Management of mood and memory problems during menopause

More than 20% of the US population will suffer from an episode of depression, and women have a 2-fold greater risk than men.¹ Several large prospective trials have shown an increased risk of depressed mood and a major depressive episode during the menopausal transition.^2-5 Risk factors associated with development of depressed mood during the menopausal transition include history of depression, insomnia, stressful life events, inadequate social support, elevated body mass index, current smoker status, younger age, and African-American race.

In addition, hormonal changes taking place during menopause play a role, as evidenced by increased risk of depression in association with variability of estradiol levels, increasing follicle-stimulating hormone levels, and surgical menopause. Depressive symptoms tend to precede hot flashes in women who develop both symptoms.⁶

A gradual decline in some cognitive functions occurs with normal aging, beginning around age 50. Many women complain of changes in their cognitive function during the menopausal transition, with the majority reporting worsening of verbal memory. In one study of 205 menopausal women, 72% reported some subjective memory impairment.⁷ The symptoms were more likely to be associated with perceived stress or depressive symptoms than perimenopause, but overall, cognitive symptoms were more prevalent early in the menopausal transition. Women exposed to any form of hormonal therapy prior to their final menstrual period performed better on memory testing than those who initiated it after menopause.⁸ Whether women who have cognitive difficulties during the menopausal transition are at increased risk of cognitive impairment later in life is unknown.

Illustration by Alex Baker, DNA Illustrations, Inc.

It is important to remember that some types of cognitive changes, together called mild cognitive impairment (MCI), are thought to be a sign of very early dementia. MCI and dementia are highly unlikely in people younger than 50, but the risk increases significantly with age, with greater than 10% of the population over age 65 at risk of developing dementia.⁹

Alzheimer’s disease is the most common type of dementia, but other types can occur with varying presentations, including vascular dementia, Lewy body dementia, and frontotemporal dementia. In some individuals with MCI, dementia may never develop, and improvement can be seen over time. Depression can also be present with MCI, and it can be difficult to discern whether the depression is causing the memory impairment, or if MCI puts an individual at risk of developing depression. There is some evidence to suggest that depression may be an early manifestation of cognitive decline.¹⁰

Diagnosis

Many women do not seek or cannot access psychiatric services for management of their depressive symptoms and therefore many remain undiagnosed and/or inadequately treated. Primary care providers, including ob/gyns, are in a unique position to identify and treat these patients because women may feel more comfortable discussing their symptoms and initiating treatment with providers whom they have seen regularly for many years. Diagnosis and treatment of depression in a primary care setting are subject to practical limitations, including lack of time and resources and the potential overlap of medical comorbidities. 

Here we review the diagnostic criteria, helpful screening tools, and initial treatment guidelines in order to better equip the ob/gyn to manage these patients.

Definitions. A major depressive episode is defined by the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) (2013) as 5 or more of the following symptoms, present most of the day nearly every day for a minimum of 2 consecutive weeks. At least one symptom is either depressed mood or loss of interest or pleasure.

• Depressed mood

• 
Loss of interest or pleasure in most or all activities

• Insomnia or hypersomnia

• Significant weight loss or weight gain or decrease or increase in appetite

• Psychomotor retardation or agitation

• Fatigue or low energy

• Decreased ability to concentrate, think, or make decisions

• Thoughts of worthlessness or excessive or inappropriate guilt

• Recurrent thoughts of death or suicidal ideation, or a suicide attempt

A complete interview for depressive symptoms in every perimenopausal patient is neither necessary nor efficient. Screening tools can be used to determine who will need further evaluation. One appropriate tool, used frequently in the primary care setting in older adults, is the 5-item Geriatric Depression Scale (GDS).¹¹ This may be helpful in perimenopausal patients because it excludes physical symptoms related to medical illness and aging that may be present during menopause (Table 1). The longer version of the GDS has been validated in both younger and older adults.

With time often short in the clinical encounter, even briefly asking patients whether, during the past month, they have felt down, depressed, or hopeless, or have felt little interest or pleasure in doing things, may help to determine who requires further evaluation.

