterdam.

Corticotropin-releasing hormone (CRH) plays a central role in the regulation of the hypothalamic-pituitary-adrenal (HPA)-axis, i.e., the final common pathway in the stress response. The action of CRH on ACTH release is strongly potentiated by vasopressin, that is co-produced in increasing amounts when the hypothalamic paraventricular neurons are chronically activated. Whereas vasopressin stimulates ACTH release in humans, oxytocin inhibits it. ACTH release results in the release of corticosteroids from the adrenal that, subsequently, through mineralocorticoid and glucocorticoid receptors, exert negative feedback on, among other things, the hippocampus, the pituitary and the hypothalamus. The most important glucocorticoid in humans is cortisol, present in higher levels in women than in men. During aging, the activation of the CRH neurons is modest compared to the extra activation observed in Alzheimer's disease (AD) and the even stronger increase in major depression. The HPA-axis is hyperactive in depression, due to genetic factors or due to aversive stimuli that may occur during early development or adult life. At least five interacting hypothalamic peptidergic systems are involved in the symptoms of major depression. Increased production of vasopressin in depression does not only occur in neurons that colocalize CRH, but also in neurons of the supraoptic nucleus (SON), which may lead to increased plasma levels of vasopressin, that have been related to an enhanced suicide risk. The increased activity of oxytocin neurons in the paraventricular nucleus (PVN) may be related to the eating disorders in depression. The suprachiasmatic nucleus (SCN), i.e., the biological clock of the brain, shows lower vasopressin production and a smaller circadian amplitude in depression, which may explain the sleeping problems in this disorder and may contribute to the strong CRH activation. The hypothalamo-pituitary thyroid (HPT)-axis is inhibited in depression. These hypothalamic peptidergic systems, i.e., the HPA-axis, the SCN, the SON and the HPT-axis, have many interactions with aminergic systems that are also implicated in depression. CRH neurons are strongly activated in depressed patients, and so is their HPA-axis, at all levels, but the individual variability is large. It is hypothesized that particularly a subgroup of CRH neurons that projects into the brain is activated in depression and induces the symptoms of this disorder. On the other hand, there is also a lot of evidence for a direct involvement of glucocorticoids in the etiology and symptoms of depression. Although there is a close association between cerebrospinal fluid (CSF) levels of CRH and alterations in the HPA-axis in depression, much of the CRH in CSF is likely to be derived from sources other than the PVN. Furthermore, a close interaction between the HPA-axis and the hypothalamic-pituitary-gonadal (HPG)-axis exists. Organizing effects during fetal life as well as activating effects of sex hormones on the HPA-axis have been reported. Such mechanisms may be a basis for the higher prevalence of mood disorders in women as compared to men. In addition, the stress system is affected by changing levels of sex hormones, as found, e.g., in the premenstrual period, ante- and postpartum, during the transition phase to the menopause and during the use of oral contraceptives. In depressed women, plasma levels of estrogen are usually lower and plasma levels of androgens are increased, while testosterone levels are decreased in depressed men. This is explained by the fact that both in depressed males and females the HPA-axis is increased in activity, parallel to a diminished HPG-axis, while the major source of androgens in women is the adrenal, whereas in men it is the testes. It is speculated, however, that in the etiology of depression the relative levels of sex hormones play a more important role than their absolute levels. Sex hormone replacement therapy indeed seems to improve mood in elderly people and AD patients. Studies of rats have shown that high levels of cumulative corticosteroid exposure and rather extreme chronic stress induce neuronal damage that selectively affects hippocampal structure. Studies performed under less extreme circumstances have so far provided conflicting data. The corticosteroid neurotoxicity hypothesis that evolved as a result of these initial observations is, however, not supported by clinical and experimental observations. In a few recent postmortem studies in patients treated with corticosteroids and patients who had been seriously and chronically depressed no indications for AD neuropathology, massive cell loss, or loss of plasticity could be found, while the incidence of apoptosis was extremely rare and only seen outside regions expected to be at risk for steroid overexposure. In addition, various recent experimental studies using good stereological methods failed to find massive cell loss in the hippocampus following exposure to stress or steroids, but rather showed adaptive and reversible changes in structural parameters after stress. Thus, the HPA-axis in AD is only moderately activated, possibly due to the initial (primary) hippocampal degeneration in this condition. There are no convincing arguments to presume a causal, primary role for cortisol in the pathogenesis of AD. Although cortisol and CRH may well be causally involved in the signs and symptoms of depression, there is so far no evidence for any major irreversible damage in the human hippocampus in this disorder.
PMID: 15996533

  Luteinizing Hormone

Luteinizing hormone pulse characteristics in depressed women.

Meller WH,Zander KM,Crosby RD,Tagatz GE.
Am J Psychiatry. 1997 Oct;154(10):1454-5.
Department of Psychiatry, University of Minnesota Hospital, Minneapolis, USA.

OBJECTIVE: Luteinizing hormone (LH) pulse characteristics in depressed and normal women were compared to determine whether hypothalamic dysregulation in depression extends to the hypothalamic-pituitary-gonadal axis. METHOD: The subjects were 10 depressed and 13 normal comparison women admitted to a clinical research center. For each woman, an intravenous line was started and blood was withdrawn every 10 minutes for 8 hours. Blood samples were assayed for LH and LH pulse characteristics determined by using the computerized cluster algorithm of Veldhuis and Johnson. RESULTS: The depressed women differed significantly from the comparison women in LH pulse amplitude, rhythmicity, and area under the curve. CONCLUSIONS: Major depressive disorder is associated with abnormal regulation of luteinizing hormone. Gonadotropin regulation may provide a hormonal link between major depressive disorder and impaired fertility.
PMID: 9326832

Elevated serum LH and androgens in affective disorder related to the menstrual cycle: with reference to polycystic ovary syndrome.

Matsunaga H, Sarai M.
Jpn J Psychiatry Neurol. 1993 Dec;47(4):825-42.
Department of Psychiatry, Osaka Prefectural Hospital, Japan.

The hypothalamo-pituitary-gonadal axis was studied in 12 young women with manic-depressive or psychotic symptoms which obviously fluctuated in association with the menstrual cycle, and also in 36 psychiatric patients with other diagnoses. The hormonal features frequently observed among these 12 cases were elevated basal LH (8 of 12 cases), decreased basal FSH (6 of 12), elevated serum testosterone (6 of 12), androstenedione (5 of 12) and/or dehydroepiandrosterone-sulfate (3 of 11). These abnormalities resemble those of polycystic ovary syndrome (PCOS). An ultrasonographical study revealed polycystic changes in 8 out of the 12 cases. In 10 cases clomiphene citrate was administered, and was effective in 8. In comparison with the pathophysiology of PCOS, a possible relationship was suggested between the psychiatric problems and the PCOS-like hormonal abnormalities in these cases.
PMID: 8201793


Quality of life, psychosocial well-being, and sexual satisfaction in women with polycystic ovary syndrome.

Elsenbruch S, Hahn S, Kowalsky D, Offner AH, Schedlowski M, Mann K, Janssen OE.
J Clin Endocrinol Metab. 2003 Dec;88(12):5801-7.
Department of Medical Psychology, University of Essen, Essen, Germany.

Polycystic ovary syndrome (PCOS) is a common endocrine disorder characterized by chronic anovulation and hyperandrogenism. PCOS is one of the leading causes of infertility and manifests with hirsutism, acne, and obesity. To investigate its impact on health-related quality of life and sexuality, 50 women with PCOS and 50 controls were evaluated with standardized questionnaires (36-item short-form health survey, symptom checklist revised, and life satisfaction questionnaire). The impact of hirsutism, obesity, and infertility was assessed using five-point rating scales, and sexual satisfaction was analyzed with visual analog scales. Patients showed greater psychological disturbances on the symptom checklist revised dimensions, obsessive-compulsive, interpersonal sensitivity, depression, anxiety, aggression, and psychoticism, along with a lower degree of life satisfaction in the life satisfaction questionnaire scales health, self, and sex. Health-related quality of life measured with the 36-item short-form health survey revealed significantly decreased scores for physical role function, bodily pain, vitality, social function, emotional role function, and mental health in patients with PCOS. Although patients had the same partner status and frequency of sexual intercourse, they were significantly less satisfied with their sex life and found themselves less attractive. Most of the differences were not affected by correction for body weight. In conclusion, PCOS causes a major reduction in the quality of life and severely limits sexual satisfaction.
PMID: 14671172

Depression and body image among women with polycystic ovary syndrome.

Himelein MJ, Thatcher SS.
J Health Psychol. 2006 Jul;11(4):613-25.
Department of Psychology, University of North Carolina at Asheville, USA.

Common features of polycystic ovary syndrome (PCOS), including hyperandrogenism, ovarian dysfunction and obesity, can be highly distressing. We compared 40 women with PCOS to women with infertility but not PCOS, and to women with neither PCOS nor infertility, on measures of depression and body image. Women with PCOS reported higher depression scores and greater body dissatisfaction (p < .001) than comparison group women. Body image was strongly associated with depression overall, even after controlling body mass. Among women with PCOS, body dissatisfaction measures and education explained 66 percent of the variance in depression, suggesting explanations of the PCOS-depression link should consider the role of potentially mediating psychosocial variables.
PMID: 16769740

The effect of polycystic ovary syndrome on health-related quality of life.

Coffey S, Mason H.
Gynecol Endocrinol. 2003 Oct;17(5):379-86.
Graduate Entry Programme, St George's Hospital Medical School, London, UK.

