Thursday, May 3, 2012

Depression during the Transition to Menopause

It is a commonly accepted and popular myth that as woman enters the menopausal years, it is “normal” to feel depressed.  Serious depression, however, should never be viewed as a “normal” event, and women who suffer from it at any time in life should receive the same attention as for any other medical illness. 

Depression affects up to 25% of women at some point in their lives, a far higher proportion than is seen among men. Depression can be a debilitating disease, limiting daily activity as much as severe arthritis or heart disease. Large-scale research studies have shown that most problems with depression begin when women are in their 20s or younger. It is actually unusual for depression to appear for the first time after menopause, when all menstruation has ceased. However, there is a transitional time in mid-life known as perimenopause when women become somewhat more vulnerable to depression. This is the time when menstrual periods gradually lighten and become less frequent. The transition to complete menopause may last anywhere from a few months to a few years.

Minor mood problems, insomnia, and hot flashes are common during perimenopause. In some women, these symptoms progress to a more severe mood disorder known as major depression.  The risk for major depression is greatest in women who have a history of depression in the past or who had depression after childbirth (postpartum depression).  Women who have had problems with depressed mood around the time of their menstrual periods (premenstrual dysphoric disorder) may also be at higher risk for major depression in perimenopause.  And some women do become depressed for the first time in their lives during perimenopause.

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Why there is elevated depression risk associated with Menopause?

Several theories have been proposed to explain the increase in depression during perimenopause. A traditional psychological view is that the “empty nest syndrome” or other aspects of middle age lead to feelings of loss and sadness. More recently, scientists  have  focused  on  the  biological  effects  of  hormonal fluctuations  on  mood,  since  this  is  a  time  when  the  ovaries begin to make less estrogen. Estrogen interacts with chemicals in the brain that can affect mood.  In some women, the decrease in estrogen during perimenopause may lead to depression. Hot flashes and insomnia during this transition may also cause emotional distress.

The hypothesis that fluctuations in female reproductive hormones could influence different neuro-chemical pathways linked to depression is extensively supported by animal studies and existing clinical data. Estradiol receptors have been found in different brain regions (such as the medial amygdala, hippocampus, and limbic system) known to influence mood and behavior. It is now well established that estrogens interact with membrane and nuclear receptors; through nuclear receptors, estrogens bind to specific response elements in DNA and regulate the expression of targeted genes. The effects of estrogens on membrane receptors, on the other hand, may modulate the synthesis, release and metabolism of monoamines. Estrogens may also up- or down-regulate the excitability of neurons quite rapidly, probably acting through G-protein dependent mechanisms. Estrogens exert an agonist effect on serotonergic activity by increasing the number of serotonergic receptors and the transport and uptake of the neurotransmitter; estrogens also increase synthesis of serotonin, up-regulate 5-HT1 receptors, down- regulate 5-HT2 receptors, and decrease monoamine oxidase activity.

Estrogen availability may also influence the binding affinity for 5-HT receptors, as shown in animal models and in neuro-imaging clinical studies. In addition to its effects on 5-HT circuitry, estrogen also appears to augment noradrenergic (NA) activity by increasing NA turnover and decreasing NA reuptake, and decreasing the number and sensitivity of dopamine D2 receptors. This complex modulatory effect of estrogen on brain functioning reinforces the theory that wide sex hormone fluctuations could result in an adverse impact on various systems.

The menopausal transition is frequently characterized by the occurrence of vasomotor symptoms (e.g., hot flushes, night sweats), sleep disturbances and changes in sexual function. It is still controversial whether this transition is particularly associated with the occurrence of clinically significant depressive symptoms or with a particular form of depression; a so-called “menopause-specific” depression. This controversy is, in part, derived from inconsistent findings in the literature; heterogeneous studies trying to investigate this association have included women from different settings (specialized menopause clinics, other clinical facilities, community-based samples), which may make generalization of their findings difficult. In most of these studies, depression was defined based on self-report measures that indicate distress or depressive symptoms, but do not conclusively indicate a clinical diagnosis of Major Depression. Contradictory findings also derived from the fact that menopausal status was, in some of these studies, based on somewhat simplistic criteria (e.g., only on age or menstrual regularity).

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What is major depression?

Major depression is a kind of illness called a mood disorder that affects a person’s ability to experience normal mood states. Mood disorders are biological illnesses believed to be caused by changes in brain chemistry, and the tendency to depression is sometimes inherited genetically.  Physical or emotional stress can trigger the biological changes that occur in depression, and the hormonal changes leading up to menopause may also trigger such changes, especially in women who may be prone to depression because of underlying brain chemistry or family history.