Referral of patients to a mental health specialist depends on the primary care provider’s level of expertise in assessment and treatment of depression, the availability of mental health resources, and patient/family preference. Evidence of suicidal or homicidal ideation, inability to care for self or others, failure to respond to initial treatment trials, presence of psychotic symptoms, history of bipolar disorder or psychotic disorder, significant psychiatric comorbidity, or an unclear diagnosis of depression usually require immediate referral to a mental health specialist.

When a perimenopausal or postmenopausal woman presents with cognitive complaints, the practitioner will most often be able to reassure her that these complaints are frequent and not necessarily progressive, and may even improve over time. As is true for depressive symptoms, patients with cognitive impairment will often first present to a primary care provider such as an ob/gyn. Women who report worsening of verbal memory are likely experiencing a normal change associated with the menopausal transition and can be reassured.

The decline in memory is usually most pronounced within 12 months after the final menstrual period. No specific monitoring is recommended, unless a woman experiences progressive memory loss. In that case, referral to a neurologist or mental health professional may be warranted.

In 2001, the American Academy of Neurology (AAN) published practice guidelines for the early detection of progressive memory problems.⁹ The AAN workgroup of specialists identified the following criteria for an MCI diagnosis:

• Memory complaint, preferably confirmed by an informant

• Objective memory impairment on standard neuropsychological batteries assessing memory (for age and education)

• Normal general thinking and reasoning skills

• Ability to perform normal daily activities

MCI patients do not meet criteria for dementia, which involves impaired daily functioning. The evaluation for MCI and dementia includes a thorough history provided by the patient and preferably a partner or family members in close contact with the patient. Medical history and review of systems will aid in determining if any other medical illnesses could be contributing (particularly infectious illnesses or disorders of the cardiovascular, neurologic, or endocrine systems). A medication history is also particularly important because often analgesics, anticholinergics, psychotropic medications, and sedative-hypnotics can affect cognition.

Eliciting information about family members with dementia of possible early onset (before age 60) and other neurologic disorders is also important. A physical examination-including a basic neurologic exam and some cognitive assessment-should also be completed.

The cognitive test most often used as a screen for cognitive impairment is the Mini-Mental State Exam (MMSE),¹² which takes only a few minutes to complete (Table 2). It tests a broad range of cognitive functions including orientation, recall, attention, calculation, language manipulation, and constructional praxis. A score of 24 points or less is suggestive of dementia or delirium. MMSE scores may also be influenced by age and education, as well as language, motor, and visual impairments.

Initial laboratory work-up should include thyroid stimulating hormone and vitamin B12 to rule out potentially reversible causes of cognitive impairment (hypothyroidism and vitamin B12 deficiency). Screening for neurosyphilis may be indicated, but only if there is a high clinical suspicion. Other laboratory studies, such as complete blood count, electrolytes, renal function and liver function tests, are neither recommended nor indicated unless specific clinical suspicion is present. Brain imaging should be completed if MCI or dementia is diagnosed. Once such a diagnosis is made, those patients should be referred to a neurologist or geriatric psychiatrist for further evaluation and/or treatment.

Treatment

First-line treatment of a major depressive episode may involve psychotherapy, pharmacotherapy, or a combination of these modalities. Treatment is often tailored to patient preference and severity of depression. More severe episodes usually require combined psychotherapy and pharmacotherapy. A mild to moderate episode may respond to either psychotherapy or an antidepressant alone. If a patient is interested in a trial of medication, she may benefit significantly if it is started soon after diagnosis. Gynecologists frequently make the initial diagnosis of depression and are in a position to begin this treatment in a timely manner when possible.

Selective serotonin reuptake inhibitors (SSRIs) are first-line medications used in treatment of depression. Once initiated, it may take 6 to 8 weeks for a patient to respond. Often, however, patients notice a difference within the first month of treatment. Dosage can be titrated to achieve improved effectiveness, with increases approximately every month as tolerated.