This article reviews current literature regarding polycystic ovary syndrome (PCOS) and health-related quality of life (HRQoL), as well as examining how some of the manifestations of PCOS affect HRQoL. The only quantitative study was performed in adolescent girls. It used a well-validated instrument and showed that HRQol was worse in those with PCOS in the areas of general health perceptions, behavior, physical functioning and family activity. No comparable study exists for adults with PCOS. However, qualitative psychological studies have demonstrated higher levels of depression, psychological and psychosexual morbidity and an increased response to stress in women with PCOS compared with controls. Low self-esteem, decreased social activity and less romantic contentment were reported in women with PCOS. Weight and hirsutism consistently caused more concern than menstrual problems or infertility. The symptoms associated with PCOS, namely hirsutism, acne, diabetes mellitus and obstructive sleep apnea syndrome (OSAS) were all reported to reduce HRQoL in separate studies. Encouragingly, treatment for acne and OSAS improved the HRQoL, although treatment for hirsutism did not. Quantitative studies on the effect of PCOS on HRQoL and the benefit of treatments need to be conducted.
PMID: 14710585

The polycystic ovary syndrome--a medical condition but also an important psychosocial problem.

Eggers S, Kirchengast S.
Coll Antropol. 2001 Dec;25(2):673-85.
Laboratory of Biological Antropology, Centre of Human Genome Studies, Institute of Bioscience.

PCOS, the leading cause of anovulatory infertility that affects up to one fifth of the female population, is a complex chronic disease of genetic as well as environmental determination, but still unclear etiology. Besides of infertility, PCOS leads to menstrual dysfunctions, hirsutism and obesity--symptoms that are known to cause profound psychosocial distress. The present paper review the problematic of etiology and symptom expression of PCOS, which is not only a disease needing medical treatment but also a psychosocial problem for the affected women. PCOS may not only coinduced by psychosocial factors, the main symptoms of PCOS such as infertility, menstrual dysfunctions, hirsutism and obesity cause by themselves increased psychosocial stress.
PMID: 11811299

The lived experience of women diagnosed with polycystic ovary syndrome.

Snyder BS.
J Obstet Gynecol Neonatal Nurs. 2006 May-Jun;35(3):385-92.
School of Nursing, The College of New Jersey, Ewing, NJ 08628, USA.

OBJECTIVE: To uncover the meaning of living with polycystic ovary syndrome. DESIGN: Phenomenology. SETTING: A women's health care practice in northeast United States. PARTICIPANTS: A purposive sample consisting of 12 women, ages 21 to 48 years, who had been previously diagnosed with polycystic ovary syndrome. DATA COLLECTION: Semistructured interviews. RESULTS: Analysis of the participants' responses revealed the following themes: (a) identifying differences, (b) wanting to be normal, (c) searching for answers, (d) gaining control, (e) attempting to achieve femininity, (f) letting go of guilt, and (g) dealing with it. CONCLUSIONS: Polycystic ovary syndrome is a syndrome that impacts women both physically and psychosocially. Nurses can play a key role in assisting women afflicted with this hormonal disturbance through education and support.
PMID: 16700688

Women living with facial hair: the psychological and behavioral burden.

Lipton MG, Sherr L, Elford J, Rustin MH, Clayton WJ.
J Psychosom Res. 2006 Aug;61(2):161-8.
Department of Primary Care and Population Sciences, Royal Free and University College Medical School, Hampstead Campus, Rowland Hill Street, NW3 2PF London, UK.

OBJECTIVE: While unwanted facial hair is clearly distressing for women, relatively little is known about its psychological impact. This study reports on the psychological and behavioral burden of facial hair in women with suspected polycystic ovary syndrome. METHODS: Eighty-eight women (90% participation rate) completed a self-administered questionnaire concerning hair removal practices; the impact of facial hair on social and emotional domains; relationships and daily life; anxiety and depression (Hospital Anxiety and Depression Scale); self-esteem (Rosenberg Self-esteem Scale); and quality of life (WHOQOL-BREF). RESULTS: Women spent considerable time on the management of their facial hair (mean, 104 min/week). Two thirds (67%) reported continually checking in mirrors and 76% by touch. Forty percent felt uncomfortable in social situations. High levels of emotional distress and psychological morbidity were detected; 30% had levels of depression above the clinical cut off point, while 75% reported clinical levels of anxiety; 29% reported both. Although overall quality of life was good, scores were low in social and relationship domains--reflecting the impact of unwanted facial hair. CONCLUSION: Unwanted facial hair carries a high psychological burden for women and represents a significant intrusion into their daily lives. Psychological support is a neglected element of care for these women.
PMID: 16880018

  Quality of Life

Health-related quality of life issues in women with polycystic ovary syndrome.

McCook JG, Reame NE, Thatcher SS.
J Obstet Gynecol Neonatal Nurs. 2005 Jan-Feb;34(1):12-20.
East Tennessee State University College of Nursing, Johnson City, TN, USA.

OBJECTIVE: To evaluate the influence of obesity, fertility status, and androgenism scores on health-related quality of life in women with polycystic ovary syndrome (PCOS). DESIGN: Cross-sectional, correlational. SETTING: Private reproductive endocrinology practice in two southeast U.S. cities. PARTICIPANTS: Convenience sample of 128 women with PCOS, half of whom were attempting to conceive in addition to being treated for PCOS. Most were White (97%), married (78%), with a mean age of 30.4 years (SD +/- 5.5). MAIN OUTCOME MEASURES: The Health-Related Quality of Life Questionnaire (PCOSQ) for women with polycystic ovary syndrome. A laboratory panel and clinical measures, including body mass index, waist-to-hip ratio, and degree of hirsutism. RESULTS: The most common health-related quality of life concern reported by women with PCOS was weight, followed in descending order by menstrual problems, infertility, emotions, and body hair. CONCLUSIONS: The psychological implications of PCOS are easily underestimated and have been largely ignored. Nursing has a pivotal role in recognizing these concerns and implementing therapy to improve quality of life in women with PCOS.
PMID: 15673641

Polycystic Ovary Syndrome and Mental Health: A Review.

Himelein MJ, Thatcher SS.
Obstet Gynecol Surv. 2006 Nov;61(11):723-732.
University of North Carolina at Asheville, North Carolina; Center for Applied Reproductive Science; and Center for Applied Reproductive Science.

Although physical symptoms of polycystic ovary syndrome (PCOS) are increasingly recognized by practicing clinicians, little attention has focused on psychological correlates of this frequent endocrine disorder. This review of medical and psychological literature indicates that PCOS is associated with several mental health problems, including depression and anxiety, body dissatisfaction and eating disorders, diminished sexual satisfaction, and lowered health-related quality of life. Although the causal direction of these relationships has not been established, it is clear that effective and comprehensive treatment of women with PCOS must encompass careful attention to psychological symptomatology. Recommendations for the assessment of specific mental health problems, management of related physical concerns, and treatment of obesity among women with PCOS are presented. Target Audience: Obstetricians & Gynecologists, Family Physicians Learning Objectives: After completion of this article, the reader should be able to explain that, in addition to physiologic changes, women with polycystic ovary syndrome (PCOS) have various mental health problems and lowered health-related quality of life issues and state that treatment must address these concerns.
PMID: 17044949

Health-related quality of life in women with polycystic ovary syndrome: a comparison with the general population using the Polycystic Ovary Syndrome Questionnaire (PCOSQ) and the Short Form-36 (SF-36).

Coffey S, Bano G, Mason HD.
Gynecol Endocrinol. 2006 Feb;22(2):80-6.
Graduate Entry Programme, St. George's, University of London, London, UK.

BACKGROUND: We examined whether women with polycystic ovary syndrome (PCOS) have poorer health-related quality of life (HRQoL) than women in the general population and than patients with other medical conditions. METHOD: Women with PCOS were recruited from an outpatient clinic and a control group was recruited from a family planning clinic. Both groups completed the Short Form-36 (SF-36) and the Polycystic Ovary Syndrome Questionnaire (PCOSQ). SF-36 data from the Oxford Health and Lifestyle Survey were used to compare PCOS with other conditions. RESULTS: Twenty-two women with PCOS and 96 control women took part. Women with PCOS scored lower in both summary scores of the SF-36 and in all domains of the PCOSQ. After adjusting for body mass index, the differences between the groups in the SF-36 disappeared, while those in the PCOSQ remained. When compared with asthma, epilepsy, diabetes, back pain, arthritis and coronary heart disease, our PCOS group had the same or better physical HRQoL but poorer psychological HRQoL. The PCOSQ showed good internal reliability, good concurrent validity and good discriminant validity. CONCLUSIONS: PCOS has a negative impact on HRQoL even when compared with other serious health conditions. The PCOSQ is reliable and valid for clinical use.
PMID: 16603432

Determinants of emotional distress in women with polycystic ovary syndrome.

Elsenbruch S, Benson S, Hahn S, Tan S, Mann K, Pleger K, Kimmig R, Janssen OE.
Hum Reprod. 2006 Apr;21(4):1092-9. Epub 2006 Feb 3.
Department of Medical Psychology, Endokrinologikum Ruhr, Center for Endocrine and Metabolic Diseases, Bochum, Germany.

BACKGROUND: The goals were to analyse the incidence of mental distress in women with untreated polycystic ovary syndrome (PCOS) using self-report measures, to characterize PCOS patients at risk for psychiatric disease with regard to sociodemographic and clinical characteristics, and to assess the impact of emotional distress on quality of life. METHODS AND RESULTS: Complete metabolic, hormonal, clinical and self-report psychological data [emotional distress, Symptom Check List 90 (SCL-90-R); quality of life, Short-Form Health Survey 36 (SF-36); sexual satisfaction, visual analogue scales; sociodemographic data] were obtained from n = 143 untreated women with PCOS. Prior psychiatric diagnoses were exclusionary. Twenty-two patients (15.4%) had a possible psychological disorder, based on SCL-90-R global severity index (GSI) scores > or =63 (SCL cases). SCL cases had significantly elevated body mass index (BMI), but did not differ from SCL non-cases in other clinical, endocrine, metabolic or sociodemographic variables. Stepwise multiple regression analyses identified GSI as a significant predictor of SF-36 Psychological Sum score, along with age and current wish to conceive (R2 = 0.47); the SF-36 Physical Sum score was predicted by BMI and education (R2 = 0.27), but not GSI. CONCLUSIONS: Psychiatric illness may go undetected in a proportion of PCOS patients. Although the majority of patients exhibit subclinical levels of psychological disturbances, emotional distress together with obesity lead to large decrements in quality of life in PCOS.
PMID: 16459352

Diagnosis and treatment of polycystic ovarian syndrome and insulin resistance.

