Dr. Strada is attending psychologist in the Department of Pain Medicine and Palliative Care at Beth Israel Medical Center and assistant professor of Neurology and Psychiatry at Albert Einstein College of Medicine in New York City.

Disclosure: Dr. Strada reports no affiliation with or financial interest in any organization that may pose a conflict of interest.

Please direct all correspondence to: E. Alessandra Strada, PhD, Attending Psychologist, Department of Pain Medicine and Palliative Care, Beth Israel Medical Center, 12 Baird Hall, 1st Avenue and 15th Street, New York, NY 10003; Tel: 212-844-8844; E-mail: AStrada@chpnet.org.


 

Focus Points

• Grief, demoralization, and depression are commonly experienced by patients with advanced illness in the palliative care setting.
• Differentiating grief reactions from depression and demoralization is complicated by the overlap of symptoms in their clinical presentation.
• The nature of normative grief and demoralization generally makes them more likely to improve with psychotherapeutic interventions, rather than medication.
• Major depression and complicated or prolonged grief disorder have more significant physiologic components along with more pronounced psychological distress and often warrant the use of psychotropic medication. 
 

Abstract

Patients with advanced illness and their caregivers are intimately familiar with the experience of grief and loss. Being diagnosed with a serious illness is often the beginning of emotional and physical losses that may end with the patient’s death. Along the difficult journey through illness, patients and caregivers may develop varying degrees and types of emotional distress. Depression, severe grief reactions, and demoralization are common types of disorders experienced by patients and caregivers in the palliative care setting. While commonly recognized as separate diagnostic entities, these disorders share many symptoms, making their differentiation challenging. Accurate diagnosis is crucial because of its treatment implications. This article reviews the characteristic features of these disorders in the context of palliative and end-of-life care. Assessment and non-pharmacologic treatment modalities are presented.

Introduction

Depression, demoralization, and complicated or prolonged grief reactions can cause severe distress in patients and families in palliative care settings. As these disorders share many clinical features, the initial presentation can result in misdiagnoses and, not uncommonly, undertreatment.

Demoralization and normative grief may respond more positively to psychosocial support and psychotherapeutic interventions, without the need for psychotropic medications. Major depressive disorder (MDD) and complicated or prolonged grief reactions may have a more significant physiologic component and more disruptive psychopathology, which often warrants the addition of medication. Developing the ability to differentiate among these conditions will allow providers to recommend the most suitable treatment option to the patients or the family.

Grief and Bereavement

While the experience of grief is a normal reaction to loss, it is a multidimensional process and its course is varied and complex, involving a multitude of distressing symptoms that can significantly impact on individuals’ level of functioning.1-5

Research has shown that bereaved survivors have higher mortality rates than control participants from cardiovascular disease6 and infectious diseases.7 Loss of a spouse is associated with increased mortality in surviving spouses8-11 and in widowers it has been associated with a 40% increase in mortality rates compared to controls.12 Suicide is also a consequence of bereavement for many individuals.13 In particular, elderly bereaved individuals tend to be at greater risk for suicide given higher rates of social isolation and depression, especially if they have cared for a loved one during a long illness.13,14 Mental illness, especially MDD and posttraumatic stress disorder, is one of the most common consequences of bereavement.15-18

The first empirical study of survivors mourning was conducted by Lindemann19 in 1944, after the fire at the Cocoanut Grove Nightclub in Boston. The features of mourning he described were guilt, anger, loss of regular pattern of conduct, identification with physical symptoms of the deceased, and preoccupation with sad memories about the deceased. Bowlby20 conceptualized grief as a series of attachment behaviors that could also be observed in infants separated from their caregivers. Parkes21 described the bereaved individual’s experience of loss as having the power to change the “assumptive world,” meaning the set of beliefs, expectations, and thoughts about how the world functions or is supposed to function. The loss of a loved one shatters the set of familiar expectations and leaves the individual in an unfamiliar territory, where familiar assumptions are no longer valid.

Even though the process of recovering from a loss is highly individual and does not follow a predictable course, most bereaved individuals are able to integrate the loss into their lives, as a result of a complex process that can be accurately described by the dual process model of grief developed by Stroebe and colleagues.22 The dual process model of grief includes a loss-oriented response and a restoration-oriented response. While the former represents the active form of grieving and can be highly distressing, the latter runs parallel to it and involves the expression of active coping skills that allow the individual to process the loss and integrate it into their lives.

Normative Grief

Normative, non-pathologic grief is characterized by a constellation of physical, cognitive, psychological, and spiritual symptoms that can create significant suffering but with varying frequency and severity. The various models of grief share the principle that bereavement involves an initial period of shock, disbelief, or denial, often followed by a phase characterized by distressing physical and emotional symptoms.23,24 In the majority of cases, bereaved individuals are able to integrate the loss and continue to function. However, the length of time necessary for the loss to be processed and integrated, which is usually referred to in the literature as a period of “restitution,” is variable, unique to the individual, and often unpredictable.23 The course of normal grief is affected by numerous factors, such as the survivor’s relationship to the deceased, the survivor’s level of functioning and mental health prior to the loss, and the nature and circumstances of the death (Table 1).23 Normative grief reactions include physical, psychological, and spiritual symptoms. Physical symptoms to loss may include shortness of breath, tightness in the throat, feeling of emptiness and heaviness, physical numbness, feeling outside one’s body, muscle tension, body aches, headaches, dizziness, nausea, gastrointestinal problems, and heart palpitations. Commonly experienced are also somatic symptoms of depression, such as crying spells, fatigue, disturbances in sleeping and eating patterns, anorexia, weight loss, lack of strength, loss of sexual desire, or hypersexualiy.23 Normative grief can also include perceptual disturbances such as visual and auditory hallucinations, impaired memory, and constant worry; slowed and disorganized thinking; suicidal ideation; and constant preoccupation with the deceased. The content of the perceptual disturbances is often related to traumatic circumstances surrounding the death of the loved one or unresolved issues that may elicit guilt. Spiritual symptoms may include conflicts in faith beliefs and loss of meaning and purpose.23

 

 

Complicated Grief

The last decade has seen a significant amount of research aimed at understanding the nature of grief and its manifestations, distinguishing what is commonly referred to as normative grief from pathologic forms of grief. This investigation has been motivated by the clinical observation that even though the majority of bereaved individuals are able to integrate the loss of a loved one after a variable period of time, in 15% to 25% of cases bereaved individuals continue to experience maladaptive reactions and psychiatric symptoms that significantly impair their level of functioning.25-27

Horowitz and colleagues28 offered a diagnostic algorithm differentiating complicated grief from MDD. Subsequently, Prigerson and colleagues25 demonstrated that symptoms of pathologic grief form a cluster that is different from depression and anxiety. As a result, complicated grief was proposed as a newly recognized disorder and diagnostic entity different from MDD and anxiety.29

In the most recent conceptualization, Boelen and Prigerson30 have revised the diagnostic criteria for complicated grief, renaming the disorder prolonged grief disorder (PGD). In order to be diagnosed with PGD, bereaved individuals must experience one of three symptoms in the “separation distress” category, and five of nine symptoms in the “cognitive, emotional, and behavioral symptoms” category. PGD has been proposed for inclusion in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition.31

Grief in the Palliative Care Setting

Grief assessment and bereavement care should begin at the first contact between the patients and family and the palliative care or hospice team. Research has shown that complicated grief (ie, PGD) is associated with physical and psychiatric morbidity, including increased suicidal ideation and overall reduced quality of life.29 Therefore, identifying individuals at risk for developing complicated grief should be a particular focus of the palliative care team. Factors described in the literature as exposing bereaved individuals to a higher risk for bereavement include a childhood history of separation anxiety, overly-controlling parent, parental abuse, early parental death, and insecure attachment styles. Additionally, a history of mental illness prior to the loss and an ambivalent relationship with the deceased increase the risk for developing prolonged grief disorder and may seriously undermine patients and families’ ability to cope with the progression of illness and impending death.29

The Experience of Grief in Patients with Advanced Illness

The grief experience of patients who are dying should also be carefully understood, assessed, and treated because it presents unique features that warrant an individualized approach. The term preparatory grief has been used in the literature to indicate a normative grieving process that may be experienced by patients with advanced illness as they approach death.32-35 It has been described as a natural element of the life cycle,35 with the potential to create significant suffering for the patient and the family system. Kubler-Ross’36 description of anticipatory grief as the grief that “the terminally ill patient has to undergo to prepare himself for his final separation from this world” has been frequently utilized to indicate this process, unique to each patient. Patients’ grieving process has a multidimensional nature that involves the physical, emotional, and spiritual domain. While preparatory grief can elicit intense negative affect, it is arguably different from depression (Table 2).37

 

Patients’ preparatory grief to some extent parallels the anticipatory grief experienced by family members. Spiritual orientation and religious affiliations modulate the extent to which the patient’s own death is perceived as an absolute loss of self or a transition to another existence of self that is primarily spiritual. In this sense, patients with advanced illness who are grieving their own death may be faced with the same tasks involved in grieving the loss of a loved one.

Applying Worden’s38 task model of grief to dying patients’ preparatory grief may allow providers to understand the nature and manifestations of preparatory grief and identifying areas that may require specific interventions to minimize distress for the patient. According to the original model, the tasks of grief work involved in processing the loss of a loved one include accepting the reality of the loss, working through the pangs of grief, adjusting to a world without the loved one, and emotionally relocating the loved one and continuing on with life.

When applied to patients, the first task involves dealing with awareness of a limited prognosis and impending death. While this task involves a pragmatic and cognitive process for family members, it allows room for various shades of gray when it comes to dying patients. In other words, bereaved family members are faced with the task of accepting that the loved one is, in fact, dead, and no longer living. Patients may, however, experience various degrees of awareness and acceptance of the fact that their death is near. Their willingness to openly acknowledge that they are dying should not necessarily be interpreted as a sign of benign acceptance and “better” adjustment to the dying process, the same way that unwillingness to openly acknowledge that death is near is not necessarily a sign of unhealthy denial. Open awareness of dying does not automatically translate into acceptance or peace. Similarly, while patients may choose not to openly acknowledge they are dying, they may still be internally engaged in processing this reality. Death awareness is a complex construct, initially explored in Glaser and Straus’s39 landmark study which described possible scenarios reflective of awareness contexts between patients and caregivers. The types of awareness described in their study are open, suspected, mutual pretense, and closed. In open awareness both patient and caregiver are aware that the patient is dying and are open to talk about it. In closed awareness the caregiver is aware that the patient is dying, but this awareness is hidden from the patient. In suspected awareness the patient suspects, but the topic is not openly discussed. In mutual pretense one or both parties in the patient-caregiver dyad pretend that they do not know the patient is dying. Many factors impact how awareness of dying is conceptualized by patients and caregivers. Culture, spiritual and religious beliefs, and family history, including perceived ability of patient or caregiver’s ability to cope with the impending death, are some of the factors that add to the complexity of the issue.

The second task of Worden’s38 model involves working through the pangs of grief. For dying patients, this task may become a major source of distress as their care transitions from a curative to a palliative mode. For many patients with advanced illness, the moment they first hear about hospice care may mean getting in touch with the fact that their illness will not improve and they will probably die soon. This moment of awareness is not experienced by all patients, nor do patients who have awareness of their impending death experience the same level of emotional distress as a result of it. However, whatever resources can be mobilized by the palliative care team should be used to relieve suffering for the patient and the family.

The third task involves adjusting to a world without the loved one. For dying patients, this task may involve progressively withdrawing from a world that will soon be without them. It is possible that the progressive emotional withdrawal that many patients experience as they are entering the terminal stage may not only be caused by the physical decline but also by a progressive grieving process that facilitates patients’ symbolic disinvestment of emotional energy from the outside world.

The fourth task applied to bereaved individuals involves “emotionally relocating” the loved one and continuing on with life. For patients who are dying, this task may involve emotionally relocating loved ones, family members, and other sources of emotional attachment, in order to find some form of peace with their own death and dying process. For the palliative care team, the task is to understand and facilitate dying patients’ grieving process as well as guide and support the family.