Of particular concern in this population is the risk of sexual side effects (decreased libido and difficulty with arousal and achieving orgasm). Depression can also affect a woman’s sexual function, but the risks of discontinuance of medication may outweigh the burden of these adverse effects. A switch to a different SSRI, other antidepressant class, or addition of bupropion, which acts on the dopaminergic system, may be helpful.

Estrogen can be helpful in treating perimenopausal depression and changes in sexual function as well. Conversely, several different SSRI and SSNRI (selective serotonin-norepinephrine reuptake inhibitor) antidepressants have been shown to be effective in treating perimenopausal vasomotor symptoms (Table 3).¹³

Several other classes of antidepressants are also available for patients whose depression has failed to respond to an SSRI or who have difficulty with adverse effects, although a trial of a different SSRI first may prove beneficial. SSNRIs such as venlafaxine or duloxetine can be particularly helpful in patients with comorbid anxiety. Bupropion can be helpful when patients have low energy, but can exacerbate anxiety and insomnia.

Tricyclic antidepressants and monoamine oxidase inhibitors are useful in treatment-resistant depression. They often are associated with more significant adverse effects (particularly in older patients), may interact with many other medications, and can pose a serious overdose risk. Electroconvulsive therapy is often very well tolerated, safe, and effective in older patients whose condition fails to respond to medications or who do not tolerate medications.

Several forms of psychotherapy may be beneficial for patients with depression, including cognitive behavioral therapy, interpersonal therapy, and psychodynamic psychotherapy. A range of providers with psychotherapy training are available, but resources may be limited by a patient’s insurance, location, and financial situation. Women who present with multiple psychological complaints such as depression plus anxiety or bipolar disease are usually better referred to a mental-health specialist.

For mild or moderate depressive episodes, limited evidence suggests that estrogen may be beneficial, but only for women who are perimenopausal. Dose equivalents of 50 to 100 mcg of transdermal 17β-estradiol daily (equivalent to a 0.625- to 1.25-mg oral dose of conjugated estrogens daily) have been shown to be of modest benefit.¹⁴ Estrogen can be used in conjunction with antidepressants. Although the North American Menopause Society does not recommend estrogen use for sole treatment of depression or cognitive dysfunction, it may be helpful in patients who also experience vasomotor symptoms.

After evaluating cognitive complaints in a perimenopausal or postmenopausal woman, some treatment options may be useful. For the most part, though, the absence of an established treatment for MCI limits the value of early detection. Acetylcholinesterase inhibitors have been shown to provide benefit for patients with early dementia, but have not been shown to decrease the rate of progression to dementia in patients with MCI.¹⁵ Estrogen therapy is not recommended for this purpose.

Antidepressant medications may result in improved cognition if comorbid depression is present. Atomoxetine, a selective norepinephrine reuptake inhibitor often used to treat adult attention deficit disorder, has recently been shown to provide significant subjective improvement in memory and attention in perimenopausal and postmenopausal women presenting with midlife-onset subjective cognitive impairment.¹⁶

Similarly, stimulant medication may have a role in the treatment of subjective cognitive impairment, particularly for women with comorbid fatigue or impaired concentration who are not showing evidence of objective impairment.

There is some evidence that modifying lifestyle factors can decrease the risk of dementia and even cognitive decline associated with normal aging. Patients should be encouraged to maintain a normal body weight, exercise regularly, maintain a nutritious diet, engage in regular social activities, and participate in cognitive exercise (reading, crossword puzzles, etc.). They should also be encouraged to maintain good cardiovascular health, with treatment of hyperlipidemia, hypertension, and diabetes mellitus.

Patients and their clinicians can be reassured that for the majority of women, cognitive function is not likely to worsen in postmenopause in any pattern other than that expected with normal aging. Although it is not likely that in postmenopause, a woman’s cognitive function will return to what it was premenopause, she may adapt to and compensate for the symptoms with time.

Dr. Santoro reports ownership interest in Menogenix and investigator initiated grant support from Bayer Inc.

Dr. Skaznik-Wikiel has no conflict of interest to report with respect to the content of this article.

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