Fleischman A, Mansfield J.
Pediatr Ann. 2005 Sep;34(9):733-8, 741-2.
Joslin Diabetes Center, Boston, MA 02215, USA.

PCOS is a complex syndrome that includes clinical and biochemical evidence of hyperandrogenism and hyperinsulinism. Adolescents with PCOS are affected by the diagnosis with both short-term and long-term consequences. Adolescents with PCOS report lower self-esteem and quality of life, based on standard assessments, when compared with age matched peers. These young women also are concerned about future fertility, which may affect psychological well being and health behaviors. In addition, patients with PCOS are at an increased risk for development of insulin resistance, type 2 diabetes, metabolic syndrome, and cardiovascular disease. Therefore, this identified at-risk group requires rigorous evaluation, treatment and long-term counseling and management by healthcare providers.
PMID: 16222950

Increased risk of depression in women with polycystic ovary syndrome.

Hollinrake B, Abreu, A, Van Voorhis B, Dokras A.
Fertil Steril. 2005 Sep;84(1):S55-S55.
University of Iowa, Iowa City, IA.
Presented at the 61st ASRM/CFAS meeting, Montreal.

A total of 35% of those with polycystic ovary syndrome also had depression in a case-control study of 206 women.
Summary in OB/GYN News


Screening for bipolar disorder in women with polycystic ovary syndrome: a pilot study.

Klipstein KG, Goldberg JF.
J Affect Disord. 2006 Apr;91(2-3):205-9. Epub 2006 Feb 17.
Department of Psychiatry, Mount Sinai Medical Center, 1 Gustave L. Levy Place, New York, USA.

OBJECTIVE: Previous reports have attributed polycystic ovary syndrome (PCOS) to valproate treatment in women with bipolar disorder and with epilepsy. However, since high rates of mood disorders have been identified in women with PCOS, we sought to investigate the hypothesis that an intrinsic association may exist between PCOS and bipolar disorder, independent of pharmacotherapy. METHOD: Seventy-eight women identified with PCOS were screened for the presence of bipolar illness using the Mood Disorders Questionnaire (MDQ), a validated self-assessment screen for bipolar disorder. RESULTS: Twenty-eight percent of subjects had either a previous bipolar diagnosis or met MDQ threshold criteria for bipolar screen positivity. Ninety seven percent of previously diagnosed or MDQ screen-positive subjects had no valproate exposure before PCOS diagnosis. LIMITATIONS: Possible selection bias, lack of direct comparison with a control group, and lack of knowledge of specific diagnostic work up for PCOS, should all be considered in interpretation of these results. The MDQ as a self-report screen may be less sensitive to detect bipolar II or NOS than bipolar I disorder, and was not corroborated by a diagnostic interview. CONCLUSION: These preliminary findings suggest a higher rate of bipolar screen positivity among women with PCOS than is expected in the general population, independent of an association with valproate. This observed link between PCOS and bipolar screen-positivity is consistent with a possible shared hypothalamic-pituitary-gonadal axis abnormality.
PMID: 16487597

Associations between bipolar disorder and metabolic syndrome: A review.

J Clin Psychiatry. 2006 Jul;67(7):1034-41.
Taylor V, MacQueen G.

Department of Psychiatry and Behavioral Neurosciences, McMaster University, Hamilton, Ontario, Canada.

OBJECTIVES: To examine the pathophysiologic mechanisms that may link bipolar disorder and metabolic syndrome and to discuss whether the consequences of metabolic syndrome underlie a substantive portion of the premature morbidity and mortality observed in persons with bipolar disorder. DATA SOURCES: A MEDLINE search, citing articles from 1966 onward, supplemented by a review of bibliographies, was conducted to identify relevant studies. Bipolar disorder, mood disorder, metabolic syndrome, diabetes, cardiovascular illness, and obesity were used as keywords. Criteria used to select studies included (1) English language, (2) published studies with original data in peer-reviewed journals, and (3) studies that confirmed the nature of the mood disorder examined. RESULTS: Ninety-seven studies met criteria and were reviewed for evidence of dysregulation in various physiologic systems. Bipolar disorder and metabolic syndrome share features of hormonal, immunologic, and autonomic nervous system dysregulation. CONCLUSION: Lifestyle features may account, in part, for the premature mortality observed in bipolar disorder, but the somatic correlates of the illness may also predispose patients to metabolic syndrome and the consequent increased risk of diseases such as diabetes and vascular disease.
PMID: 16889445

Reproductive function and risk for PCOS in women treated for bipolar disorder.

Bipolar Disord. 2005 Jun;7(3):246-59.
Rasgon NL, Altshuler LL, Fairbanks L, Elman S, Bitran J, Labarca R, Saad M, Kupka R, Nolen WA, Frye MA, Suppes T, McElroy SL, Keck PE Jr,Leverich G, Grunze H, Walden J, Post R, Mintz J.
Department of Psychiatry, Stanford School of Medicine, Palo Alto, CA, USA.

INTRODUCTION: This study examined the reproductive function and prevalence of polycystic ovary syndrome (PCOS) in women with bipolar disorder taking antimanic medications. METHOD: Women aged 18-45 treated for bipolar disorder and not taking steroid contraceptives were recruited to complete questionnaires about their menstrual cycle and to provide blood samples for measurement of a range of reproductive endocrine and metabolic hormone levels. Eighty women participated in completing the questionnaires and 72 of them provided blood samples. RESULTS: Fifty-two of the 80 women (65%) reported current menstrual abnormalities, 40 of which (50%) reported one or more menstrual abnormalities that preceded the diagnosis of bipolar disorder. Fifteen women (38%) reported developing menstrual abnormalities since treatment for bipolar disorder, 14 of which developed abnormalities since treatment with valproate (p = 0.04). Of the 15 patients reporting menstrual abnormalities since starting medication, 12 (80%) reported changes in menstrual flow (heavy or prolonged bleeding) and five (33%) reported changes in cycle frequency. No significant differences were observed between women receiving or not receiving valproate in mean levels of free or total serum testosterone levels. This was true for the total sample and for the sub-group without preexisting menstrual problems. However, within the valproate group, duration of use was significantly correlated with free testosterone levels (r = 0.33, p = 0.02). Three of the 50 women (6%) taking VPA, and 0% of the 22 taking other antimanic medications, met criteria for PCOS (p = 0.20). Other reproductive and metabolic values outside the normal range across treatment groups included elevated 17 alpha-OH progesterone levels, luteinizing hormone: follicle-stimulating hormone ratios, homeostatic model assessment (HOMA) values, and low estrogen and dehydroepiandrosterone sulfate (DHEAS) levels. Preexisting menstrual abnormalities predicted higher levels of 17 alpha-OH progesterone, free testosterone, and estrone as well as development of new menstrual abnormalities. Body mass index (BMI) was significantly positively correlated with free testosterone levels and insulin resistance (HOMA) across all subjects, regardless of medication used. CONCLUSIONS: Rates of menstrual disturbances are high in women with bipolar disorder and, in many cases, precede the diagnosis and treatment for the disorder. Treatment with valproate additionally contributes significantly to the development of menstrual abnormalities and an increase in testosterone levels over time. A number of bipolar women, regardless of type of medication treatment received, have reproductive and metabolic hormonal abnormalities, yet the etiology of such abnormalities requires further study. Women with preexisting menstrual abnormalities may represent a group at risk for development of reproductive dysfunction while being treated for bipolar disorder.
PMID: 15898962

Longitudinal evaluation of reproductive function in women treated for bipolar disorder.

J Affect Disord. 2005 Dec;89(1-3):217-25. Epub 2005 Sep 19.
Rasgon NL, Reynolds MF, Elman S, Saad M, Frye MA, Bauer M, Altshuler LL.
Department of Psychiatry and Behavioral Sciences, Stanford School of Medicine, Stanford University, 401 Quarry Road, Palo Alto, Ca 94305-5723 Stanford, California, United States.

BACKGROUND: We assessed reproductive endocrine and metabolic markers in women treated for bipolar disorder over a 2-year time period, controlling for valproate use. METHODS: Twenty-five women ages 18-45 with bipolar disorder underwent longitudinal evaluations. Subjects completed a reproductive health questionnaire and endocrinological exam at baseline. Total and free testosterone, progesterone, LH, FSH, fasting insulin and glucose, and other hormones were measured across the menstrual cycle at baseline and at 2-year follow-up. RESULTS: Ten subjects were currently receiving valproate as a mood stabilizing agent; of the remaining subjects, six received lithium and five received atypical antipsychotics. Of all subjects, 41.7% reported current oligomenorrhea, while 40% reported oligomenorrhea before starting medication. Rates of oligomenorrhea and clinical hyperandrogenism did not differ by medication use. Eighty percent of women had a high homeostatic model assessment of insulin resistance (HOMA-IR) at baseline; all other measures were normal. Over time, all subjects exhibited a significant decrease in luteal phase progesterone and increase in free testosterone concentrations. Valproate use was associated with an increase over time in total testosterone. Baseline values and changes in BMI were similar across groups. LIMITATIONS: Limitations include small sample size and the absence of a control group. CONCLUSION: We confirm our previous observations of high rates of menstrual abnormalities, hyperandrogenemia and insulin resistance in women with bipolar disorder. These results tentatively support the role of valproate in hyperandrogenemia; however, rates of oligomenorrhea and clinical hyperandrogenism did not differ between medication groups.
PMID: 16171873

Medication status and polycystic ovary syndrome in women with bipolar disorder: a preliminary report.