The symptoms of major depression include:
  • Depressed mood most of the day, nearly every day for 2 weeks or longer and/or
  • Loss of interest or pleasure in activities that the person usually enjoys.

Other symptoms can include:
  • Fatigue or lack of energy
  • Restlessness or feeling slowed down
  • Feelings of guilt or worthlessness
  • Difficulty concentrating
  • Trouble sleeping or sleeping too much
  • Recurrent thoughts of death or suicide.

Mood disorders like major depression are not the fault of the person suffering from them or the result of a “weak” or unstable personality.  Rather,  they  are  treatable medical  illnesses  for  which  there  are  specific medications  and psychotherapy approaches that help most people.

How is depression assessed in a woman nearing menopause?

A  woman  who  feels  depressed  and  thinks  she  also  may  be entering menopause should be evaluated by a gynecologist to determine whether her symptoms could be related to the hormonal  transition.  She should also see a psychiatrist or other mental health professional, especially if her depression is severe or if she has been depressed in the past. As part of the evaluation, the doctor will:
  • Take a careful history of current and past symptoms, both emotional and physical
  • Perform a physical exam and do blood tests to evaluate the function of the woman’s ovaries (if she is still having some menstrual periods) and thyroid gland (which may cause depression when underactive)
  • Ask about life stressors that may be affecting the woman.

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Treatment recommendations for major depression that occurs in association with menopause depend on how severe the woman’s symptoms are and whether she has had previous episodes of depression.

Whenever  symptoms  are  severe,  the  experts  recommend treatment  with  antidepressant  medication,  generally  in  combination with hormone replacement therapy (usually estrogen plus progesterone, or occasionally estrogen alone). The combination of an antidepressant and hormones is advised whether or not the woman has had depression in the past.

If  the  woman’s  symptoms  are  relatively  mild  and  she  has never  been  depressed  before,  experts  do  not  agree  on  a  single best strategy but suggest trying hormones or  antidepressants, 1 at  a  time.  Hormone replacement therapy by itself will usually relieve physical symptoms such as hot flashes and will sometimes improve mood significantly. On the other hand, some women prefer to avoid hormones, especially if they have few physical symptoms, and may do better with an antidepressant.

In women who are clearly in menopause rather than transition, the experts believe that antidepressant medication is more likely to relieve depression than hormone replacement.  However, many women should consider hormone replacement for its other health benefits.

In all of these situations, experts also recommend the use of psychotherapy along with whatever medication is chosen.  Just working with a psychotherapist, however, is unlikely to help severe depression unless medication is used as well.

Antidepressant medication

Many  types  of  antidepressants  are  available,  with  different chemical  mechanisms  of  action  and  potential  side  effects.  For women with depression associated with menopause, the experts prefer a type of antidepressant that affects a brain chemical called serotonin.  These medications are called selective serotonin reuptake inhibitors (SSRIs). Among these, the expert panel prefers fluoxetine (Prozac), sertraline (Zoloft), and paroxetine (Paxil) as first choices, with citalopram (Celexa) an alternative.

SSRIs  can  have  the  following  side  effects:  nervousness,  insomnia,  restlessness,  nausea,  diarrhea,  and  sexual  problems. Side effects differ from 1 person to another. Also, what may be a side effect for 1 person (e.g., drowsiness) may benefit someone else (e.g., a woman with insomnia).  Fortunately, most women with depression do not have many problems with side effects from the SSRIs. To try to reduce the risk of side effects, many doctors start with a low dose and increase it slowly.  If you are having problems with side effects, tell your doctor right away.  If side effects persist, your doctor may lower the dose or suggest trying a different SSRI.

Hormonal treatments

While antidepressants are the most appropriate treatment for severe major depression  in perimenopausal  women, estrogen may  also  be  appropriate  for  mild  to  moderate  symptoms,  particularly if the woman has never been depressed before. Studies are underway to compare estrogen and antidepressants and to determine for which patient’s estrogen may be preferred. Estrogen can be given either as a pill (e.g., Premarin, Estrace, and Estratab) or through the skin by a patch. The woman should discuss the benefits and risks of each formulation with her doctor. There is no doubt that estrogen controls the physical symptoms of menopause, especially hot flashes. There is controversy over how long it should be taken and whether it’s other general health benefits, such as keeping bones strong and possibly preventing memory problems and heart disease, may be outweighed by risks of breast cancer and stroke.