Treatment Approaches for Normative and Prolonged Grief

Educating patients and families about the nature of grief and its manifestations in the context of palliative and end-of-life care should be approached early. Normalizing the distressing symptoms in the early phases of grief should not take the place of ongoing assessment to identify the presence of risk factors for developing prolonged grief or severe depressive symptoms that should be addressed pharmacologically.

Shear and colleagues40 conducted a randomized controlled trial of an intervention for the treatment of complicated grief comparing 16 sessions of interpersonal therapy, in lieu of a control, with 16 sessions of complicated grief treatment. Results showed that even though participants in both groups improved, participants who received the complicated grief treatment experienced faster improvement of greater magnitude. Complicated grief treatment involved a combination of modified in vivo and imaginal exposure focusing on processing traumatic symptoms related to the death, promoting a sense of connection with the deceased loved one, and restoration from the grief. Recently, treatment of complicated grief has been tested in randomized controlled studies41 combining Shear’s therapy for complicated grief with pharmacotherapy. Results showed that adding an antidepressant improved compliance with treatment in the experimental group, but not in the control (interpersonal therapy) group. Interpretive, supportive group therapy and cognitive-behavioral group therapy have been studied with promising results.42,43 Escitalopram, bupropion, and paroxetine have also been studied in the context of complicated grief and have shown to reduce symptoms of depression without worsening grief symptoms.44-47

Family interventions should be the preferred choice when the family as a system is at risk, if there are children or adolescents at risk, or if one or more family members develop a substance use disorder as a way of managing emotional difficulties. Family-focused grief therapy, developed by Kissane and Bloche,48 is a six- to eight- session family therapy intervention aimed at reducing emotional distress and dysfunctional communication patters among family members, while facilitating appropriate expression of emotions.

Depression in Patients with Advanced Illness

As patients’ medical care shifts from a curative to a palliative modality, they may experience emotional distress as a result. After intensely focusing physical and emotional energy on pursuing curative treatments, as in the case of many patients with cancer, transitions of care often mean not only that cure cannot be achieved but that the prognosis may be poor and death may become an increasingly certain and near outcome. Patients and caregivers may experience profound disappointment, sadness, and grief.

It has been estimated that rates of MDD in patients who are dying can be between 22% to 75%.49-51 Identifying risk factors for depression should be a priority of the palliative care team and a major focus of the initial assessment. Untreated depression creates significant suffering for patients and caregivers and is associated with suicidal ideation and increased requests for hastened death in terminal patients.52-55 Diagnosing depression in patients with advanced illness is challenging. While the term depression is sometimes used to indicate a variety of situations where the patient feels low, sad, or demoralized, a diagnosis of MDD implies that DSM-IV-TR56 criteria are met. However, many of the somatic symptoms of depression, such as fatigue, disturbances in the sleep cycle, loss of energy, and weight loss are common in patients with advanced illness. Clinicians should focus on patients’ psychological symptoms and utilize structured assessment tools that do not include somatic symptoms of depression. It has been argued that the majority of depression assessment tools are not appropriate for use palliative care patients. The Geriatric Depression Scale and the Hospital Anxiety and Depression Scale exclude most of the somatic complaints associated with depression, focusing on emotional complaints, and have been widely used in patients with advanced illness.57,58

Treatment of Depression

The palliative care team should carefully consider available treatment options when caring for patients with advanced illness who are suffering from depression. Depression is not developed by the majority of palliative care patients and should be actively treated. Antidepressants and psycho stimulants may have an important role in treating depression in patients with advanced illness. Goals of treatment, side-effect profile, drug interaction, and patient’s prognosis are important considerations that guide clinicians in their choice of pharmacologic agents. These issues have been reviewed elsewhere.59,60

Psychological treatment of depression can be effectively provided alone or in conjunction with psychotropic medications. Cognitive-behavioral therapy and interpersonal therapy have been demonstrated to improve depressive symptoms in patients with advanced cancer.61 Dignity-conserving and meaning-centered psychotherapies may allow patients to safely explore existential and psycho-spiritual questions and should be included in the treatment plan.61

Demoralization

The term demoralization is not a new concept in the psychiatric literature. It was originally proposed by Frank62 to indicate a state of perceived incompetence, inability to cope, hopelessness, existential despair, and meaninglessness frequently prompting individuals to seek mental health treatment.63 Feeling demoralized involves a sense of “giving up,” described extensively in the psychosomatic literature.64 The predominant cognitive style in this syndrome is “giving up” because the individual feels hopeless and feels that the amount of energy utilized to accomplish a goal does not translate into a tangible result.

More recently, Kissane and colleagues65-67 have proposed the existence of the demoralization syndrome as a diagnostic category separate from depression and recognizable in palliative care and hospice settings. While researchers have highlighted the need to include demoralization in the psychiatric nomenclature,68 currently it is often referred to as adjustment disorder. However, it has been argued that adjustment disorder does not place sufficient emphasis on the personal narrative of incompetence that characterizes the lives of demoralized individuals.69 Bodily disfigurement, physical disability, chronic medical illness, and social isolation are some of the main clinical features associated with this syndrome.65-67 Predisposing, precipitating, and perpetuating factors have also been identified. A personal history characterized by early medical illness and multiple losses can predispose to demoralization as well as life stressors that abruptly change the individual’s sense of hope and meaning in life. Factors that are important in maintaining the sense of demoralization include dysfunctional family dynamics, unmanaged countertransference on the part of clinicians, and lack of social support. While demoralization is prevalent in various patient populations, its recognition is especially important in the context of palliative care settings. It has been hypothesized that untreated demoralization can expose individuals to chronic distress, MDD, social withdrawal, impulsive suicidal behavior, and requests for physician-assisted suicide.65-67

Treatment Approaches for Demoralization

Many authors agree that antidepressants do not address the sense of incompetence or meaninglessness. However, they should be used in conjunction with psychotherapy if patients have comorbid depression. Interventions that can foster hope and connection with a sense of meaning in life should be utilized to address demoralization.68 Narrative therapy can help patients reframe personal stories of failure and sadness into resilience and hope. Negative cognitive styles such as pessimism, magnification, selective focus on the negative, and self-labeling can be particularly maladaptive and increase patients’ suffering. Cognitive therapy can be utilized to address cognitive distortions and maladaptive cognitive styles typical of demoralized patients. Interpersonal therapy can foster a sense of interpersonal connection. Additionally, appropriate referrals to community resources and volunteer organizations can be particularly helpful for palliative care patients with no caregiver, or whose caregivers are unable to meet the patients’ need due to psychosocial stressors, physical illness, or mental illness.

Differentiating Demoralization from Depression

Demoralization and depression share clinical symptoms and the differentiation may be challenging. While the core feature of depression is anhedonia and loss of pleasure or interest in present or future activities that used to elicit pleasure, the core feature of demoralization is meaninglessness and helplessness. Patients who are demoralized may not exhibit the psycho-motor changes typical of depression, such as retardation or agitation. Unlike patients suffering from MDD, patients who are demoralized can exhibit normal behavior or full range of affect and are capable of experiencing pleasure from engaging in pleasurable activities. Therefore, ability to experience pleasure in activities that are meaningful to the patients and ability to exhibit full range of affect can help providers distinguish between demoralization and depression.69-72

Conclusion

Depression, demoralization, and grief reactions are separate diagnostic entities commonly experienced by patients with advanced illness in the palliative care setting. Clinicians should become familiar with the core features of each condition in order to make appropriate treatment decisions and adequate referrals to members of the interdisciplinary palliative care team. PP

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71.    Mangelli L, Fava GA, Grandi S, et al. Assessing demoralization and depression in the setting of medical disease. J Clin Psychiatry. 2005;66(3):391-394.
72.    Marchesi C, Maggini C. Socio-demographic and clinical features associated with demoralization in medically ill in-patients. Soc Psychiatry Psychiatr Epidemiol. 2007;42(10):824-829.

 

Dr. Levenson is professor in the Departments of Psychiatry, Medicine, and Surgery, chair of the Division of Consultation-Liaison Psychiatry, and vice chair for clinical affairs in the Department of Psychiatry at Virginia Commonwealth University School of Medicine in Richmond.

Disclosure: Dr. Levenson is a consultant to Eli Lilly.


 

This column reviews medical aspects of catatonia, including medical disorders that can cause catatonia as well as medical complications of acute and chronic catatonia. Before the introduction of antipsychotics, most cases of primary psychiatric catatonia were due to (catatonic) schizophrenia. Presently, affective disorders (bipolar disorder, severe major depressive disorder) are more common than schizophrenia as a cause of catatonia.

Diagnosis

Although it is a relatively rare condition, catatonia may be acute or chronic. Catatonia is now recognized as a syndrome that may be encounterd in a wide range of conditions including primary psychiatric disorders, metabolic disorders, neurologic disorders and brain injury, and drug-induced disorders.1 Idiopathic catatonic states such as periodic catatonia have also been described. The core features of catatonia are stupor, motoric immobility, mutism, negativism, excitement, catalepsy, and posturing. The core features are the same regardless of whether the condition occurs in the context of a mood, psychotic, or medical state. The characteristic signs of catatonia and its diagnosis are reviewed in detail elsewhere.2 The Bush-Francis Catatonia Rating Scale is a validated rating scale that is very useful clinically and in research.3,4 While the diagnosis of catatonia can easily be missed when its most classic signs are absent (eg, waxy flexibility with posturing), catatonia is also misdiagnosed. In psychiatric settings, catatonia may be mistakenly diagnosed in patients with a severe negative symptom or deficit state of schizophrenia, in those suffering the effects of prolonged institutionalization, or in withdrawn patients with dementia who have diminished social interaction. Medical, neurologic, and substance-induced conditions that may be mistaken for catatonia are discussed below.

Prognosis

The prognosis in catatonia, both in response to treatment and after multiple episodes, is determined by the nature and severity of the disease state of which catatonia is a manifestation. Classical catatonic signs, such as mutism, stupor, negativism, and excitement, do not by themselves indicate the etiology or determine the prognosis. The prognosis is better for catatonia occurring in a mood disorder than in schizophrenia. Among medical causes of catatonia, the prognosis is better in metabolic or substance-induced disorders than in those involving injury to the brain. The prognosis is poorer in very chronic cases, those with incomplete recovery after electroconvulsive therapy (ECT), those with early relapse, and when catatonia is accompanied by dementia.

Differential Diagnosis of Catatonia in Medical Settings

The evaluation and differential diagnosis in catatonia are challenging because a history and those aspects of the physical examination requiring cooperation are usually not obtainable from a catatonic patient; thus, collateral sources of information must be obtained. Other disease states can mimic catatonia and should be considered in the differential diagnosis.1 These conditions include stiff-person syndrome,5 akinetic Parkinson’s disease, malignant hyperthermia,6 locked-in syndrome,7 selective mutism, conversion disorder, and other hyperkinetic and hypokinetic states.8

Stiff-person syndrome is an uncommon autoimmune disorder with progressive muscle stiffness, rigidity, and spasm, slowly progressive over the course of years.5 Akinetic Parkinson’s disease also can produce a state similar in some respects to catatonia (ie, mute, immobilized), but it occurs well after the diagnosis of Parkinson’s disease has been established, later in the course of the disease. Malignant hyperthermia is a familial disorder and may include some of the characteristics of catatonia, but it only occurs following general anesthesia. Selective mutism shares only that one feature with catatonia and is mainly found in young children.9 In adults, selective mutism occurs as a manifestation of personality disorder, factitious disorder, or malingering.10

Catatonia has been reported to result from a variety of medical conditions, including metabolic, neurologic, and substance-induced disorders. A review11 of 261 published cases of catatonia found that in 75% of cases there was no relevant psychiatric disorder associated with the catatonic state. The most common cause of “organic catatonia” (ie, catatonia resulting from a general medical condition) is injury to the central nervous system (CNS), whether from stroke, trauma, vasculitis, tumor, or anoxia.12 Strokes involving the anterior cerebral circulation may cause akinetic and apathetic states.13,14 Bilateral infarction of the medial frontal lobes15 or parietal lobes16 has been reported to result in catatonia. Catatonia has occurred with a variety of CNS tumors in various brain locations17-20 and as a manifestation of a paraneoplastic syndrome.21 A catatonic-like state may also be caused by epilepsy,22 rarely as a post-ictal phenomenon,23 and even as an adverse effect of anticonvulsants.24