J Clin Psychiatry. 2000 Mar;61(3):173-8.
Rasgon NL, Altshuler LL, Gudeman D, Burt VK, Tanavoli S, Hendrick V,Korenman S.
Department of Psychiatry and Biobehavioral Sciences, University of California Los Angeles (UCLA), USA.

BACKGROUND: In patients with epilepsy, polycystic ovary (PCO) syndrome has been reported to be associated with the use of the anticonvulsant divalproex sodium. Whether PCO syndrome is associated with divalproex use in patients with bipolar disorder has not previously been explored. METHOD: Twenty-two female outpatients with a DSM-IV diagnosis of bipolar disorder who were between the ages of 18 and 45 years (inclusive) and who were taking lithium and/or divalproex (10, divalproex monotherapy; 10, lithium monotherapy; 2, divalproex/lithium combination therapy) were evaluated. Patients completed questionnaires about their medical, psychiatric, and reproductive health histories, and body mass indices were calculated. In the early follicular phase of their menstrual cycle, women were examined for hirsutism, given a pelvic ultrasound, and/or assessed for changes in laboratory values such as serum levels of testosterone, free testosterone, estradiol, estrone, dehydroepiandrosterone, dehydroepiandrosterone sulfate, luteinizing hormone, follicle-stimulating hormone, and 17-OH progesterone. RESULTS: All 10 patients on lithium monotherapy, 6 of 10 patients on divalproex monotherapy, and both of the patients on divalproex/lithium combination therapy reported some type of menstrual dysfunction, which, in 4 cases, had preceded the diagnosis of bipolar disorder. Hirsutism was not common in any group, but obesity was prominent in all groups. Ovarian ultrasound revealed an increased number of ovarian follicles in 1 patient taking lithium and in none of the patients taking divalproex. Hormonal screening did not indicate PCO-like changes in any patient. CONCLUSION: In this pilot study of bipolar patients, PCO-like changes were not seen in women receiving divalproex or lithium. However, independent of therapeutic agent used, the bipolar women in this study reported high rates of menstrual disturbances, suggesting that the hypothalamic-pituitary-gonadal axis may be compromised in some women with bipolar disorder.
PMID: 10817101

  Insulin Resistance

Depression and insulin resistance: applications to polycystic ovary syndrome.

Brown AJ.
Clin Obstet Gynecol. 2004 Sep;47(3):592-6.
Duke University Medical Center, Durham, North Carolina.

PMID: 15326421

Insulin resistance in depressive disorders and Alzheimer's disease: revisiting the missing link hypothesis.

Rasgon NL, Kenna HA.
Neurobiol Aging. 2005 Dec;26 Suppl 1:103-7. Epub 2005 Oct 11.
Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine.

Several lines of evidence suggest an association between depressive disorders and Alzheimer's disease (AD). We previously suggested central nervous system (CNS) effects of insulin resistance (IR) to be an important link between depressive disorders and AD. Although the exact mechanism of central IR is not known, it is thought that central IR results in inadequate glucose metabolism in the brain. According to our hypothesis, inadequate glucose utilization resulting from IR underlies neuronal changes in crucial brain regions (i.e. limbic system) observed among patients with depressive disorders, the same brain regions affected in AD. Further, in patients with undetected and/or untreated IR, such changes in glucose utilization, if unresolved, may lead to neurodegeneration. Our studies have demonstrated a high prevalence of IR in patients with depressive disorders, and reciprocally, a high prevalence of depression in patients with the primary IR disorder polycystic ovary syndrome (PCOS), and we believe these populations have significantly increased risk of cognitive decline. Herein, we review the IR link in depressive disorders and AD and describe the results of our studies and others in support of this hypothesis.
PMID: 16225963

Insulin resistance after oral glucose tolerance testing in patients with major depression.

A Winokur, G Maislin, JL Phillips and JD Amsterdam.
Am J Psychiatry. 1988 Mar;145(3):325-30.
Department of Psychiatry, School of Medicine, University of Pennsylvania, Philadelphia 19104.

An association between affective disorders and alterations in glucose utilization has been recognized. The authors administered a 5-hour oral glucose tolerance test (GTT) to 28 depressed patients and 21 healthy volunteer control subjects and measured serum glucose as well as plasma insulin and glucagon responses. Depressed patients demonstrated significantly higher basal glucose levels, greater cumulative glucose responses after the GTT, and larger cumulative insulin responses after the GTT than control subjects. Values for cumulative glucagon did not significantly differ between groups. These findings indicate the presence of a functional state of insulin resistance during major depressive illness and suggest the presence of a more generalized biological disturbance in some depressed patients.
PMID: 2894176

A biochemical and functional characterization of diet-induced brain insulin resistance.

Mielke JG, Taghibiglou C, Liu L, Zhang Y, Jia Z, Adeli K, Wang YT.
J Neurochem. 2005 Jun;93(6):1568-78.
Brain and Behaviour Program, Hospital for Sick Children, Toronto, Ontario, Canada.
While considerable research has examined diminished insulin responses within peripheral tissues, comparatively little has been done to examine the effects of this metabolic disruption upon the CNS. The present study employed biochemical and electrophysiological assays of acutely prepared brain slices to determine whether neural insulin resistance is a component of the metabolic syndrome observed within the fructose-fed (FF) hamster. The tyrosine phosphorylation levels of the insulin receptor (IR) and insulin receptor substrate 1 (IRS-1) in response to insulin were significantly reduced within FF hamsters. Also, insulin-mediated phosphorylation of both residues necessary for activation of the serine-threonine kinase Akt/PKB, a key effector of insulin signaling, was markedly decreased. Elevated levels of the protein tyrosine phosphatase 1B, which dephosphorylates the IR and IRS-1, were also observed within the cerebral cortex and hippocampus of FF hamsters. Examination of whether a nutritionally induced compromise of neural insulin signaling altered synaptic function revealed a significant attenuation of insulin-induced long-term depression, but no effect upon either paired-pulse facilitation or electrically induced long-term potentiation. Collectively, our results demonstrate, for the first time, that nutritionally induced insulin resistance significantly affects the neural insulin signaling pathway, and suggest that brain insulin resistance may contribute to cognitive impairment.
PMID: 15935073

The relationship between central serotonergic activity and insulin sensitivity in healthy volunteers.

Horacek J, Kuzmiakova M, Hoschl C, Andel M, Bahbonh R.
Psychoneuroendocrinology. 1999 Nov;24(8):785-97.
3rd Faculty of Medicine, Charles University, Prague, Czech Republic.

In order to determine whether central serotonin (5-HT) activity is related to sensitivity of insulin receptors, 19 healthy volunteers with normal basal glycemia and HbAlc were studied. The relationship between prolactin response to D-fenfluramine (delta PRL) in a challenge test and metabolic clearance rates (MCR) of glucose during the hyperinsulinemic-euglycemic clamp technique was evaluated. delta PRL had been chosen as a correlate of central 5-HT activity. Two levels of insulin concentration of approximately 70 mU/l (MCRsubmax) and 2000 mU/l (MCRmax) were used in a clamp, each for a duration of 120 min. A negative correlation was found between delta PRL and MCRsubmax (r = -0.55, P < 0.02) and between delta PRL and MCRmax (r = -0.51, P < 0.03). We did not find any correlation between the prolactin response to D-fenfluramine and body weight, body mass index (BMI) or waist and hip circumference (WHR). The data support the hypothesis of a close connection between 5-HT activity in the brain and peripheral sensitivity to insulin. The possible physiological mechanisms of this connection are discussed.
PMID: 10581650

The metabolic syndrome is associated with reduced central serotonergic responsivity in healthy community volunteers.

Muldoon MF, Mackey RH, Korytkowski MT, Flory JD, Pollock BG,Manuck SB.
J Clin Endocrinol Metab. 2006 Feb;91(2):718-21. Epub 2005 Nov 22.
Division of Clinical Pharmacology, Departments of Medicine and Epidemiology, University of Pittsburgh.

CONTEXT: The pathobiology of the metabolic syndrome remains unclear. The central nervous system is likely to be involved via regulation of eating, physical activity, blood pressure, and metabolism. OBJECTIVE: The objective of this study was to test the hypothesis that low central serotonergic activity is associated with the metabolic syndrome. DESIGN, SETTING, PARTICIPANTS: This was a cross-sectional study of 345 healthy community volunteers, aged 30-55 yr, not taking medications for hypertension, lipid disorders, or diabetes. OUTCOME MEASURES: Central serotonergic responsivity was assessed with the iv citalopram challenge test. The serum prolactin area under the curve (AUC) over 150 min was calculated, and all analyses were adjusted for age, sex, plasma citalopram concentration, and baseline prolactin. The metabolic syndrome was defined according to the National Cholesterol Education Program (NCEP) and International Diabetes Federation (IDF) criteria. Insulin resistance was estimated by homeostasis model assessment. RESULTS: Compared with other individuals, persons meeting either NCEP or IDF criteria for the metabolic syndrome had lower mean prolactin responses (P < 0.05 for both). Using logistic regression, a decrease in prolactin AUC of 1 sd (-13.6 ng/ml.h) more than doubled the odds of having the metabolic syndrome (NCEP criteria: odds ratio, 2.38; 95% confidence interval, 1.14-4.97; P = 0.02; IDF criteria: odds ratio, 2.80; 95% confidence interval, 1.48-5.30; P = 0.002). Finally, the prolactin AUC was negatively associated with insulin resistance (beta = -0.03, P = 0.02). CONCLUSIONS: Corroborating previous evidence, the metabolic syndrome was associated with diminished brain serotonergic activity as reflected in a comparative blunting of the prolactin response to a selective serotonergic challenge. This association may have implications for the etiology, prevention, and treatment of the metabolic syndrome.
PMID: 16303834

Low central nervous system serotonergic responsivity is associated with the metabolic syndrome and physical inactivity.