Progesterone, the other major female hormone, does not by itself treats or prevents perimenopausal depression or physical symptoms. However, it  is  often  combined  with  estrogen  (except in women who have had a hysterectomy) to ensure that excessive buildup of the uterus does not occur, which may lead to  a  risk  of  cancer.  The major disadvantage of progesterone can be uncomfortable side effects such as bloating, headaches, and even mood changes.  Should side effects occur, different forms and dose schedules of progesterone may help.

Depression  is  sometimes  a  side  effect  of  hormone  replacement  therapy,  for  reasons  that  are  not  understood.  (It may also occur in some younger women who take birth control pills.) When this happens in a woman, who has never been depressed before, it may help to try a different hormone preparation. However, in women who have significant histories of depression and become depressed again when starting hormone replacement therapy, the experts usually advise treating with antidepressant medication and/or stopping hormones altogether.


Two types of psychotherapy are highly recommended for depression related to menopause. Interpersonal therapy focuses on understanding how changing human relationships may contribute to, or relieve, depression. Cognitive-behavioral therapy (CBT) focuses on identifying and changing the pessimistic thoughts and beliefs that accompany depression.  When used alone, psychotherapy usually works more gradually than medication, taking 2 months or more to show its full effects. However, the benefits may be long-lasting. Psychotherapy is usually combined with medication in major depression. It is unlikely to help severe depression if used by itself.

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What if the first treatment isn’t helping?

It is important to give each treatment strategy enough time to work before considering another. If hormones are tried first, a response should be seen within 2-4 weeks. If the response is not satisfactory, the experts strongly suggest adding an antidepressant. If an antidepressant is used first, it must be adjusted to a high enough dose, and then given for at least 1–2 months to tell if it will help. If an SSRI antidepressant does not work in this time frame or produces intolerable side effects and has to be   stopped   sooner, the experts strongly recommend switching to a second SSRI. The doctor may also suggest combining the SSRI with a second medication, which could be either another kind of antidepressant or hormone replacement therapy if not already in use.

Latest research

One of the latest studies investigating connection between menopause and depression were performed by Seattle Midlife Women’s Health Study in 2008. Most of the 302 participating women were in their late 30s or early 40s in the early 1990s, when the 15-year study began. The women recorded depressive symptoms, kept daily menstrual calendars (to determine stage of menopausal transition), and answered questions about hot flashes. Nearly half of them provided regular urine samples for hormone assays. The study also assessed a range of health and psychosocial factors, including those related to the menopausal transition, age, and depression at other times in life.

The researchers analyzed these factors individually and in various combinations. The results confirmed findings from other studies correlating depressive symptoms with later-stage perimenopause, sleep disruption, current stress, and the presence of hot flashes. Other factors associated with depression during perimenopause were negative life-event stress, a history of postpartum depression or sexual abuse, and a family history of depression. Women who had not borne children and women who had taken antidepressants were also at greater risk. Striking by its absence was any significant connection between depression and levels of hormones associated with perimenopause — primarily estrogen or follicle-stimulating hormone.

The results of this study argue that the picture of depressive symptoms during perimenopause is far more complex than fluctuating hormone levels or hot flashes. A variety of factors — including past emotional distress — may increase a woman’s vulnerability to depression during these years. And the menopausal transition presents its own set of challenges, both physiological and psychosocial.

The Seattle researchers say their findings should serve as a reminder that depressed mood during the menopausal transition “is attributable not only to this time of a woman’s life but also to the cumulative history of events over the life course.” One important implication is that for some women, treating depression during perimenopause requires not only antidepressants but also psychotherapy, which can help address current difficulties rooted in the past.

While the weight of the different factors increasing risk of depression in this critical life stage is still subject of discussion, there is no doubt that the risk itself multiplies during this period.

Researchers at the University of Pennsylvania followed 231 premenompausal women (aged 35-47) who had never been depressed for eight years. Depression was four times more likely to occur in a woman during her perimenopausal period. It was independently associated with deranged hormonal blood levels, hot flashes and weight gain.

A Harvard Study followed 460 premenopausal women (35-46 years old) who had never been depressed for up to nine years. Perimenopausal women were 2-4 times more likely to become depressed than premenopausal women. Risks were increased by hot flashes independent of negative stressful life events.

Depression symptoms include: sadness, emptiness, decreased pleasure or interest, appetite and weight changes, difficulty sleeping or excessive sleepiness, restlessness or retardation, loss of energy, feelings of worthlessness, inappropriate guilt, difficulty thinking concentrating or deciding, morbid thoughts even without a plan for suicide.

If you notice first signs of depression, and you need to get more information on this health condition, feel free to explore different aspects of it on my blog devoted to Depression.

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