Metabolic disorders causing catatonia have included hypo- and hyperthyroidism, hypo- and hyperadrenalism, and vitamin B12 deficiency.1 Numerous drugs and toxins have been reported to cause catatonia, including neuroleptics, dopamine-blocking antiemetics, corticosteroids, cyclobenzaprine, disulfiram, and tetraethyl lead poisoning.1,25

Hallucinogens can cause an excited catatonic state, including 3,4-methylenedioxymethamphetamine (ecstasy) and phencyclidine (angel dust). Carbon monoxide poisoning can cause catatonia due to damage to the basal ganglia. Neuroleptics can cause a parkinsonian catatonic state or catatonia as part of neuroleptic malignant syndrome as well as aggravate catatonia due to other causes.2 If a patient with catatonia of any etiology is treated with a neuroleptic, it can be difficult, if not impossible, to discriminate the original catatonia from neuroleptic-induced catatonia, with a subsequent high risk of evolution into neuroleptic malignant syndrome. Neuroleptic malignant syndrome can be particularly difficult to distinguish from “acute lethal catatonia,” ie, severe agitatedprimary catatonia.26 As if this was not diagnostically and therapeutically challenging enough, catatonia has also been reported as a result of withdrawal from clozapine,27 anticonvulants,28 and benzodiazepenes.29

Medical Complications of Catatonia

Not all patients with chronic catatonia fit the classic picture of the rigid stuporous patient in a fixed posture, but it is such patients who are most at risk for medical complications. Chronic catatonic patients are particularly vulnerable as their physicians may fail to diagnose or treat medical complications or coincident medical illnesses, for several reasons. First, recognition and treatment of medical problems are difficult due to patients’ mutism or other communication impairments, inability to cooperate, and prolonged immobility. A second reason is related to physician attitudes. Swartz and Galang30 described three cases with long delays before serious medical problems were recognized because the patients were mislabeled as hopelessly demented, leading to therapeutic nihilism. Even when a patient’s chronic catatonia is clearly recognized, physicians sometimes become passive in the pursuit of treatment and prevention of complications, out of pessimism and a sense of helplessness. Third, chronic catatonic patients typically reside in long-term care facilities (eg, nursing homes, state psychiatric hospitals) where general medical care resources may not be adequate. For all of these reasons, care providers for catatonic patients must be vigilant for medical morbidity. The following reviews the major medical complications frequently encountered in chronic catatonic patients.

Pulmonary Complications

The most common pulmonary complication of catatonia is aspiration. While the frequency of aspiration and its contribution to mortality in catatonia have not been quantified, aspiration is the most common cause of death in patients with dysphagia caused by neurologic disorders and the most common cause of death in patients on tube feedings.31 Aspiration can result in pneumonitis (inflammation caused by aspirated acidic gastric contents) and/or pneumonia (bacteria infection). Prophylactic antibiotics are not beneficial in patients who are considered at high risk for aspiration. In patients who do have aspiration pneumonia, broad-spectrum antibiotics that include coverage against gram negative organisms are recommended.31 While corticosteroids are often prescribed for aspiration pneumonitis, the practice is not supported by the available data.31 Based on a single case of fatal aspiration pneumonitis in a patient with catatonia, Bort32 recommended prophylactic administration of antacids in catatonia. However, this is not a good idea. While antacids would neutralize gastric acidity and, therefore, would be expected to reduce pneumonitis, gastric acidity normally keeps stomach contents sterile. Hence, neutralization with antacids may promote colonization by pathogenic organisms, making aspiration pneumonia more likely and more severe.31 The same rationale would argue against routine administration of histamine-2 blockers or proton pump inhibitors.

Other forms of pneumonia are also common in patients with chronic catatonia. Multiple risk factors include malnutrition, weak cough, poor respiratory effort, atelectasis, and crowded institutional settings which also makes infection more likely with an antibiotic-resistant organism. When respiratory effort is extremely poor, respiratory failure may result.33

Pulmonary embolus is another common cause of death in patients with catatonia. Prolonged inactivity promotes venous stasis which, in turn, may lead to thrombosis. Dehydration is another factor promoting venous thrombosis. In a retrospective study, Carroll34 found 6% of catatonic patients developed venous thrombosis. Case reports1,2,35,36 of thrombosis often leading to pulmonary embolism have been frequent in catatonia. A review37 of 22 cases of pulmonary embolism in psychogenic catatonia found that death from pulmonary embolus occurred only after the second week of catatonic symptoms, often without warning. Potential preventive measures include hydration, physical therapy, support hose, and prophylactic anticoagulation. Low-dose subcutaneous heparin and low molecular weight heparin are well supported by studies in post-surgical patients at high risk for deep vein thrombosis and pulmonary embolus. However, the risk appears to be lower in chronically immobilized patients,38 for whom prophylactic anticoagulation is not standard care. Whether anticoagulation would reduce morbidity and mortality in catatonia is unknown but worthy of study. Pulmonary emboli are not a contraindication for ECT, and ECT has been safely administered to catatonic patients after they had pulmonary emboli.39,40

Malnutrition and Gastrointestinal Complications

Malnutrition and gastrointestinal complications are also common in chronic catatonia. Reduced oral intake leads to dehydration and malnutrition, which, in turn, promote other complications, especially infection and skin breakdown.41 Dehydration also leads to constipation or ileus, which can be profound in catatonia.42 For all of these reasons, it may become necessary to provide enteral feeding, either via nasogastric (NG) or percutaneous gastrostomy (PEG) tubes. Unfortunately, both carry risk of significant morbidity. As noted above, aspiration is the most common cause of death in patients with feeding tubes. NG tubes’ complications include esophagitis, pneumothorax, empyema, and bronchopleural fistula. Feeding tubes are associated with diarrhea, dependent edema, and bacterial colonization of gastric contents.41 While duodenal placement of a PEG or a jejunostomy may be more effective in providing nutrition, they too can cause aspiration. Potential adverse metabolic consequences of feeding tubes include hypoglycemia, hypercapnia, and electrolyte abnormalities. The difficult decision regarding whether the benefits of enteral feeding outweigh its burdens may be avoided altogether if catatonia is treated early, aggressively, and effectively with ECT.

Oral and Cutaneous Complications

Chronic catatonia also may result in numerous adverse oral effects. Dental caries and gum disease are frequent. Poor oral hygiene promotes colonization with bacteria more pathogenic than normal flora, in turn making aspiration more likely to result in serious pneumonia. Frequent administration of antibiotics to treat infection leads to antibiotic-resistant bacteria and secondary oral fungal infections. Skin breakdown is extremely common. Stasis, immobility, and pressure all contribute to the development of decubitus ulcers.

Genito-urinary Tract Complications

Genito-urinary tract complications are frequent as well, including urinary retention due to bladder distention and urinary incontinence, requiring catheterization or diapers. Malnutrition, poor hygiene, and an indwelling catheter create high risk for urinary tract infection. Carroll34 found urinary tract infections in 8% of catatonic patients, but this is likely an underestimate. Institutionalized patients are more likely to develop urinary tract infections with resistant organisms. When feasible, intermittent catheterization is preferable to an indwelling catheter. Despite precautions, the majority of patients with indwelling catheters for >2 weeks will eventually develop bacteriuria. Treatment of symptomatic bacteriuria is always indicated. For the asymptomatic patient, removal of the catheter and a short course of antibiotics are usually successful. If the catheter cannot be removed, antibiotic therapy for asymptomatic bacteriuria is unlikely to be successful and may just result in infection with a resistant strain.

In females with chronic catatonia, menstrual hygiene may be neglected, leading to vaginal infection. Treatment with antibiotics for other infections may result in candida vaginitis.

Neuromuscular Complications

Last, neuromuscular complications are also common in immobilized patients with chronic catatonia, including flexion contractures and postural nerve palsies. Both can be prevented through physical therapy and mobilization. Prolonged immobilization is a risk factor for rhabdomyolysis. While rhabdomyolysis has been recognized as a complication of acute lethal catatonia, neuroleptic malignant syndrome, and severe acute neuroleptic-induced dystonia, the incidence of rhabdomyolysis in chronic catatonia is unknown. PP