Muldoon MF, Mackey RH, Williams KV, Korytkowski MT, Flory JD, Manuck SB.
J Clin Endocrinol Metab. 2004 Jan;89(1):266-71.
Divisions of Clinical Pharmacology, Department of Medicine, University of Pittsburgh School of Medicine.

The metabolic syndrome, recognized by the co-occurrence of general or abdominal obesity, hypertension, dyslipidemia, insulin resistance, and dysglycemia, appears to involve disturbances in metabolism, autonomic function, and health-related behaviors. However, physiological processes linking the components of the metabolic syndrome remain obscure. The current study examined associations of central nervous system serotonergic function with each metabolic syndrome risk variable, the metabolic syndrome, and physical activity. The subjects were 270 adult volunteers who participated in a study of cardiovascular disease risk factors and neurobehavioral functioning. Central serotonergic responsivity was indexed as the prolactin (PRL) response evoked by the serotonin-releasing agent, fenfluramine. Across the sample, low PRL response was associated with greater body mass index, higher concentrations of triglycerides, glucose, and insulin, higher systolic and diastolic blood pressure, greater insulin resistance, and less physical activity (P < 0.03-0.001). There also existed an inverse linear relationship between PRL response and the number of metabolic syndrome risk factors individuals possessed (P for trend = 0.002). Finally, a 1 SD decline in PRL response was associated with an odds ratio for the metabolic syndrome of 2.05 (95% confidence interval, 1.10-3.83; P = 0.002) and 5.70 (95% confidence interval, 1.69-19.25; P = 0.005), according to the definitions of the National Cholesterol Education Program and the World Health Organization, respectively. These findings reveal a heretofore unrecognized association between reduced central serotonergic responsivity and the metabolic syndrome.
PMID: 14715860

Depressive symptoms, insulin resistance, and risk of diabetes in women at midlife.

Everson-Rose SA, Meyer PM, Powell LH, Pandey D, Torrens JI, Kravitz HM, Bromberger JT, Matthews KA.
Diabetes Care. 2004 Dec;27(12):2856-62.
Department of Preventive Medicine, Rush University Medical Center, Chicago.

OBJECTIVE: To examine depression and 3-year change in insulin resistance and risk of diabetes and whether associations vary by race. RESEARCH DESIGN AND METHODS: We analyzed data from 2,662 Caucasian, African-American, Hispanic, Japanese-American, and Chinese-American women without a history of diabetes from the Study of Women's Health Across the Nation. We estimated regression coefficients and odds ratios to determine whether depression (Center for Epidemiological Studies Depression Scale score > or =16) predicted increases in homeostasis model assessment of insulin resistance (HOMA-IR) and greater risk of incident diabetes, respectively, over 3 years. RESULTS: Mean baseline HOMA-IR was 1.31 (SD 0.86) and increased 0.05 units per year for all women (P <0.0001). A total of 97 incident cases of diabetes occurred. Depression was associated with absolute levels of HOMA-IR (P <0.04) but was unrelated to changes in HOMA-IR; associations did not vary by race. The association between depression and HOMA-IR was eliminated after adjustment for central adiposity (P=0.85). Depression predicted a 1.66-fold greater risk of diabetes (P <0.03), which became nonsignificant after adjustment for central adiposity (P=0.12). We also observed a depression-by-race interaction (P <0.05) in analyses limited to Caucasians and African Americans, the only groups with enough diabetes cases to reliably test this interaction. Race-stratified models showed that depression predicted 2.56-fold greater risk of diabetes in African Americans only, after risk factor adjustment (P=0.008). CONCLUSIONS: Depression is associated with higher HOMA-IR values and incident diabetes in middle-aged women. These associations are mediated largely through central adiposity. However, African-American women with depression experience increased risk of diabetes independent of central adiposity and other risk factors.
PMID: 15562197

Insulin resistance: a metabolic link between depressive disorder and atherosclerotic vascular diseases.

Med Hypotheses. 2002 Nov;59(5):537-51.
Ramasubbu R.
Department of Psychiatry, University of Calgary, Foothills Hospital, Canada.

The association of depression with insulin resistance (IR) and athersclerotic vascular diseases has been well documented. This review examines the relevance of IR as a link between depressive disorder and atherosclerotic vascular diseases. Relevant articles collected from Medline database over the period of 1966-2001 were reviewed. Studies have shown that IR is a state-dependent abnormality in depression and depression increases the risk of vascular morbidity and mortality. Given that IR is a central component of cardiovascular risk factors, depression-related IR might play a role in the development and progression of coronary and cerebral atherosclerosis in chronic-resistant depression. Further, IR may contribute to the pathophysiology of depressive disorder. In conclusion IR could account for the linkage between depression and atherosclerotic vascular diseases. More studies are needed to examine the importance of improving insulin sensitivity in the treatment of chronic-resistant depression and prevention of depression-related vascular morbidity and mortality.
PMID: 12376076

Metabolism, mood and cognition in aging: the importance of lifestyle and dietary intervention.

Hendrickx H, McEwen BS, Ouderaa F.
Neurobiol Aging. 2005 Dec;26 Suppl 1:1-5. Epub 2005 Nov 14.
Unilever Corporate Research, Colworth House, Sharnbrook MK44 1LQ, UK.

We are witnessing an unprecedented rise in obesity and Type 2 diabetes. Until recently, study of the relation between metabolic dysregulation and higher brain function was limited. This paper summarizes the findings of a Spark workshop that focussed on the impact of obesity and diabetes on mood and cognition. Disturbances in peripheral glucose regulation are associated with cognitive impairment and depressed mood, especially in older adults. Multiple mechanisms and mediators underlie this association including insulin, glucose, neurotropic factors, glucocorticoids, inflammatory agents and reactive oxygen species. Importantly, prevention and even reversal of diabetes and obesity related cognitive impairment and depressive mood can be brought about by lifestyle modification. In particular, increasing physical fitness and moderating/changing food intake will have beneficial effects. Prevention of obesity and hyperglycemia by adopting a healthy lifestyle will contribute to the maintenance of functional integrity and mental health later in life.
PMID: 16290269

Alpha lipoic acid: a novel treatment for depression.

Salazar MR.
Med Hypotheses. 2000 Dec;55(6):510-2.
Amherst College, Amherst, Massachusetts.

Insulin resistance has been associated with people diagnosed with depression. Conversely, it has also been documented that diabetics have an increased risk of depression. Evidence suggests that insulin activity plays a role in serotonergic activity by increasing the influx of tryptophan into the brain. This increased influx of tryptophan has been shown to result in an increase in serotonin synthesis. In accordance with the serotonin theory of depression, it may be possible to treat depression by increasing insulin activity. The antioxidant alpha lipoic acid has been shown to increase insulin sensitivity and is used to treat people with diabetes. Therefore, the nutrient alpha lipoic acid should be clinically tested as an adjunct treatment for depression. Copyright 2000 Harcourt Publishers Ltd.
PMID: 11090300


Secondary amenorrhea: Don't dismiss it as 'normal'.

Pritts S.
Current Psychiatry Online. 2006 Oct;3(10).
University of Cincinnati College of Medicine.

A young or middle-aged patient who stops menstruating may be pregnant or have an underlying medical problem that, left undiagnosed, could cause obesity, sexual dysfunction, infertility, osteoporosis, endometrial hyperplasia, or endometrial cancer. Yet clinicians too often dismiss secondary amenorrhea as a “normal” result of a mental disorder or psychotropic. Psychiatrists need to: identify when a psychiatric disorder or drug disrupts menses; diagnose medical causes, including thyroid dysfunction, pituitary adenomas, and polycystic ovary syndrome (PCOS). This article outlines the most common and serious causes of secondary amenorrhea among psychiatric patients, and offers an algorithm for ruling out medical problems in nonpregnant women of child-bearing age who have stopped menstruating for 3 months. The diagnostic approach described here does not apply to women with primary amenorrhea (have never menstruated).
Article in Current Psychiatry Online

Psychological correlates of functional hypothalamic amenorrhea.

Fertil Steril. 2001 Aug;76(2):310-6.
Marcus MD, Loucks TL, Berga SL.
Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.

OBJECTIVE: To determine whether mood, attitudes, or symptoms of disordered eating discriminated women with functional hypothalamic amenorrhea (FHA) from those with organic causes of amenorrhea and eumenorrhea. DESIGN: Cross-sectional comparison of women with FHA, women with organic amenorrhea, and eumenorrheic control women. SETTING: Clinical research center in an academic medical institution. PATIENT(S): Seventy-seven women > or =18 years old with time since menarche > or =5 and < or =25 years were recruited by advertisement. INTERVENTION(S): Ovulation was confirmed in eumenorrheic control women. Causes of anovulation were carefully documented in amenorrheic participants and LH pulse profiles were obtained to document the diagnosis of FHA. All participants were interviewed and completed questionnaires. MAIN OUTCOME MEASURE(S): Self-report measures of dysfunctional attitudes, coping styles, and symptoms of depression and eating disorders. RESULT(S): Women with FHA reported more depressive symptoms and dysfunctional attitudes than did eumenorrheic women, but not significantly more than women with organic amenorrhea. However, women with FHA reported significantly more symptoms of disordered eating than did either anovulatory or ovulatory women. CONCLUSION(S): The findings are consistent with the hypothesis that FHA is precipitated by a combination of psychosocial stressors and metabolic challenge.
PMID: 11476778

Eating disorders and Axis I psychiatric comorbidity in amenorrheic women.

Verri A, Nappi RE, Cecchini AP, Vallero E, Luzi S, Zara C.
Int J Eat Disord. 1998 Sep;24(2):137-46.
University Center of Adaptive Disorders and Headache (UCADH), Department of Neurology, IRCCS C. Mondino, University of Pavia, Italy.