References

1. Masand PS, Christopher E, Clary GL, et al. Mania, catatonia, and psychosis in the medically ill. In: Levenson JL, ed. The American Psychiatric Publishing Textbook of Psychosomatic Medicine. Washington, DC: American Psychiatric Publishing, Inc; 2005:235-250.
2. Caroff SN, Mann SC, Francis A, Fricchione GL. Catatonia: From Psychopathology to Neurobiology. Washington, DC: American Psychiatric Publishing; 2004.
3. Bush G, Fink M, Petrides G, Dowling F, Francis A. Catatonia. I. Rating scale and standardized examination. Acta Psychiatr Scand. 1996;93(2):129-136.
4. Wong E, Ungvari GS, Leung SK, Tang WK. Rating catatonia in patients with chronic schizophrenia: Rasch analysis of the Bush-Francis Catatonia Rating Scale. Int J Methods Psychiatr Res. 2007;16(3):161-170.
5. Lockman J, Burns TM. Stiff-person syndrome. Curr Treat Options Neurol. 2007;9(3):234-240.
6. Ali SZ, Taguchi A, Rosenberg H. Malignant hyperthermia. Best Pract Res Clin Anaesthesiol. 2003;17(4):519-533.
7. Smith E, Delargy M. Locked-in syndrome. BMJ. 2005;330(7488):406-409.
8. Fink M, Taylor MA. Catatonia: A Clinician’s Guide to Diagnosis and Treatment. New York, NY: Cambridge University Press; 2003.
9. Sharp WG, Sherman C, Gross AM. Selective mutism and anxiety: a review of the current conceptualization of the disorder. J Anxiety Disord. 2007;21(4):568-579.
10. Daniel AE, Resnick PJ. Mutism, malingering, and competency to stand trial. Bull Am Acad Psychiatry Law. 1987;15(3):301-308.
11. Thorpe LU, Keegan DL, Veeman GA. Conversion mutism: case report and discussion. Can J Psychiatry. 1985;30(1):71-73.
12. Carroll BT, Anfinson TJ, Kennedy JC, Yendrek R, Boutros M, Bilon A. Catatonic disorder due to general medical conditions. J Neuropsychiatr. 1994;6(2):122-133.
13. Wolff V, Saint Maurice JP, Ducros A, Guichard JP, Woimant F. Akinetic mutism and anterior bicerebral infarction due to abnormal distribution of the anterior cerebral artery [French]. Rev Neurol (Paris). 2002;158(3):377-380.
14. Kumral E, Bayulkem G, Evyapan D, Yunten N. Spectrum of anterior cerebral artery territory infarction: clinical and MRI findings. Eur J Neurol. 2002;9(6):615-624.
15. Reichman WE. Neuropsychiatric aspects of cerebrovascular diseases and tumors. In: Kaplan HI, Sadock BJ, eds. Comprehensive Textbook of Psychiatry. 6th ed. Baltimore, MD: Williams & Wilkins; 1995:189-190.
16. Howard RJ, Low-Beer TS. Catatonia following biparietal infarction with spontaneous recovery. Postgrad Med J. 1989;65(763):316-317.
17. Sheline YI, Miller MB. Catatonia relieved by oral diazepam in a patient with a pituitary microadenoma.Psychosomatics. 1986;27(12):860-862.
18. Neuman E, Rancurel G, Lecrubier Y, Fohanno D, Boller F. Schizophreniform catatonia on 6 cases secondary to hydrocephalus with subthalamic mesencephalic tumor associated with hypodopaminergia. Neuropsychobiology. 1996;34(2):76-81.
19. Arora M, Praharaj SK. Butterfly glioma of corpus callosum presenting as catatonia. World J Biol Psychiatry. 2007;8(1):54-55.
20. Muqit MMK, Rakshi JS, Shakir RA, Larner AJ. Catatonia or abulia? A difficult differential diagnosis. Mov Disord. 2001;16(2):360-362.
21. Tandon R, Walden M, Falcon S. Catatonia as a manifestation of paraneoplastic encephalopathy. J Clin Psychiatry. 1988;49(3):121-122.
22. Adachi N, Onuma T, Nishiwaki S, et al. Inter-ictal and post-ictal psychoses in frontal lobe epilepsy: a retrospective comparison with psychoses in temporal lobe epilepsy. Seizure. 2000;9(5):328-335.
23. Gunduz A, Benbir G, Bayar R. Postictal catatonia in a schizophrenic patient and electroconvulsive treatment. J ECT. 2008;24(2):166-167.
24. Chouinard MJ, Nguyen DK, Clément JF, Bruneau MA.Catatonia induced by levetiracetam. Epilepsy Behav. 2006;8(1):303-307.
25. Duggal HS, Singh I. Drug-induced catatonia. Drugs Today (Barc). 2005;41(9):599-607.
26. Mann SC, Caroff SN, Bleier HR, Welz WK, Kling MA, Hayashida M. Lethal catatonia. Am J Psychiatry. 1986;143(11):1374-1380
27. Yeh AW, Lee JW, Cheng TC, Wen JK, Chen WH. Clozapine withdrawal catatonia associated with cholinergic and serotonergic rebound hyperactivity: a case report. Clin Neuropharmacol. 2004;27(5):216-218.
28. Rosebush PI, MacQueen GM, Mazurek MF. Catatonia following gabapentin withdrawal. J Clin Psychopharmacol. 1999;19(2):188-189.
29. Deuschle M, Lederbogen F. Benzodiazepine withdrawal-induced catatonia. Pharmacopsychiatry. 2001;34(1):41-42.
30. Swartz C, Galang RL. Adverse outcome with delay in identification of catatonia in elderly patients. Am J Geriatr Psychiatry. 2001;9(1):78-80.
31. Marik PE. Aspiration pneumonitis and aspiration pneumonia. N Engl J Med. 2001;344(9):665-671.
32. Bort RF. Catatonia, gastric hyperacidity, and fatal aspiration: a preventable syndrome. Am J Psychiatry. 1976;133(4):446-447.
33. Boyarsky BK, Fuller M, Early T. Malignant catatonia-induced respiratory failure with response to ECT. J ECT. 1999;15(3):232-236.
34. Carroll BT. Complications of catatonia. J Clin Psychiatry. 1996;57(2):95.
35. Lachner C, Sandson NB. Medical complications of catatonia: a case of catatonia-induced deep venous thrombosis. Psychosomatics. 2003;44(6):512-514.
36. Woo BK. Basal Ganglia calcification and pulmonary embolism in catatonia. J Neuropsychiatry Clin Neurosci. 2007;19(4):472-473.
37. McCall WV, Mann SC, Shelp FE, Caroff SN. Fatal pulmonary embolism in the catatonic syndrome: two case reports and a literature review. J Clin Psychiatry. 1995;56(1):21-25.
38. Heit JA, O’Fallon WM, Petterson TM, et al. Relative impact of risk factors for deep vein thrombosis and pulmonary embolism: a population-based study. Arch Intern Med. 2002;162(11):1245-1248.
39. Suzuki K, Takamatsu K, Takano T, Tanabe Y, Fujiyama K, Matsuoka H. Safety of electroconvulsive therapy in psychiatric patients shortly after the occurrence of pulmonary embolism. J ECT. 2008;24(4):286-288.
40. Tsao C, Nusbaum A. Successful ECT course for catatonia after large pulmonary embolus and placement of inferior vena cava filter. Gen Hosp Psychiatry. 2007;29(4):374.
41. Thomas DR. Prevention and treatment of pressure ulcers: what works? what doesn’t? Cleve Clin J Med. 2001;68(8):704-707,710-714,717-722.
42. Kaufmann RM, Schreinzer D, Strnad A, Mossaheb N, Kasper S, Frey R. Case report: intestinal atonia as an unusual symptom of malignant catatonia responsive to electroconvulsive therapy. Schizophr Res. 2006;84(1):178-179.

 e-mail: ns@mblcommunications.com

 

Dr. Sussman is editor of Primary Psychiatry as well as professor of psychiatry and interim chairman in the Department of Psychiatry at the New York University School of Medicine in New York City.

Dr. Sussman reports no affiliation with or financial interest in any organization that may pose a conflict of interest.


 

Two studies1, 2 published in the February issue of the Archives of General Psychiatry suggest that taking a careful psychiatric history and performing a timely, routine blood test can predict the likelihood of developing postpartum depression (PPD) and of needing hospitalization. In each article, the authors described some of their findings as being “remarkable.” Given that the focus of this issue of Primary Psychiatry is women’s mental health, I thought it useful to share the published information with you.

As any experienced clinician knows, PPD is both serious and common. PPD may have a prevalence approaching 20% and can have a profound impact on the well being of the new mother and on the cognitive and behavioral development of the newborn infant. In the first study,1 the investigators looked for long-suspected endocrine risk factors for PPD. Endocrine-associated mood changes have been described in association with reproductive hormones during pregnancy, a history of premenstrual syndrome, and a history of oral contraceptive-induced mood changes. It has already been shown that corticotropin-releasing hormone (CRH) plays an important role in the etiology of depression among non-pregnant individuals and that hyperactivity of CRH neurons and the hypothalamic-pituitary-adrenal (HPA) axis may trigger depressive symptoms.

CRH regulates the HPA axis. According to the authors, this study is the first to identify a point in midpregnancy during which placental CRH (pCRH) maternal plasma “is a moderate and independent predictor of PPD symptoms.”1 They propose that pCRH be used as a diagnostic test to identify women at high risk for developing PPD symptoms. The presence of depressive symptoms during mid-pregnancy appears to increase the predictive power of pCRH concentrations. Levels of pCRH in maternal plasma increase dramatically throughout and then drop precipitously after delivery. The authors speculate that the onset of PPD may represent pCRH withdrawal, with consequent suppression of hypothalamic CRH release and HPA axis dysregulation. The study data show that elevated pCRH but not cortisol or adrenocorticotropic hormone is a significant predictor of PPD symptoms.

Moreover, pCRH was found to be an independent predictor of PPD symptoms, but it was not associated with concurrent depressive symptoms. Being the only study to report this association, it obviously needs to be replicated. However, among women with family histories of postpartum mood disorders or with personal histories of depression, screening for pCRH is worth considering. Since blood is usually drawn to test for gestational diabetes at 24–28 weeks of pregnancy, this could be conducted at the same time.

The second study2 examined risks and predictors of readmission for a mental disorder during the postpartum period. To the knowledge of the authors, this study is the first to compare psychiatric readmission rates of mothers and nonmothers with mental disorders. The authors compared mothers and nonmothers to assess whether childbirth increases the risk for psychiatric readmission and to identify predictors of psychiatric readmission during the postpartum period. It was a population-based cohort study merging data from the Danish Civil Registration System and the Danish Psychiatric Central Register. The main outcome measure was readmission rates to psychiatric hospitals during the 12 months after childbirth (first live-born child).

In summary, the study found that the period of highest risk of psychiatric readmission in new mothers was 10–19 days postpartum and the period of lowest risk was during pregnancy. Childbirth was associated with an increased risk of readmission during the first postpartum month, after which risk for readmission was higher among nonmothers. A previous diagnosis of bipolar affective disorder was the strongest predictor of readmissions 10–19 days postpartum. In all, 26.9% of mothers with this diagnosis were readmitted within the first postpartum year.

According to the findings, “mothers with mental disorders have lower readmission rates compared with women with mental disorders who do not have children. However, in the group of new mothers, the first month after childbirth is associated with increased risk of psychiatric readmission.”2 When applied to clinical practice, these findings should lead physicians to closely monitor women with a history of bipolar affective disorder the first postpartum year.

In addition to the clinical focus articles in this issue, there is a case report of schizophrenia-like symptoms presenting in a patient with a subtype of Niemann-Pick disease. Sami Richa, MD, and colleagues describe the case of a 27-year-old man hospitalized with a diagnosis of paranoid schizophrenia. The authors report that this is only the third published case of Niemann-Pick type B associated with a psychiatric disorder, and the first in which the neurologic disease presented before schizophrenia. Hepatosplenomegaly had developed before the onset of psychiatric symptoms. The authors conclude that psychiatric symptoms without neurologic impairment may be a manifestation of Niemann-Pick disease (intermediate type AB) or a chance association (type B). However, it is important to remember that neurologic causes always need to be excluded as possible causes of new-onset mental status changes, including psychosis.

Also in this issue is a new regular feature that will address a current research article that may (or may not) have immediate implications for clinical decision making. For example, this month, the article3 discussed is a meta-analysis of studies of the newer antidepressants. As it used an interesting approach to comparing the studies, and also showed some specific differences among the antidepressants, it could influence the way in which clinicians select first-line treaments. My intention for the column is to reach out to experts on each topic and get their take on the findings of each study. This month, I asked Michael E. Thase, MD, at the Unviersity of Pennsylvania in Philadelphia to be my expert interviewee. The one constant in this new column is the fact that the selected research paper will have been published after the previous issue of Primary Psychiatry has gone to press. I hope our readers find the information helpful. PP

References

1.    Yim IS, Glynn LM, Dunkel-Schetter C, Hobel CJ, Chicz-DeMet A, Sandman CA. Risk of postpartum depressive symptoms with elevated corticotropin-releasing hormone in human pregnancy. Arch Gen Psychiatry. 2009;66(2):162-169.
2.    Munk-Olsen T, Laursen TM, Mendelson T, Pedersen CB, Mors O, Mortensen PB. Risks and predictors of readmission for a mental disorder during the postpartum period. Arch Gen Psychiatry. 2009;66(2):189-195.
3.    Cipriani A, Furukawa TA, Salanti G, et al. Comparative efficacy and acceptability of 12 new-generation antidepressants: a multiple-treatments meta-analysis. Lancet. 2009 Jan 28. [Epub ahead of print].

 

Dr. Allison is assistant professor of psychology in psychiatry and co-director of education at the Center for Weight and Eating Disorders and Dr. Sarwer is associate professor of psychology in the Departments of Psychiatry and Surgery and director of Clinical Services at the Center of Weight and Eating Disorders, both at the University of Pennsylvania School of Medicine in Philadelphia. Ms. Lavery is a PsyD candidate at LaSalle University in Philadelphia.

Disclosure: Dr. Allison received funding from the National Institutes of Health/National Center on Minority Health and Health Disparities. Ms. Lavery reports no affiliation with or financial interest in any organization that may pose a conflict of interest. Dr. Sarwer is consultant to Ethicon Endo-Surgery and receives funding from the American Society of Metabolic and Bariatric Surgery, the American Society of Plastic Surgery, and the National Institutes of Health.

Please direct all correspondence to: Kelly C. Allison, PhD, Assistant Professor of Psychology in Psychiatry, University of Pennsylvania School of Medicine, 3535 Market St, Suite 3108, 3rd Floor, Philadelphia, PA 19104-3309; Tel: 215-898-2823; Fax: 215-898-2878; E-mail: kca@mail.med.upenn.edu.


 

Focus Points

• There is a strong relationship between obesity, fertility,  and pregnancy that can affect psychiatric well being.
• Growing evidence shows that there is a relationship between mood and polycystic ovarian syndrome and weight.
• Certain factors influence pregnancy weight gain and postpartum weight retention.
• There are interventions associated with weight control during pregnancy and in the postpartum period.
 

Abstract

The United States is in the midst of an obesity crisis. The majority of American women of childbearing age are overweight or obese. The presence of excess body weight in a woman can negatively impact fertility, pregnancy, postnatal recovery, and the health of her child. Psychiatric comorbidities, including eating and mood disorders, can influence nutrition and weight gain during pregnancy and weight loss in the postpartum period. Stress associated with caretaking in the postpartum period impacts levels of sleep and physical activity, which further impact postpartum weight retention. This article reviews the literature in these areas; the article discusses the management of excess body weight during and after pregnancy as well as related psychiatric conditions in pregnant and postpartum women.

Introduction

Approximately two-thirds (65.1%) of American women >20 years of age are overweight (Body Mass Index [BMI] >25 kg/m2).1 Almost 50% are obese (BMI ≥30 kg/m2).1 In the United States, there were >4 million live births in 2003, with >50% likely born to overweight or obese mothers.2 While overweight and obesity affect women of all ethic groups, they differentially affect those from minority groups. Almost half (49%) of non-Hispanic white women and 70% of non-Hispanic black women between 20–39 years of age are overweight or obese. Obesity has often been miscategorized as a psychiatric disorder, although it does not appear in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition–Text Revision.3 Disorders of eating and mood, however, have been associated with obesity. These characteristics may negatively impact reproductive functioning and pregnancy outcomes. This article reviews the relationship among obesity, psychopathology, and reproductive functioning, including fertility, pregnancy, and the postpartum period.

Obesity and Reproductive Functioning

Numerous comprehensive reviews4,5 have characterized the relationships between obesity and reproductive functioning. Obesity has been associated with an early onset of menarche6 and an increased risk of menstrual problems in adolescence and early adulthood.7 Obesity is also associated with many adverse effects on fertility.8-10 These include irregular menstrual cycles, increased androgenization, oligo/amenorrhea, anovulation, polycystic ovarian syndrome (PCOS), decreased conception rates after fertility treatments, increased risk of morbidity and miscarriage in pregnancy, and worsened outcomes of preterm deliveries. Excess abdominal fat is associated with irregular menstrual cycles, several hormone-sensitive cancers, and increased risk of miscarriage (Table 1).4,11,12

 

Polycystic Ovarian Syndrome and Psychological Functioning

PCOS is the most common endocrine disorder in women of reproductive age, affecting 5% to 10% of females, ~50% of whom are obese.13-15 The syndrome is characterized by chronic anovulation and hyperadrogenism and is manifested by hirsutism, cystic acne, hair loss, insulin resistance, and weight gain.15,16 PCOS is also one of the primary causes of infertility.17

Women diagnosed with PCOS experience increased incidence of depression18,19 and report significantly decreased quality of life (QOL)14,20 and emotional well-being.16 Barnard and colleagues19 found that women with PCOS were significantly more depressed than controls, with >66% of participants with PCOS experiencing some level of depression. Further, Elsenbruch and colleagues16 reported that women with PCOS, as compared to age-matched controls, reported higher levels of distress as assessed by the Symptom Checklist-Revised.

Weight appears to be the strongest determinant of psychological distress associated with PCOS.16,19-22 Excess hair growth, acne, obesity, and menstrual irregularity are also correlated with distress and anxiety. Women with PCOS report greater body image dissatisfaction and less sexual satisfaction and see themselves as less feminine than other females.14,22,23 Recent evidence suggests that some of these symptoms may be associated with the physiologic manifestations of PCOS, including hyperandrogenism and insulin resistance.24,25

The experience of infertility, faced by 66% of women with PCOS,14 may be one of the strongest determinants of psychosocial distress and reduced QOL in women with PCOS.17,26,27

It is well documented that weight loss is associated with improved social and physical functioning within obese populations.22 However, few studies have examined changes in psychological functioning for PCOS patients who lose weight. A recent study28 examined the effects of metformin on psychosocial functioning for women with PCOS. Results indicated that improvements in health-related QOL and emotional well-being were significantly correlated with weight loss and regulated menstrual cycles, suggesting that weight loss may be associated with enhanced psychosocial functioning for women with PCOS.28

Weight Loss for Infertility

Weight loss is often recommended as the first line of treatment for obese women with fertility problems.8,9,29-32 Moderate weight loss has been repeatedly shown to improve menstrual regularity, ovulation, and infertility.5,9,30,33,34 Similar improvements have been shown for women with PCOS.31,32,35,36 A weight loss of ≥5% of initial body weight appears necessary to improve markers of infertility in most women.35,36 Weight reduction of this magnitude is attainable for the majority of women treated in behavioral weight-loss programs or with pharmacotherapy.37 Few studies38,39 have examined the effect of bariatric surgery on markers of infertility. At least one investigation40 has found that 70% of females who were anovulatory prior to bariatric surgery reported regular menstrual cycles postoperatively.

Obesity and Complications During Pregnancy

Obesity is associated with numerous complications during pregnancy, many of which have increased along with rates of obesity. The Cesarean section rate in the US rose to the highest recorded level (27.6%) in 2003.2 Preterm (12.3%) and low birth weight (7.9%) births also rose to their highest levels in 30 years.2 The rates of pregnancy-associated hypertension and diabetes, the most frequently reported medical risk factors in pregnancy, also rose steadily from 1990–2002.41 Obesity has been independently associated with an increased risk of numerous pregnancy complications, including gestational diabetes, preeclampsia, congenital malformations, preterm labor and delivery, Cesarean sections, and high maternal and infant morbidity rates.12,42-47 Seemingly, none of these studies, which have typically been undertaken by obstetricians and not mental health professionals, have investigated the impact of these complications on psychological functioning either in the short term or later in the postpartum period.

Pregnancy as a Risk Factor for the Development of Obesity

Many women anecdotally report weight gain during pregnancy as a major catalyst in the subsequent development of obesity.48 Numerous studies49-52 have confirmed that excess weight gain during pregnancy, and/or failure to lose weight in the first few years after a pregnancy, are associated with later-life obesity. In these investigations, a sizable percentage of women have exceeded the Institute of Medicine (IOM) recommendations for weight gain during pregnancy. These recommendations state that women with a BMI <19.8 kg/m2 gain 28–40 lbs (13–18 kg); 19.9–26.0 kg/m2 gain ~25–35 lbs (11.4–15.9 kg); 26.1–29.0 kg/m2 gain 15–25 lbs (6.8–11.4 kg); and >29 kg/m2 gain a minimum of 15 lbs (6.8 kg) during the course of pregnancy (Table 2).4,53

 

The IOM recommendations, published in 1990, have been criticized for being too liberal and for failing to consider the potential adverse effects of excessive weight gain during pregnancy.54,55 Two prominent groups have provided guidelines for attaining these recommendations. The American College of Obstetricians and Gynecologists56 suggest that nutritional support be provided for overweight women during and after pregnancy. The National Institute of Diabetes and Digestive and Kidney Diseases57 have provided specific dietary and physical activity guidelines for pregnancy and across the lifespan. It is unknown whether expectant mothers are aware of these guidelines or if practitioners routinely use them in clinical practice.

Several factors, both internal and external, likely contribute to women’s difficulty following these guidelines. Psychosocial factors such as depressive symptoms at early and late stages of pregnancy, as well as believing that fetal health is influenced by external (rather than internal) factors, were associated with inadequate gestational weight gain.58 Another study59 suggested that either a lack of a weight gain recommendation, or a recommendation above the IOM guidelines, was associated with excessive weight gain during pregnancy. In another study,59 minority status, pre-pregnancy weight, and excessive gestational weight gain, particularly during the first trimester, have been identified as risk factors for excessive weight retention.

These factors, however, are shaped by the Western world’s “toxic” food environment, in which calorically dense and high-fat foods make the development of excessive body weight almost inevitable.60 Reliance on fast food and other prepared foods is, in some respects, a logical by-product of the workaholic, stress-filled American way of life. The effects of this environment may be exaggerated during pregnancy when many women feel less pressure to restrict food intake.4

Disordered Eating, Obesity, and Pregnancy

Generally, two forms of disordered eating are linked to overweight and obesity: binge eating disorder (BED)3 and night eating syndrome (NES).61 Both disorders typically begin during early adulthood when most pregnancies occur and could contribute to excessive weight gain during pregnancy or the retention of excessive amounts of weight during the postpartum period, although the relative newness of NES has led to little study of the condition as it relates to pregnant women.

BED occurs both before and during pregnancy. Recently, the Norwegian Mother and Child Cohort Study62 prospectively surveyed >41,000 women. The prevalence of pregestational BED was 3.5%, with 39% of these cases remitting during pregnancy. The BED incidence rate during pregnancy was 1.1 per 1,000 person-weeks (711 new cases), with increased risk among those of lower socioeconomic status (SES). The incidence of other eating disorders was rare. Bulik and colleagues62 concluded that most eating pathology improves during pregnancy, but pregnancy may be a vulnerable time for the development of BED, particularly among women of low SES.

Siega-Riz and colleagues63 also studied the nutritional habits of 34,000 women during the first half of pregnancy. Women with BED consumed higher total energy, total fat, monounsaturated and saturated fat, and lower folate, potassium, and vitamin C than those without the disorder. BED diagnosis was also related to the consumption of less juice, fruit, and chicken, and more candy, fats, chocolate and milk desserts, artificially sweetened beverages, and coffee. These findings suggest that BED, either before or during pregnancy, is related to obesity-promoting behaviors.

Several studies have found a relationship between restrained eating and pregnancy-related distress.64-67 DiPietro and colleagues64 studied 130 women between 28–36 weeks of pregnancy. Those with higher levels of dietary restriction reported higher anxiety, depression, anger, and stress, and felt less uplifted by pregnancy. Pre-pregnancy BMI was not independently related to distress, and even those who gained within their recommended weight ranges endorsed negative attitudes about weight gain. It may be that pregnancy both legitimizes increased food intake and removes any previous intentions to eat less, even among those with high levels of restraint before pregnancy.65

Controlling Excessive Weight Gain During Pregnancy

A sizable body of research37,68 has investigated the efficacy of behavioral and pharmacologic treatment for obesity. Behavioral and pharmacologic treatments typically produce a weight loss of ~5% to 10% when used alone. These weight losses can be increased if behavioral and pharmacologic treatments are used in combination.34

Unfortunately, few investigations have studied the potential utility of interventions designed to control weight gain during pregnancy. In one study,69 120 women with a pre-pregnancy BMI >19.8 kg/m2 were assigned to a behavioral intervention or control group. The behavioral intervention consisted of clinic visits where women were weighed and provided with written information regarding appropriate weight gain, exercise, and healthy eating during pregnancy. Those who exceeded the IOM weight gain guidelines during pregnancy weigh-ins were given more intensive care in the form of additional nutrition information and behavioral counseling. The control group received the standard nutrition counseling which emphasized a well-balanced diet and multivitamin/iron supplementation.

Average weight women in the intervention group were significantly less likely to exceed the weight gain recommendations as compared to average weight women in the control group (63% vs. 94%). For overweight women, however, the intervention was not effective. Approximately 66% of overweight women in each treatment group exceeded the weight gain recommendations.

Olson and colleagues70 also investigated the efficacy of a psychoeducational intervention for controlling weight gain during pregnancy in both average weight and overweight women. Participants were mailed materials on healthy weight gain, nutrition, and exercise during pregnancy. The proportion of participants gaining more than the recommended amount did not differ by group (41% intervention vs. 45% control). However, low income participants in the intervention group, regardless of pre-pregnancy weight status, were less likely to gain excess weight than those in the control group (52% vs. 33%).

Although these two studies69,70 suggest that pregnancy weight control interventions are ineffective for the prevention of excessive weight gain among overweight women, two more recent studies have found that such interventions can be effective.71,72 For example, Wolff and colleagues72 randomly assigned 50 obese pregnant females to an intervention or control group. Participants in the intervention group received ten 1-hour dietary consultations focusing on consuming a healthy diet and energy intake restriction. Women who received the intervention gained significantly less weight compared to controls, 6.6 versus 13.3 kg.

Obesity and Mood in the Postpartum Period

Weight Retention After Childbirth

The discussion above intuitively suggests that overweight and obese women may experience significant weight retention after childbirth. The empirical evidence, however, is inconclusive, as variability in the methods to assess body weight and length of follow-up have contributed to a range of outcomes. One review73 concluded the average postpartum weight retention was 0.5–3.0 kg, but could be as high as 17.7 kg. As detailed above, excessive weight gain during pregnancy is strongly associated with weight gain over the life cycle.