OBJECTIVE: The present study aimed to investigate the relationship between secondary amenorrhea due to different etiologic mechanisms, eating disorders, and psychiatric morbidity in a nonpsychiatric population observed in a gynecological department. METHOD: Amenorrheic women (n = 95) with hypogonadotropic, hyperandrogenic, and hyperprolactinemic features were interviewed individually using the SCID-R (Structured Clinical Interview for DSM-III-R) to diagnose Axis I disorders including mood disorders, anxiety disorders, somatoform disorders, adjustment disorders, and eating disorders. Binge eating disorder was diagnosed according to DSM-IV criteria. RESULTS: The incidence of eating disorders was significantly higher in hypogonadic women than in hyperandrogenic and hyperprolactinemic subjects (chi 2 = 23.03, p < .003). However, we also found a high percentage of hyperandrogenic women suffering from an eating disorder (40.9%) with a prevalence of binge eating disorder (27.2%), while the only eating disorder described in the hyperprolactinemic group was the not otherwise specified. In addition, a marked psychiatric comorbidity was found in amenorrheic women suffering from an eating disorder but a similar trend of pathologies was also found in amenorrheic women, without any positive SCID diagnosis for an abnormal eating disorder. DISCUSSION: Our study demonstrated that a high incidence of eating disorders, mainly anorexia and binge eating, characterizes hypogonadic and hyperandrogenic women, respectively. In addition, secondary amenorrhea displays a wide spectrum of Axis I diagnoses, without a significant comorbidity with eating disorders. Whether or not the endocrine findings related to the amenorrheic condition constitute a common background for the occurrence of psychopathology or, alternatively, the presence of psychiatric disturbances may contribute to the development of menstrual dysfunction remain to be clarified.
PMID: 9697012


TNFalpha signaling in depression and anxiety: behavioral consequences of individual receptor targeting.

Simen BB, Duman CH, Simen AA, Duman RS.
Biol Psychiatry. 2006 May 1;59(9):775-85. Epub 2006 Feb 3.
Department of Psychiatry, Division of Molecular Psychiatry, Yale University.

BACKGROUND: Increased serum levels of TNFalpha and other pro-inflammatory cytokines have been found in patients with major depression and several other psychiatric conditions. In rodents, these cytokines produce symptoms commonly referred to as "sickness behavior." Some of these, including reduced feeding and decreased social and exploratory behavior, are reminiscent of those seen in depressed patients. Interpretation of these effects is complicated by the malaise caused by acute injections of pro-inflammatory cytokines, however. Thus, it is unclear whether cytokines are involved in the etiology of depressive symptoms. METHODS: We used a panel of behavioral assays to assess TNFR1(-/-) and TNFR2(-/-) mice for anxiety and depression-like behaviors. RESULTS: We show that deletion of either TNFR1 or TNFR2 leads to an antidepressant-like response in the forced swim test and that mice lacking TNFR2 demonstrate a hedonic response in a sucrose drinking test compared with wildtype littermates. In addition, deletion of TNFR1 leads to decreased fear conditioning. There were no differences in behavior in anxiety tests for either null mutant. CONCLUSIONS: These results are consistent with the hypothesis that TNFalpha can induce depression-like symptoms even in the absence of malaise and demonstrate that both receptor subtypes can be involved in this response.
PMID: 16458261

Clinical depression and regulation of the inflammatory response during acute stress.

Miller GE, Rohleder N, Stetler C, Kirschbaum C.
Psychosom Med. 2005 Sep-Oct;67(5):679-87.
Department of Psychology, University of British Columbia.

OBJECTIVE: This study examined whether clinical depression is associated with a differential inflammatory response to an acute bout of psychological stress. METHODS: A total of 72 women participated in the study; half met diagnostic criteria for clinical depression; the others had no history of psychiatric illness. The groups were matched with respect to age and ethnicity. All subjects were exposed to a 17-minute mock-job interview; blood was drawn to assess secretion and regulation of inflammatory molecules. RESULTS: The stressor was associated with feelings of shame and anxiety, a mobilization of monocytes, neutrophils, and C-reactive protein into the circulation, and greater endotoxin-stimulated production of interleukin-6 and tumor necrosis factor-alpha by white blood cells in vitro. Depressed subjects began the session with greater sensitivity to the antiinflammatory properties of glucocorticoids than control subjects. Following exposure to the stressor protocol, however, sensitivity decreased among depressed subjects and increased among controls. This was manifest by disparities in interleukin-6 and tumor necrosis factor-alpha production in the presence of dexamethasone. CONCLUSIONS: These findings suggest that under acutely challenging conditions, depression is associated with greater resistance to molecules that normally terminate the inflammatory cascade. An impaired capacity to regulate inflammation could underlie some of the excess morbidity and mortality that has been associated with depression.
PMID: 16204423

Cytokines and major depression.

Schiepers OJ, Wichers MC, Maes M.
Prog Neuropsychopharmacol Biol Psychiatry. 2005 Feb;29(2):201-17. Epub 2005 Jan 25.
Department of Psychiatry and Neuropsychology, Maastricht University, Netherlands.

In the research field of psychoneuroimmunology, accumulating evidence has indicated the existence of reciprocal communication pathways between nervous, endocrine and immune systems. In this respect, there has been increasing interest in the putative involvement of the immune system in psychiatric disorders. In the present review, the role of proinflammatory cytokines, such as interleukin (IL)-1, tumour necrosis factor (TNF)-alpha and interferon (IFN)-gamma, in the aetiology and pathophysiology of major depression, is discussed. The 'cytokine hypothesis of depression' implies that proinflammatory cytokines, acting as neuromodulators, represent the key factor in the (central) mediation of the behavioural, neuroendocrine and neurochemical features of depressive disorders. This view is supported by various findings. Several medical illnesses, which are characterised by chronic inflammatory responses, e.g. rheumatoid arthritis, have been reported to be accompanied by depression. In addition, administration of proinflammatory cytokines, e.g. in cancer or hepatitis C therapies, has been found to induce depressive symptomatology. Administration of proinflammatory cytokines in animals induces 'sickness behaviour', which is a pattern of behavioural alterations that is very similar to the behavioural symptoms of depression in humans. The central action of cytokines may also account for the hypothalamic-pituitary-adrenal (HPA) axis hyperactivity that is frequently observed in depressive disorders, as proinflammatory cytokines may cause HPA axis hyperactivity by disturbing the negative feedback inhibition of circulating corticosteroids (CSs) on the HPA axis. Concerning the deficiency in serotonergic (5-HT) neurotransmission that is concomitant with major depression, cytokines may reduce 5-HT levels by lowering the availability of its precursor tryptophan (TRP) through activation of the TRP-metabolising enzyme indoleamine-2,3-dioxygenase (IDO). Although the central effects of proinflammatory cytokines appear to be able to account for most of the symptoms occurring in depression, it remains to be established whether cytokines play a causal role in depressive illness or represent epiphenomena without major significance.
PMID: 15694227

Cytokines: abnormalities in major depression and implications for pharmacological treatment.

O'Brien SM, Scott LV, Dinan TG.
Hum Psychopharmacol. 2004 Aug;19(6):397-403.
Department of Psychiatry, University College Cork, Cork University Hospital, Ireland.

The role of cytokines in depression was first considered when the cytokine interferon resulted in "sickness behaviour", the symptoms of which are similar to those of major depression. The latter is associated with an increase in pro-inflammatory cytokines such as interleukin-1 (IL-1), interleukin-6 (IL-6) and tumour necrosis factor alpha (TNF-alpha). These cytokines are potent modulators of corticotropin-releasing hormone (CRH) which produces heightened hypothalamic-pituitary-adrenal axis (HPA) activity characterized by increases in ACTH and cortisol, both of which are reported elevated in major depression. Antidepressant treatment has immunomodulatory effects with increases in the production of IL-10, which is an anti-inflammatory cytokine. This review based on a Medline search from 1980-2003, focuses on the evidence available of cytokine changes in acute stress, chronic stress and major depression. It examines the effects of antidepressant treatment on immune parameters in both animal models and clinical trials. We suggest that future antidepressants may target the immune system by either blocking the actions of pro-inflammatory cytokines or increasing the production of anti-inflammatory cytokines. Copyright 2004 John Wiley & Sons, Ltd.
PMID: 15303243

Increased serum tumor necrosis factor alpha concentrations in major depression and multiple sclerosis.

Mikova O, Yakimova R, Bosmans E, Kenis G, Maes M.
Eur Neuropsychopharmacol. 2001 Jun;11(3):203-8.
Department of Psychiatry, Medical University of Sofia, Bulgaria.

There is now evidence that major depression is accompanied by activation of the inflammatory response system (IRS) as indicated by an increased production of pro-inflammatory cytokines. There is circumstantial evidence implicating pro-inflammatory cytokines, such as tumor necrosis factor-alpha (TNFalpha) in the pathogenesis of multiple sclerosis (MS). The aims of the present study were to examine (i) the serum concentrations of interleukin-6 (IL-6), IL-8, TNFalpha, IL-2 receptor (IL-2R) and CC16 (uteroglobulin), an endogenous anti-cytokine, in depressed and MS patients compared to normal controls, and (ii) the effects of treatment with antidepressants on the above IRS variables in depressed patients. Serum TNFalpha was significantly higher in depressed and MS patients than in normal controls. Serum IL-8 was significantly higher in depressed patients than in patients with MS. Serum CC16 was significantly higher in patients with MS than in normal controls and depressed patients. Nonresponders to treatment with antidepressants had significantly higher serum IL-2R and lower serum CC16 concentrations than responders to treatment. The results show that (i) depression is accompanied by activation of the IRS and that this activation is more pronounced in depression than in MS, and (ii) IRS activation in depressed patients is related to a nonresponse to treatment with antidepressants.
PMID: 11418279

Illness, cytokines, and depression.

Yirmiya R, Pollak Y, Morag M, Reichenberg A, Barak O, Avitsur R, Shavit Y, Ovadia H, Weidenfeld J, Morag A, Newman ME, Pollmacher T.
Ann N Y Acad Sci. 2000;917:478-87.
Department of Psychology, Hebrew University, Hadassah Hospital, Jerusalem.