Postpartum Depression and Obesity

The increased time demands and sense of responsibility associated with caring for an infant may have a deleterious effect on weight control efforts as well as negatively impact mood and QOL. Postpartum depression affects 10% to 15% of mothers.74 Prior history of depression, depression or anxiety during pregnancy, lack of social support, and stressful life events have been consistently related to postpartum depression.74-76

The relationship between postpartum depression and obesity has received little attention. In one of the few studies in this area, Herring and colleagues77 found that new-onset postpartum depression was associated with substantial weight retention in the first postpartum year. In general, the relationship between depression (postpartum or other) and obesity is complex and likely bidirectional.78 Most postpartum depression studies have not explicitly mentioned weight and the role it may play. However, women with bulimia nervosa and BED experience up to three times higher rates of postpartum depression than women without eating disorders.79

Postnatal distress has also been linked to disordered eating attitudes and behaviors. Among 181 healthy women interviewed at 1-week postpartum, postnatal distress was associated with higher body weight, shape concerns, and disordered eating—including binge eating, vomiting, fear of weight gain, and distracting thoughts about food before and during pregnancy.80 Low-intensity exercise during pregnancy was related to lower postpartum distress.

Randomized intervention studies for postpartum depression are limited. One small, but innovative study80 found that 81 women assigned to walking with baby strollers for 12 weeks improved their depression and fitness levels significantly more than those in a social support group. These results suggest that exercise is not only important during pregnancy to protect against postpartum depression but may improve postpartum symptoms.

Facilitating Weight Loss During the Postpartum Period

Few studies have investigated the efficacy of weight loss interventions during the postpartum period. In one study,82 participants were assigned to either a control group (brochure on healthy eating and exercise) or an intervention group. The intervention consisted two in-person counseling sessions where participants were encouraged to follow a low-calorie (1,000–1,500 kcal/day), low-fat (20% of daily intake) diet and to exercise regularly. The intervention group also received 16 lessons on nutrition, exercise, and behavior change strategies by mail and was contacted by phone at least bi-weekly. The intervention group lost significantly more weight during the postpartum period (7.8±4.5 kg) compared to the control group (4.9±5.4 kg). Women in the intervention group were more likely to reach or weigh less than their pre-pregnancy weight.

There are countless barriers to successful weight control during the postpartum period. One such barrier during this time is significant sleep disruption.83 Recent studies84,85 have linked sleep debt with obesity and potential weight gain. Women who are up at night with their newborns may be especially susceptible to weight gain, or, perhaps, resistant to postpartum weight loss. For example, women sleeping ≤5 hours/day reported substantially higher postpartum weight retention (>5 kg) than those receiving >5 hours/day of sleep, suggesting that increasing sleep time may be an important target for postpartum weight loss.85

Low levels of physical activity are another likely barrier to postpartum weight control. Qualitative research suggests that women who plan on exercising during the postpartum period tend to lose more weight than those who do not.86 In one87 of the few empirical studies on this issue, women reporting higher levels of postpartum activity retained significantly less weight at 6 weeks than those reporting lower levels of activity (3.9 kg vs. 5.1 kg).

Many other variables may also impact postpartum weight control efforts, including marital status, age, smoking, and dietary changes in the postpartum period.88-90 While lactation may facilitate weight loss for the first few months after childbirth, it does not appear to have significant long-term effects on weight unless breast feeding continues past 12 months.88,89,91

Conclusion

A rather sizable literature has demonstrated the detrimental health effects of obesity on reproductive functioning and pregnancy outcomes. These health conditions, such as PCOS, in turn, are often related to distress and depressed mood. Encouragingly, numerous studies37,68 have suggested that modest weight losses, perhaps as small as 5% to 10%, may be associated with improvements in fertility.

For some women, it appears that pregnancy may be a catalyst for the development of obesity. Studies designed to prevent excessive weight gain during pregnancy appeared to be particularly effective for average weight (as compared to overweight) women and those from lower socioeconomic status. Given the current obesity epidemic and the potential increased risk of adverse pregnancy outcomes, pregnant women and their physicians should work together to limit excessive weight gain during pregnancy.

Presently, only a handful of studies have investigated strategies to facilitate weight loss during the postpartum period. Due to numerous barriers to treatment during the postpartum period, such as fatigue and sleep disruption, many of the inventions have been modest in scope. One clearly neglected area has been the relationship of obesity and postpartum depression which may represent the most significant barrier to successful weight control and may, over time, exacerbate the severity of obesity. PP

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91.    Dewey KG, Heinig MJ, Nommsen LA. Maternal weight-loss patterns during prolonged lactation. Am J Clin Nutr. 1993:58(2):162-166.

 

Dr. Sussman is editor of Primary Psychiatry as well as professor of psychiatry and interim chairman in the Department of Psychiatry at the New York University School of Medicine in New York City. Dr. Thase is professor of psychiatry at the University of Pennsylvania in Philadelphia.

Dr. Sussman reports no affiliation with or financial interest in any organization that may pose a conflict of interest. Dr. Thase has served as a consultant to AstraZeneca, Bristol-Myers Squibb, Cephalon, Cyberonics, Eli Lilly, Forest, GlaxoSmithKline, Janssen, MedAvante, Neuronetics, Novartis, Organon, Sepracor, Shire, Supernus, and Wyeth; is on the speaker’s bureau of AstraZeneca, Bristol-Myers Squibb, Cyberonics, Eli Lilly, GlaxoSmithKline, sanofi-aventis, Schering Plough, and Wyeth; and has received grant/research funding from Eli Lilly and Sepracor.


 

Many considerations go into the selection of an antidepressant. These include the overall clinical status of the patient, including comorbid disorders, use of other medications, sensitivities to certain side effects, and past history (if any) of treatment with antidepressants. A perennial question involving antidepressants is: Which drug is most effective? As a prescriber and an educator, I am constantly scanning the literature for studies that demonstrate differences in antidepressant efficacy, tolerability, and safety. Individual studies, usually funded by the companies that market antidepressants, have been of limited value, given what we now know about publication bias. A recent study published in the New England Journal of Medicine1 reported that among 74 Food and Drug Administration-registered studies, 31% were not published. Moreover, the authors noted:

Whether and how the studies were published were associated with the study outcome. A total of 37 studies viewed by the FDA as having positive results were published; one study viewed as positive was not published. Studies viewed by the FDA as having negative or questionable results were, with three exceptions, either not published (22 studies) or published in a way that, in our opinion, conveyed a positive outcome (11 studies). According to the published literature, it appeared that 94% of the trials conducted were positive. By contrast, the FDA analysis showed that 51% were positive. Separate meta-analyses of the FDA and journal data sets showed that the increase in effect size ranged from 11% to 69% for individual drugs and was 32% overall.1

With this in mind, a recent news headline caught my eye: “Escitalopram and Sertraline Top Comparison of 12 Newer Antidepressants.”2 Most other attempts at meta-analyses have shown inconsistent results for efficacy of second-generation antidepressants. Most, but not all, showed a slight advantage for drugs that enhanced multiple neurotransmitter systems (most notably serotonin and norepinephrine) over those that targeted only one of these systems.3-10 The most recent meta-analysis showed no difference among antidepressants.11

Of note is a recent study in Lancet by Andrea Cipriani, MD, and an international team of researchers, titled “Comparative efficacy and acceptability of 12 new-generation antidepressants: a multiple-treatments meta-analysis.”12 Not an expert at assessing the methodology used in the analysis, I consulted my colleague Michael E. Thase, MD a professor of psychiatry at the University of Pennsylvania School of Medicine in Philadelphia, to get his opinion on the study. Dr. Thase has published extensively on the subject of antidepressants in general and meta-analyses specifically. Overall, he believes that this is an important study and, because it used a method of indirect comparison, it is probably more informative than other meta-analyses. However, he also noted that it makes the study more subject to potential bias effects than meta-analyses of studies making direct comparisons.

Cipriani and colleagues reviewed 117 randomized controlled trials from 1991 up to November 30, 2007, which compared 12 new-generation antidepressants at therapeutic dose range for the acute treatment of unipolar major depressive disorder (MDD) in adults (see the Table for the drugs and doses). The main outcomes were the proportion of patients who responded to or dropped out of the allocated treatment. Analysis was conducted on an intention-to-treat basis. According to the final analysis, mirtazapine, escitalopram, venlafaxine, and sertraline were significantly more efficacious than duloxetine, fluoxetine, fluvoxamine, paroxetine, and reboxetine. Reboxetine was significantly less efficacious than all the other antidepressants tested. Escitalopram and sertraline showed the best profile of acceptability, leading to significantly fewer discontinuations than did duloxetine, fluvoxamine, paroxetine, reboxetine, and venlafaxine. According to the authors:

"Clinically important differences exist between commonly prescribed antidepressants for both efficacy and acceptability in favour of escitalopram and sertraline. Sertraline might be the best choice when starting treatment for moderate to severe major depression in adults because it has the most favourable balance between benefits, acceptability, and acquisition cost."12

 

 

Should these findings be used to help choose among new-generation antidepressants for acute treatment of major depression? The authors claim that:

"Some antidepressants differed both statistically and clinically. In terms of response, mirtazapine, escitalopram, venlafaxine, and sertraline were more efficacious than duloxetine, fluoxetine, fluvoxamine, paroxetine, and reboxetine. In terms of acceptability, escitalopram, sertraline, citalopram, and bupropion were better tolerated than other new-generation antidepressants. These results indicate that two of the most efficacious treatments (mirtazapine and venlafaxine) might not be the best for overall acceptability."12

Thus, a useful message from this is that a higher response rate alone needs to be balanced with good tolerability. In that case, sertraline came out the winner. As shown in the Figure, the various drugs have different curves for responses and tolerability.

 

Reboxetine (not available in the United States), fluvoxamine, paroxetine, and duloxetine were the least efficacious and acceptable drugs, making them less favorable options when prescribing an acute treatment for MDD. According to Dr. Thase, the fact that reboxetine came up last in both efficacy and tolerability may be the post-script to why it did not receive FDA approval for treatment of depression in the US, and is consistent with his clinical experience that noradrenergically selective antidepressants treat a smaller group of depressed people than selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors.

Surprisingly, the authors did not find evidence of sponsorship bias (ie, the bias associated with the commercial interests of industrial sponsors), since many of the studies comparing the newest antidepressants (especially mirtazapine, escitalopram, buproprion, and duloxetine) were conducted by the pharmaceutical companies marketing these compounds. The authors claim to have avoided this pitfall by making indirect and direct comparisons, decreasing the risk for possible sponsorship bias.

“The problem of sponsorship bias continues to receive a lot of discussion,” Dr. Thase said. “The major source of sponsorship bias is actually the file drawer effect—until recently sponsors did not attempt to publish their disappointing studies. Although Cipriani and colleagues discuss this as a potential problem, their results actually indicate that sponsorship did not have much impact on the results. Nevertheless, all but one of the studies of escitalopram were conducted by its sponsors, all of the studies of mirtazapine were conducted by its sponsor, and a large majority of the studies of venlafaxine and sertraline were conducted by the sponsors, so it is hard not to at least ponder the possibility.”

Doubts about some of the generalizations in the conclusions of the paper are raised when one knows the details of some of the studies analyzed. For example, only two trials compared escitalopram to venlafaxine-both designed and sponsored by the manufacturer of escitalopram-and one had a dosing schedule that favored escitalopram. The higher dose escitalopram versus venlafaxine study13 was biased in favor of escitalopram, because of the forced upward titration schedule: the venlafaxine dose was tripled over 8 days, whereas the escitalopram dose was only doubled. Escitalopram is acknowledged to be better tolerated than venlafaxine. The rapid dose escalation caused much higher dropout rates in the venlafaxine group. In a second study14 the average doses of both venlafaxine and escitalopram were comparatively low.

According to Dr. Thase, who picked up this kind of potential bias: “In a large data set, with large numbers of studies, these kind of things (ie, a single slanted study) disappear or at least no longer mean that much. However, when the numbers of studies are smaller, one or two slanted studies can be much more meaningful. That may be the bottom line with respect to why duloxetine looked unexpectedly bad in this meta-analysis.”

Dr. Thase commented on possible explanations for the observed differences among the drugs, one of these being that fluoxetine may have a smaller effect than many other newer antidepressants.

“Although not mentioned in the current report,” he observed, “there is likely to be a very simple pharmacokinetic explanation for the poorer showing of fluoxetine: it takes >1 month for the average person to get to steady state norfluoxetine levels following the initiation of therapy or up-titration, which is likely to be a real disadvantage in studies of 6 or 8 weeks duration.”

Dr. Thase is not surprised that venlafaxine, escitalopram, and mirtazapine have higher efficacy ratings, as meta-analyses of head-to-head trials have reported this for each drug.

“The findings for sertraline (one of the more effective in this study) and duloxetine (one of the least effective) are somewhat surprising and, as such, warrant closer inspection,” he said. “Duloxetine may suffer in relative terms because many of the early trials used doses that are today known to be too high, which magnified tolerability problems. Moreover, none of the trials have used the dosing strategies that, we have learned in more recent years, enhance early tolerability (ie, 60 mg with food and, when necessary, reduce to 30 mg with food). That said, duloxetine also suffers in the indirect comparisons because three of the eight comparisons were against escitalopram and six of the eight duloxetine studies were placebo controlled (a relatively high proportion in this data set); placebo-controlled studies tend to report lower response rates than studies that only have an active comparator. I do not have my ‘hands around’ similar explanations for why sertraline did better than I would have expected, though it may simply be a predominance of comparisons versus fluoxetine and other ‘weaker’ antidepressants.”

If nothing else, this latest attempt to determine the true meaning of the accumulating body of research on antidepressant clinical effects serves to underscore the heterogeneity of different classes of antidepressants, and even among the drugs within the SSRI class. Differences in both tolerability and efficacy exist. PP

References

1. Turner EH, Matthews AM, Linardatos E, Tell RA, Rosenthal R. Selective publication of antidepressant trials and its influence on apparent efficacy. N Engl J Med. 2008;358(3):252-260.
2. Journal Watch. Escitalopram and sertraline top comparison of 12 newer antidepressants. Available at: http://firstwatch.jwatch.org/cgi/content/full/2009/129/1. Accessed February 17, 2009.
3. Anderson IM. SSRIs versus tricyclic antidepressants in depressed inpatients: a meta-analysis of efficacy and tolerability. Depress Anxiety. 1998;7(suppl 1):11-17.
4. Anderson IM. Meta-analytical studies on new antidepressants. Br Med Bull. 2001;57:161-178.
5. Citalopram: clinical effect profile in comparison with clomipramine. A controlled multicenter study.  Danish University Antidepressant Group. Psychopharmacology (Berl). 1986;90(1):131-138.
6. Thase ME, Entsuah AR, Rudolph RL. Remission rates during treatment with venlafaxine or selective serotonin reuptake inhibitors. Br J Psychiatry. 2001;178:234-241.
7. Freemantle N, Anderson IM, Young P. Predictive value of pharmacological activity for the relative efficacy of antidepressant drugs. Meta-regression analysis. Br J Psychiatry. 2000;177:292-302.
8. Clerc GE, Ruimy P, Verdeau-Pallès J. A double-blind comparison of venlafaxine and fluoxetine in patients hospitalized for major depression and melancholia. The Venlafaxine French Inpatient Study Group. Int Clin Psychopharmacol. 1994;9(3):139-143.
9. Nemeroff CB, Entsuah R, Benattia I, Demitrack M, Sloan DM, Thase ME. Comprehensive analysis of remission (COMPARE) with venlafaxine versus SSRIs. Biol Psychiatry. 2008;63(4):424-434.
10. Papakostas GI, Thase ME, Fava M, Nelson JC, Shelton RC. Are antidepressant drugs that combine serotonergic and noradrenergic mechanisms of action more effective than the selective serotonin reuptake inhibitors in treating major depressive disorder? A meta-analysis of studies of newer agents. Biol Psychiatry. 2007;62(11):1217-1227.
11. Gartlehner G, Gaynes BN, Hansen RA, et al. Comparative benefits and harms of second-generation antidepressants: background paper for the American College of Physicians. Ann Intern Med. 2008;149(10):734-750.
12. Cipriani A, Furukawa TA, Salanti G, et al. Comparative efficacy and acceptability of 12 new-generation antidepressants: a multiple-treatments meta-analysis. Lancet. 2009 Jan 28. [Epub ahead of print].
13. Bielski RJ, Ventura D, Chang CC. A double-blind comparison of escitalopram and venlafaxine extended release in the treatment of major depressive disorder. J Clin Psychiatry. 2004;65(9):1190-1196.
14. Montgomery SA, Huusom AK, Bothmer J. A randomised study comparing escitalopram with venlafaxine XR in primary care patients with major depressive disorder. Neuropsychobiology. 2004;50(1):57-64.

 

Dr. Taylor is assistant professor in the Department of Psychiatry and Behavioral Neuroscience at McMaster University in Hamilton, Ontario, Canada. Dr. Soares is academic head of the Mood Disorders Division and associate professor in the Department of Psychiatry and Behavioural Neurosciences at McMaster University, as well as director of the Women’s Health Concerns Clinic at St. Joseph’s Healthcare Hamilton.

Disclosure: Dr. Taylor is a consultant to sanofi-aventis; is on the speaker’s bureaus of Allergan, AstraZeneca, and sanofi-aventis; has received grant support from the Canadian Institute of Health Research, the Center for Minimally Invasive Surgery, the Community Health, Education, and Research Fund, the National Alliance for Research on Schizophrenia and Depression, the Ontario Mental Health Foundation, and the Society of American Gastrointestinal and Endoscopic Surgeons; and has received funding from Novartis and sanofi-aventis. Dr. Soares is a consultant to Bayer, Concert, Sepracor, and Wyeth; is on the speaker’s bureaus of AstraZeneca, Lundbeck, and Wyeth; and receives research support from Allergen, NCE, AstraZeneca, the Canadian Institute of Health Research, Eli Lilly, the Hamilton Community Foundation, the National Alliance for Research on Schizophrenia and Depression, and Physicians Service Incorporated.

Please direct all correspondence to: Valerie H. Taylor, MD, PhD, FRCPC, Assistant Professor, Department of Psychiatry and Behavioral Neuroscience, McMaster University, 1280 Main St West, Hamilton, Ontario L8S4L8, Canada; Tel: 905-522-1155, ext. 35410; Fax: 905-575-6029; E-mail: taylorv@mcmaster.ca.


 

Focus Points

• Women are more likely to suffer from major depressive disorder (MDD) than men; cardiovascular disease (CVD) is the largest single cause of death among women, accounting for 33% of all deaths.
• The heightened prevalence of MDD and CVD result in a compounded burden of illness among women; nonetheless, few studies have explored the potential role of gender differences for the development and management of CVD among depressed patients.
• The prevalence of CVD in MDD female patients appears to be modulated by hormone changes and different inflammatory response across the reproductive life cycle.
 

Abstract

Worldwide, cardiovascular disease (CVD) is the largest single cause of death among women, accounting for 33% of all deaths. In many countries, more women than men die every year of CVD, highlighting the unique aspects of risk factor management of CVD in women. Major depressive disorder is also an illness that affects women more often than men; thus, cardiovascular conditions among patients with chronic mental illness such as depression represent an additional vulnerability and a compounded burden of illness for women. Clinical and hormonal changes that occur during pregnancy and the postmenopausal period also represent life events that require specific attention and represent a time of heightened vulnerability for both mood disorders and CVD risk. This article addresses the role of gender in risk stratification and in the responsiveness to preventive interventions for CVD in women with depression. Moreover, it reviews existing evidence on sex hormones as modulators of biomarkers and clinical measures of CVD in depressed patients.

Introduction

Coronary heart disease (CHD), stroke, and peripheral vascular disease all contribute to overall mortality rates attributed to cardiovascular disease (CVD); despite significant efforts in disease prevention, CVD remains a major health concern in the developed world. It kills one in every five individuals1 and remains the leading cause of death in the United States and most developed western countries. CVD is also the largest single cause of death among women.2 In many countries, including the US, more women than men die every year of CVD.2,3 While most of the attention remains focused on more “traditional” female diseases such as breast cancer, many more women die from CVD than from breast cancer (1 in 2.6 versus 1 in 30, respectively).

Major depressive disorder (MDD) is more commonly diagnosed in women.4 The occurrence of cardiovascular events in patients with chronic mental illness such as depression may, therefore, represent a compounded burden for women both in terms of disease prevalence and access to treatment. Gender seems not only to predispose women with depression to the development of CVD, but also to influence the occurrence of MDD in women with heart disease. For example, recent data suggest that young women may be at particularly high risk for depression after an acute myocardial infarction.5

Overall, patients with MDD die earlier than those without mood disorders from a variety of physical illnesses, and mortality data among patients with mood disorders from as early as 1916 has documented this increase.6,7 A 4-decade study found excess mortality for manic and depressed patients of both genders, with the increase in mortality being most prominent in the first 10 years post admission due to a mood episode. A population-based study of the specific mortality ratios (SMRs) for patients with MDD or bipolar disorder from 1973–1995 found that SMRs for all natural causes of death were 1.9 for males and 2.1 for females with bipolar disorder, and 1.5 and 1.6 for MDD, respectively.8 A meta-analysis that examined excess mortality in MDD found an increased relative risk for depressed subjects to die compared to non-depressed subjects (1.81, 95% CI: 1.58–2.07).9 A large component of this increased mortality risk is attributed to CVD.8 Among women with MDD, CVD is responsible for more deaths than suicide.8 Existing data suggest that the pathophysiology of the mood disorders and its contribution to the relative risk of cardiovascular events and heart failure may be affected by gender, which might be of potential relevance for the prevention, diagnosis, and therapy of these conditions.

Metabolic Syndrome in Women with MDD

A partial explanation for increased CVD in women in general and in particular among women with mood disorders is the heightened vulnerability in this population for the development of metabolic syndrome (MeS). MeS is defined by a cluster of risk factors that ultimately contribute to CHD.10 By definition, MeS requires the presence of any three of the following five criteria: central obesity (waist circumference >102 cm [>40 in] in men, >88 cm [>35 in] in women); elevated triglycerides (>150 mg/dL [>1.7 mmol/L] or specific treatment for this lipid abnormality); raised blood pressure (BP; systolic BP >130 or diastolic BP >85 mm Hg, or treatment of previously diagnosed hypertension); raised fasting glucose (>100 mg/dL [>5.6 mmol/L] or treatment for type 2 diabetes); and reduced high density lipoprotein (HDL) cholesterol (<40 mg/dL [<1.03 mmol/L] in males, <50 mg/dL [<1.3 mmol/L] in females or specific treatment for this lipid abnormality).11 People with MeS are twice as likely to die from, and three times as likely to suffer, a heart attack or stroke. They have up to a nine-fold greater risk of developing type 2 diabetes, compared with people without the syndrome.12-14 Given that up to 80% of the 200 million people with diabetes globally will possibly die of CHD, MeS and diabetes now rank ahead of HIV/AIDS in worldwide morbidity and mortality.15

Approximately 40% of the adult population in the US meets diagnostic criteria for MeS.16 A closer look at the National Health and Nutrition Examination (NHANES) III data that was obtained between 1984–1998, compared to the NHANES 1999–2000 results, reveals a greater increase in MeS prevalence in women. Young women (20–39 years of age) seem especially vulnerable, with a 78% increase in prevalence, compared to a non-significant 5% increase in men in this age group.17 Data on 728 women from the Women’s Ischemic Syndrome Evaluation study18 showed that MeS was strongly associated with angiographic coronary artery disease and conferred an approximate two-fold adjusted risk of death and major adverse cardiac events.

In the Atherosclerosis Risk in Communities study,19 a total of 12,809 individuals who did not have diabetes or CVD at baseline were followed for an average of 11 years. Men and women with MeS were 1.5–2.0 times more likely to develop CHD than individuals who did not have MeS after adjustment for age, smoking status, low-density lipoprotein cholesterol, and race. In addition, the risk of CHD associated with the MeS was significantly higher in women (crude hazard ratios [HRs]=2.55) than in men (HRs=1.51).