Various medical conditions that involve activation of the immune system are associated with psychological and neuroendocrine changes that resemble the characteristics of depression. In this review we present our recent studies, designed to investigate the relationship between the behavioral effects of immune activation and depressive symptomatology. In the first set of experiments, we used a double-blind prospective design to investigate the psychological consequences of illness in two models: (1) vaccination of teenage girls with live attenuated rubella virus, and (2) lipopolysaccharide (LPS) administration in healthy male volunteers. In the rubella study, we demonstrated that, compared to control group subjects and to their own baseline, a subgroup of vulnerable individuals (girls from low socioeconomic status) showed a significant virus-induced increase in depressed mood up to 10 weeks after vaccination. In an ongoing study on the effects of LPS, we demonstrated significant LPS-induced elevation in the levels of depression and anxiety as well as memory deficits. These psychological effects were highly correlated with the levels of LPS-induced cytokine secretion. In parallel experiments, we demonstrated in rodents that immune activation with various acute and chronic immune challenges induces a depressive-like syndrome, characterized by anhedonia, anorexia, body weight loss, and reduced locomotor, exploratory, and social behavior. Chronic treatment with antidepressants (imipramine or fluoxetine) attenuated many of the behavioral effects of LPS, as well as LPS-induced changes in body temperature, adrenocortical activation, hypothalamic serotonin release, and the expression of splenic TNF-alpha mRNA. Taken together, these findings suggest that cytokines are involved in the etiology and symptomatology of illness-associated depression.
PMID: 11268375

Cytokine profiles in bipolar affective disorder: focus on acutely ill patients.

O'Brien SM, Scully P, Scott LV, Dinan TG.
J Affect Disord. 2006 Feb;90(2-3):263-7. Epub 2006 Jan 10.
Alimentary Pharmabiotic Centre and Department of Psychiatry, University College Cork, Ireland.

BACKGROUND: The role of the immune system in mood disorders is predominately supported by studies in unipolar major depression. However activation of the immune system has also been demonstrated in bipolar mania. Our study examines pro-inflammatory and anti-inflammatory cytokines in both phases of bipolar affective disorder (BPAD). METHODS: Plasma concentrations of IL-6, IL-8, IL-10, TNF-alpha and sIL-6R were measured with enzyme linked immunosorbent assays (ELISA) in patients with BPAD who were depressed, or manic and in healthy controls. RESULTS: Bipolar depression had significantly higher production of the pro-inflammatory cytokines, IL-8 (p < 0.001) and TNF-alpha (p < 0.05) compared to healthy subjects. The manic group also had increased production of IL-8 (p < 0.05) and TNF-alpha (p < 0.001) as compared to healthy subjects. Anti-inflammatory cytokine levels did not differ across the 3 groups. LIMITATIONS: A small sample size was studied. All patients remained on medication for this study. CONCLUSIONS: BPAD is associated with increased production of pro-inflammatory cytokines both in the manic and in the depressed phase as compared to healthy subjects. This is the first study, which examined both mania and bipolar depression.
PMID: 16410025

Increased serum tumor necrosis factor-alpha levels and treatment response in major depressive disorder.

Tuglu C, Kara SH, Caliyurt O, Vardar E, Abay E.
Psychopharmacology (Berl). 2003 Dec;170(4):429-33. Epub 2003 Aug 30.
Department of Psychiatry, Trakya University School of Medicine, 22030 Edirne, Turkey.

RATIONALE: Over the last 15 years, an increasing body of evidence has suggested a causal relationship between depression and the immunological activation and hypersecretion of pro-inflammatory cytokines, such as interleukin-1, interleukin-6 and tumor necrosis factor-alpha (TNF-alpha). However, little is known about the probable relationship of serum TNF-alpha with major depressive disorder (MDD). OBJECTIVE: To assess whether serum TNF-alpha levels could be associated with the clinical course of MDD. SUBJECTS AND METHODS: TNF-alpha and C-reactive protein (CRP) serum concentrations, erythrocyte sedimentation rate, and leukocyte count were measured in 26 MDD patients and in 17 controls. The measurements were repeated following 6 weeks of antidepressant treatment with selective serotonin re-uptake inhibitors. Psychopathological improvement and the severity of depression were evaluated with the Hamilton Depression Rating Scale (HAMD) and Beck Depression Inventory (BDI). RESULTS: On admission, serum TNF-alpha and leukocyte count were significantly higher in MDD patients compared to controls ( P<0.001 and P=0.005, respectively). With the antidepressant treatment, both HAMD and BDI scores decreased significantly (P<0.001 for both). Comparison of pre- and post-treatment measurements revealed that TNF-alpha, CRP, and leukocyte count decreased to levels comparable with those of the control subjects ( P<0.001, P=0.01, and P=0.01, respectively). CONCLUSIONS: The results emphasized that some immunological parameters, such as CRP, leukocyte count and TNF-alpha, are significantly involved in the clinical course and treatment response in MDD. TNF-alpha in particular could be considered as a potential state marker in MDD.
PMID: 12955291


Homocysteine, folate, methylation, and monoamine metabolism in depression.

Bottiglieri T, Laundy M, Crellin R, Toone BK, Carney MW, Reynolds EH.
J Neurol Neurosurg Psychiatry. 2000 Aug;69(2):228-32.
Department of Neurology, King's College Hospital, London.

OBJECTIVES: Previous studies suggest that folate deficiency may occur in up to one third of patients with severe depression, and that treatment with the vitamin may enhance recovery of the mental state. There are, however, difficulties in interpreting serum and red cell folate assays in some patients, and it has been suggested that total plasma homocysteine is a more sensitive measure of functional folate (and vitamin B12) deficiency. Other studies suggest a link between folate deficiency and impaired metabolism of serotonin, dopamine, and noradrenaline (norepinephrine), which have been implicated in mood disorders. A study of homocysteine, folate, and monoamine metabolism has, therefore, been undertaken in patients with severe depression. METHODS: In 46 inpatients with severe DSM III depression, blood counts, serum and red cell folate, serum vitamin B12, total plasma homocysteine, and, in 28 patients, CSF folate, S-adenosylmethionine, and the monoamine neurotransmitter metabolites 5HIAA, HVA, and MHPG were examined. Two control groups comprised 18 healthy volunteers and 20 patients with neurological disorders, the second group undergoing CSF examination for diagnostic purposes. RESULTS: Twenty four depressed patients (52%) had raised total plasma homocysteine. Depressed patients with raised total plasma homocysteine had significant lowering of serum, red cell, and CSF folate, CSF S-adenosylmethionine and all three CSF monoamine metabolites. Total plasma homocysteine was significantly negatively correlated with red cell folate in depressed patients, but not controls. CONCLUSIONS: Utilising total plasma homocysteine as a sensitive measure of functional folate deficiency, a biological subgroup of depression with folate deficiency, impaired methylation, and monoamine neurotransmitter metabolism has been identified. Detection of this subgroup, which will not be achieved by routine blood counts, is important in view of the potential benefit of vitamin replacement.
PMID: 10896698

Vitamin B12, folate, and homocysteine in depression: the Rotterdam Study.

Tiemeier H, van Tuijl HR, Hofman A, Meijer J, Kiliaan AJ, Breteler MM.
Am J Psychiatry. 2002 Dec;159(12):2099-101.
Department of Epidemiology and Biostatistics, Erasmus Medical Centre, PO Box 1738, 3000 DR Rotterdam, The Netherlands.

OBJECTIVE: The associations of vitamin B(12), folate, and homocysteine with depression were examined in a population-based study. METHOD: The authors screened 3,884 elderly people for depressive symptoms. Subjects with positive screening results had psychiatric workups. Folate, vitamin B(12), and homocysteine blood levels were compared in 278 persons with depressive symptoms, including 112 with depressive disorders, and 416 randomly selected reference subjects. Adjustments were made for age, gender, cardiovascular disease, and functional disability. RESULTS: Hyperhomocysteinemia, vitamin B(12) deficiency, and to a lesser extent, folate deficiency were all related to depressive disorders. For folate deficiency and hyperhomocysteinemia, the association with depressive disorders was substantially reduced after adjustment for functional disability and cardiovascular disease, but for vitamin B(12) this appeared independent. CONCLUSIONS: The association of vitamin B(12) and folate with depressive disorders may have different underlying mechanisms. Vitamin B(12) may be causally related to depression, whereas the relation with folate is due to physical comorbidity.
PMID: 12450964

Homocysteinemia as well as methylenetetrahydrofolate reductase polymorphism are associated with affective psychoses.

Reif A, Pfuhlmann B, Lesch KP.
Prog Neuropsychopharmacol Biol Psychiatry. 2005 Sep;29(7):1162-8.
Clinical and Molecular Psychobiology, Department of Psychiatry and Psychotherapy, Julius-Maximilians-University of Wurzburg, Germany.

In the recent years, elevated homocysteine plasma levels have been reported to represent a risk factor not only for atherosclerosis, but also to be associated with dementia, depression and-in a gender-specific manner-schizophrenia. Here, we explored a possible association between homocysteinemia and psychiatric disorders. Fasting homocysteine, vitamin B12 and folate were determined in an ethnically homogeneous female population with different psychiatric disorders. Homocysteine was not elevated in females suffering from schizophrenia (mean, 11.6+/-5.8 micromol/l). As shown previously, increased homocysteine concentrations were associated not only with dementia of different aetiology (mean, 17.2+/-6.7 micromol/l; chi2=23.39, p<0.001, compared to the schizophrenia group), but also with depressive disorders (mean, 12.9+/-3.8 micromol/l; chi2=6.88, p=0.009). B12 and folate levels did not differ between different diagnostic groups. To further explore the connection between homocysteinemia and affective psychoses, a case-control study examining the C677T and the A1298C variants of methylenetetrahydrofolate reductase was conducted. The latter polymorphism not only was associated with affective psychoses in general, but also when divided in unipolar depression and bipolar affective disorder. In conclusion, we suggest that in females homocysteinemia is an unspecific risk factor for organic brain disorders like dementia, and possibly depression, but not for schizophrenia.
PMID: 16055253

Homocysteinemia in psychiatric disorders: association with dementia and depression, but not schizophrenia in female patients.

Reif A, Schneider MF, Kamolz S, Pfuhlmann B.
J Neural Transm. 2003 Dec;110(12):1401-11. Epub 2003 Oct 24.
Department of Psychiatry and Psychotherapy, Julius-Maximilians-University Wurzburg, Germany.

Homocysteinemia has been reported to be a risk factor for dementia, depression and also schizophrenia, the latter in a gender-specific manner. We have determined homocysteine in female inpatients suffering from various psychiatric diseases to further investigate a possible association between homocysteinemia and psychiatric disorders. Homocysteine was not elevated in schizophrenic females (mean, 11.6+/-5.8 micromol/l); in accordance with previous studies, homocysteinemia could be found frequently in dementia of different aetiology (mean, 17.2+/-6.7 micromol/l), but also to a slighter extent in depressive disorders (mean, 12.9+/-3.8 micromol/l), especially in elderly subjects. We thus suggest that homocysteinemia, at least in females, is an unspecific risk factor for organic brain disorders, but not endogenous psychoses.
PMID: 14666412

Homocysteine during the menstrual cycle in depressive women.

Tallova J, Bicikova M, Hill M, Tomandl J, Valentova D.
Eur J Clin Invest. 2003 Mar;33(3):268-73.
Department of Biochenmistry, Faculty of Medicine, Masaryk University Brno, Czech Republic.

BACKGROUND: Two possible factors that may have a causal relation with both depressive disorder and cardiovascular disease are elevated homocysteine and steroid hormones. Our previous study found significant changes in the plasma homocysteine concentration during the menstrual cycle in healthy women. The purpose of this study therefore was to test homocysteine in depressive women treated with fluoxetine during the menstrual cycle. MATERIALS AND METHODS: Thirteen premenopausal women suffering from mixed anxiety-depressive disorder and a control group of 15 healthy women were enrolled in this study. The homocysteine concentration was determined by high-performance liquid chromatography with fluorescence detection, and estradiol, progesterone and cortisol by RIA methods. RESULTS: We found significantly higher plasma homocysteine concentrations in the follicular phase than in the luteal phase of the menstrual cycle in both the depressive group (P < 0.003) and the controls (P < 0.0009). Moreover, the patient values of total homocysteine were significantly higher in the follicular phase (P < 0.03) and also in the luteal phase (P < 0.007) than the values of the controls. Estradiol and cortisol were significantly higher in the follicular phase of the patients compared with the control group. CONCLUSION: According to our results, women suffering from mixed anxiety-depressive disorder have not only significantly different concentrations of homocysteine in the follicular and luteal phase of the menstrual cycle but also higher plasma homocysteine compared with healthy women. More elevated homocysteine in the depressive than in the healthy premenopausal women points to the notion that psychological factors might be important when considering the homocysteine concentration.
PMID: 12641547

  Fish Oil

Omega-3 fatty acids, homocysteine, and the increased risk of cardiovascular mortality in major depressive disorder.

Severus WE, Littman AB, Stoll AL.
Harv Rev Psychiatry. 2001 Nov-Dec;9(6):280-93.
Psychopharmacology Research Laboratory, McLean Hospital, Belmont, MA, USA.

Depression is associated with elevated rates of cardiovascular morbidity and mortality. This elevation seems to be due to a significantly increased risk of coronary artery disease and myocardial infarction and, once the ischemic heart disease is established, sudden cardiac death. Recent data suggest that the increased rates of cardiovascular disease in patients with depression may be the result of one or more still-unrecognized underlying physiological factors that predispose a patient to both depression and cardiovascular disease. Two possibly related factors that may have a causal relation with both depressive disorders and cardiovascular disease are an omega-3 fatty acid deficiency and elevated homocysteine levels. We present the available data connecting cardiovascular disease, depression, omega-3 fatty acids, and homocysteine. In addition, we suggest research strategies and some preliminary treatment recommendations that may reduce the increased risk of cardiovascular mortality in patients with major depressive disorder.
PMID: 11600487

Fat food for a bad mood. Could we treat and prevent depression in Type 2 diabetes by means of omega-3 polyunsaturated fatty acids? A review of the evidence.

Pouwer F, Nijpels G, Beekman AT, Dekker JM, van Dam RM, Heine RJ, Snoek FJ.
Diabet Med. 2005 Nov;22(11):1465-75.
Vrije Universiteit Medical Centre, Department of Medical Psychology, EMGO Institute, Amsterdam, the Netherlands.

AIMS: Evidence strongly suggests that depression is a common complication of Type 2 diabetes mellitus. However, there is considerable room to improve the effectiveness of pharmacological antidepressant agents, as in only 50-60% of the depressed subjects with diabetes does pharmacotherapy lead to remission of depression. The aim of the present paper was to review whether polyunsaturated fatty acids (PUFA) of the omega-3 family could be used for the prevention and treatment of depression in Type 2 diabetes. METHODS: MEDLINE database and published reference lists were used to identify studies that examined the associations between omega-3 PUFA and depression. To examine potential side-effects, such as on glycaemic control, studies regarding the use of omega-3 supplements in Type 2 diabetes were also reviewed. RESULTS: Epidemiological and clinical studies suggest that a high intake of omega-3 PUFA protects against the development of depression. There is also some evidence that a low intake of omega-3 is associated with an increased risk of Type 2 diabetes, but the results are less conclusive. Results from randomized controlled trials in non-diabetic subjects with major depression show that eicosapentaenoic acid is an effective adjunct treatment of depression in diabetes, while docosahexanoic acid is not. Moreover, consumption of omega-3 PUFA reduces the risk of cardiovascular disease and may therefore indirectly decrease depression in Type 2 diabetes, via the reduction of cardiovascular complications. CONCLUSIONS: Supplementation with omega-3 PUFA, in particular eicosapentaenoic acid, may be a safe and helpful tool to reduce the incidence of depression and to treat depression in Type 2 diabetes. Further studies are now justified to test these hypotheses in patients with Type 2 diabetes.
PMID: 16241908


Effectiveness of chromium in atypical depression: a placebo-controlled trial.

Davidson JR, Abraham K, Connor KM, McLeod MN.
Biol Psychiatry. 2003 Feb 1;53(3):261-4.

Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, North Carolina.
BACKGROUND: Chromium picolinate (CP) has been reported to benefit patients with symptoms of atypical depression. METHODS: A placebo-controlled, double-blind, pilot study of CP was conducted in 15 patients with DSM-IV major depressive disorder, atypical type. Patients received 600 micro g of CP or matching placebo (PBO) for 8 weeks. RESULTS: Seven (70%) CP and zero (0%) PBO patients met responder criteria (p =.02). Other outcomes were consistent with greater effect of CP. Three patients on CP failed to show any improvement. Chromium picolinate was well tolerated. CONCLUSIONS: Chromium picolinate shows promising antidepressant effects in atypical depression. Its mechanism of action may relate to 5HT2A downregulation, increased insulin sensitivity, or to other effects.
PMID: 12559660

Chromium treatment of depression.

McLeod MN, Golden RN.
Int J Neuropsychopharmacol. 2000 Dec;3(4):311-314.

Eight patients with refractory mood disorders received chromium supplements and described dramatic improvements in their symptoms and functioning. In several instances, single-blind trials confirmed specificity of response to chromium. Side-effects were rare and mild, and most commonly included enhanced dreaming and mild psychomotor activation. To our knowledge, this is the first case series describing the response to chromium monotherapy. The putative antidepressant effects of chromium could be accounted for by enhancement of insulin utilization and related increases in tryptophan availability in the central nervous system, and/or by chromium's effects on norepinephrine release.
PMID: 11343609


Neuroendocrinology of the polycystic ovary syndrome.

Soule SG.
Baillieres Clin Endocrinol Metab. 1996 Apr;10(2):205-19.
Endocrine-Diabetes Unit, University of Cape Town Medical School, South Africa.

The clinical and biochemical heterogeneity of the PCOS is mirrored by the range of neuroendocrine disturbances described in women with PCOS. An increased serum LH concentration is a common, although not ubiquitous, feature and occurs primarily as a result of an increase in the amplitude of pulsatile LH, and presumably GnRH, secretion. The frequency of pulsatile GnRH secretion may, however, be increased in certain patients and may conceivably increase LH bioactivity by altering glycosylation of the molecule. Vigorous debate continues as to whether the observed changes in gonadotrophins are a primary abnormality or occur secondary to alterations in peripheral steroid concentrations. The proponents of the frequency hypothesis point to the discordant changes in gonadotrophin secretion that may be induced by rapid frequency exogenous GnRH stimulation in patients with hypogonadotrophic hypogonadism. Those who believe that the inappropriate gonadotrophin secretion is a secondary phenomenon argue that manipulation of peripheral steroid levels, by either administration of oestrogen/progesterone, induced ovulation or ovarian diathermy, may correct the disturbance of gonadotrophin secretion, which is therefore presumably a consequence of changes in ovarian steroid feedback signals. The weight of evidence at present suggests that the inappropriate gonadotrophin secretion is usually a secondary abnormality, although there may be groups of patients with a primary increase in GnRH pulsatility. The search for a unifying neuroendocrine disturbance in PCOS has been frustrated by the inability to find consistent evidence of disordered central dopaminergic, opioidergic, noradrenergic or serotoninergic pathways. Those abnormalities which have been uncovered appear to be secondary to chronic anovulation rather than of primary pathological import, and emphasize the central importance of the ovary as culprit rather than victim in PCOS.
PMID: 8773745

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