In the San Antonio Heart Study,20 the cardiovascular mortality risk in subjects who had MeS was also shown to be significantly higher in women than in men, although the gender differences seen in cardiovascular mortality were only significant in individuals who had both MeS and type 2 diabetes. This association between type 2 diabetes and fatal CHD was also examined in a recent meta-analysis21 that showed a relative higher risk in women compared to men. The subgroup analysis of two recently published meta-analyses22,23 also indicate that the MeS might be a stronger risk factor for CVD in women than in men (relative risk=2.10 vs. 1.57,22 and 2.63 vs. 1.98,23 respectively).

Many of the physical illnesses linked to MeS occur at high rates in patients with mood disorders and may represent the expression of overlapping pathophysiologies linking these illnesses. The association between MeS and mood disorders, however, remains controversial due to conflicting data.24,25 These discrepancies might be due to differences in methodology (longitudinal vs. cross-sectional), or type of population studied (age, presence or absence of associated cardiovascular risk factors, history of MDD). A potential confounder appears to be the role of gender differences. While the majority of studies addressing the association between mood disorders and MeS indicated a relationship between the two conditions, those that were unable to find a correlation between the two conditions did find a relationship between women with mood disorders and MeS when populations were divided by gender.24,25

This highlights the need to explore the potential role of gender differences for the development and management of CVD among depressed patients and to target female sub-populations during periods of heightened vulnerability for both CVD and MDD (eg, the menopausal transition).26,27

The Contribution of Obesity to CVD in Women with MDD

A key variable linking mood disorders with CVD is obesity. Obesity is associated with increased risk of all-cause mortality and, in the general population, obesity and its associated metabolic and cardiovascular complications represent a significant contribution to premature death.28,29 This relationship is especially relevant to the field of mental health. People with mood disorders are at higher risk for obesity in part due to a complex interplay of factors that include unhealthy lifestyle choices, reduced energy expenditure and increase in consumption of palatable energy-dense foods, unwanted effects of pharmacotherapy, and, ultimately, poorly understood biologic factors.

The amount of weight gain in patients with a mood disorder may not be the only factor linked to an increase in morbidity from obesity-related diseases; another factor may be the increased amount of centrally deposited adipose tissue. Abdominal fat distribution consists of two discrete depots, subcutaneous adipose tissue (SAT) and visceral (intra-abdominal) adipose tissue (VAT). These patterns of body fat distribution predict CVD better than total body fat volume.30,31 A measure of VAT, the waist to hip ratio, is positively associated with increased blood pressure, increased triglycerides, and decreased HDL cholesterol.32 This association is of particular relevance for women with mood disorders as a recent study that investigated this relationship in premenopausal women showed that the depression was associated with VAT, not SAT.33 It has been speculated that these findings may, in part, explain the association between depression and CVD in this population as the reduced tendency to accumulate fat within the intra-abdominal sites may be one of the primary metabolic differences underlying the reduced risk of cardiovascular disease, metabolic syndrome, and diabetes in women.34 Normally, premenopausal women more frequently develop peripheral obesity with SAT, whereas men and postmenopausal women are more prone to VAT. After menopause, concentrations of lipoproteins as well as body fat distribution shifts to a more male pattern. Postmenopausal women have an increased tendency of visceral fat deposition, which by virtue of its proinflammatory and prothrombotic properties, contribute to their risk of developing MeS and CVD.35

The Role of Inflammation

Women are more susceptible than men to obesity in general; presently, 2 million more women than men have a body mass index >30.36 Obesity predisposes individuals to an increased risk of developing many diseases, including atherosclerosis, diabetes, non-alcoholic fatty liver disease, certain cancers, and immune-mediated disorders such as asthma.37-39 Part of this increased vulnerability is related to the ability of adipose tissue to function as an endocrine organ and secrete a wide range of hormones. Among the soluble mediators derived from adipocytes (fat cells) are leptin, adiponectin, and resistin, all of which are considered to play a role in the regulation of energy metabolism.40-42 Obesity is also associated with a chronic inflammatory response characterized by abnormal cytokine and adipokine production, increased synthesis of acute-phase reactants, and the activation of pro-inflammatory signaling pathways. Inflammation plays an essential role in the development of insulin resistance and type 2 diabetes, the initiation and progression of atherosclerotic lesions, and plaque disruption.43

Mood disorders are also associated with the production of pro-inflammatory cytokines that influence CVD, and some studies suggest that depression promotes an inflammatory process. The most compelling evidence of this derives from studies that have ameliorated depressive symptoms through psychotherapy and found corresponding declines in the magnitude of inflammation markers.44 Conversely, inflammatory processes contribute to depression and exposure to inflammatory mediators produces a constellation of behaviors (eg, hyposomnia, anhedonia, anorexia) that resemble depressive symptoms.45,46 Existing literature links mood disorders and inflammatory markers; several cytokines that are elevated in individuals with MDD and bipolar disorder, including IL-6 and C-reactive protein (CRP), predict cardiac morbidity and mortality,47,48 while an association between adiposity and elevated Il-6 and CRP levels has been suggested in clinically depressed individuals.49 Woman seem especially vulnerable to the risks posed by inflammation. In an analysis of women participating in the Nurses’ Health Study, high levels of Il-6, tumor necrosis factor-a, and CRP were significantly related to an increased risk of CHD.50 These findings supported the results from the Women’s Health Initiative study, demonstrating white cell count and CRP as the strongest predictors for cardiovascular morbidity and mortality in postmenopausal women.51 The combination of increased central obesity and chronic low-grade inflammation appears to be a mechanism for the pathogenesis of CVD.52

Variables other than weight also play a role in inflammation in women. Sex steroids may influence inflammatory processes and hence modify cardiovascular risk. Raised levels of CRP, homocysteine, lipoprotein(a) (Lp-a), and IL-6 are each independently associated with increased risk for cardiovascular events in women. While changes in these parameters across the menopausal transition cannot clearly be attributed solely to hormonal changes, endogenous sex steroid levels and exogenous hormone therapy seem to exert a modulatory effect. Elevations of the amino acid homocysteine, which is associated with arterial and venous thromboembolic disease, and Lp-a, a known independent risk factor for the development of atherosclerosis, occur with age and/or menopause,53,54 while CRP and IL-6 appear to be influenced by endogenous sex steroid levels and exogenous hormone therapy.55,56

Prevention

It was noted with the recently updated guidelines on prevention of CHD in women that healthcare professionals should focus on women’s lifetime heart disease risk and not just on short-term risk.2 The guidelines emphasized that prevalence of CHD in women is such that nearly all women should be considered at risk for atherosclerosis. Prevention of CVD is paramount to the health of women and even modest control can have significant impact. Fortunately, most CVD in women is preventable, if recognized. Even the presence of a single risk factor at 50 years of age is associated with a substantially increased lifetime absolute risk for CVD and shorter duration of survival.57 With few exceptions, such as the use of aspirin for primary prevention of heart disease in women >65 years of age,58 recommendations to prevent CVD in women do not differ from men.2 However, there are certain circumstances in which prevention strategies or interventions should be individualized.

Hormone replacement therapy (HRT) is not recommended for either primary or secondary prevention of CVD, particularly in women in their late postmenopausal years.59 Estrogen deficiency leads to an unfavorable lipid profile,60 which until recently had been considered the main pathologic phenomenon responsible for development of atherosclerosis and CHD. However, improvement in lipid profile with HRT does not reduce cardiac disease events in clinical studies.61,62 It remains controversial whether different estrogen therapies would offer a better risks/benefit ratio when administered via different pathways or to younger versus older sub-populations of menopausal women.62

The efficacy of non-pharmacologically based treatments in women also needs further evaluation. Data suggest that women with CVD respond differently than men to psychological treatments. Subgroup analyses of the Enhancing Recovery in Coronary Heart Disease Patients trial showed a significant treatment by sex interaction on cardiovascular outcomes, suggesting a protective effect of cognitive-behavioral therapy in men, but a tendency for harm in women.63 These results mirrored those of an earlier study, the Montreal Heart Attack Readjustment Trial (M-HART), which tested the effect of a nurse-based psychosocial support intervention at home for distressed patients after myocardial infarction.64 The M-HART program had no overall impact on cardiac or all-cause mortality over the year. However, separate preplanned comparisons in men and women revealed two times the odds of cardiac and all-cause mortality in treated women compared with control women, while there was no impact in men. Altogether, these data suggest that women and men respond differently to psychological interventions and highlight the importance of performing gender-specific analyses. At the very least, gender-based stratification should be better planned in future studies to allow sufficient power to examine gender-related differences. A more targeted emphasis could also be placed on prevention programs based on gender. In a US study65 designed to examine the extent to which modifiable lifestyle behaviors are associated with the risk of having MeS, MeS was associated with physical inactivity in overweight men and in normal weight and overweight women, suggesting a high protective value of physical exercise in women.

Gender biases in the diagnosis and management of women with CVD also plays a role in the outcome of this illness,66 and this is compounded by the stigma associated with mental illness. During the past several decades, CVD mortality has markedly declined in the US, from >50% to approximately 36% as the underlying cause of death.1 Recent data suggest that the decline is largely due to improved diagnosis and treatment rather than to major successes in primary prevention. In contrast, patients with severe mental illnesses,67 lose ≥25 years of life expectancy, with the majority of the excess premature deaths due to CVD.68 There is now a sufficient consensus that depression is a risk factor for CHD as well as an important prognostic factor in cardiac patients. Nonetheless, <50% of depressed medical patients are recognized by their physicians, and recognition has only mildly increased in the last 10 years.69 During an admission for acute myocardial infarction, <15% of patients with depression are identified,70 and evaluation and treatment of depression continue to be mostly ignored during routine cardiac care.71

Conclusion

Knowledge of the unique aspects associated with the management and occurrence of CVD in women has improved significantly in the last few years, and there is now acknowledgement that gender is a confounder that needs to be addressed appropriately (Figure).

 

 

 

 

The additional risk conferred by MDD both to CVD risk and its impact on long-term outcome also needs to play a role in risk stratification and management. This way, we may hope to decrease the mortality attributed to this illness in women. PP

References

1.    Rosamond W, Flegal K, Friday G, et al. Heart disease and stroke statistics–2007 update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation. 2007;115(5):e69-e171. Erratum in: Circulation. 2007;115(5):e172.
2.    Mosca L, Banka CL, Benjamin EJ, et al. Evidence-based guidelines for cardiovascular disease prevention in women: 2007 update. Circulation. 2007;115(11):1481-1501. Erratum in: Circulation. 2007;115(15):e407.
3.    Thom T, Haase N, Rosamond W, et al. Heart disease and stroke statistics–2006 update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation. 2006;113(6):e85-e151. Erratum in: Circulation. 2006;113(14):e696. Circulation. 2006;114(23):e630.
4.    Kessler RC. Epidemiology of women and depression. J Affect Disord. 2003;74(1):5-13.
5.    Mallik S, Spertus JA, Reid KJ, et al. Depressive symptoms after acute myocardial infarction: evidence for highest rates in younger women. Arch Intern Med. 2006;166(8):876-883.
6.    Malzberg B. Mortality Among Patients with Mental Diseases. New York, NY: N.Y.S.H. Press; 1934.
7.    Odegård O. Mortality in Norwegian Mental Hospitals from 1916 to 1933. Acta Psychiatr Neurol. 1978;11(1):323-356.
8.    Osby U, Brandt L, Correia N, Ekbom A, Sparén P. Excess mortality in bipolar and unipolar disorder in Sweden. Arch Gen Psychiatry. 2001;58(9):844-850.
9.    Cuijpers P, Smit F. Excess mortality in depression: a meta-analysis of community studies. J Affect Disord. 2002;72(3):227-236.
10.    Eckel RH, Grundy SM, Zimmet PZ. The metabolic syndrome. Lancet. 2005;365(9468):1415-1428.
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12.    Laaksonen DE, Lakka HM, Niskanen LK, Kaplan GA, Salonen JT, Lakka TA. Metabolic syndrome and development of diabetes mellitus: application and validation of recently suggested definitions of the metabolic syndrome in a prospective cohort study. Am J Epidemiol. 2002;156(11):1070-1077.
13.    Lakka HM, Laaksonen DE, Lakka TA, et al. The metabolic syndrome and total and cardiovascular disease mortality in middle-aged men. JAMA. 2002;288(21):2709-2716.
14.    Isomaa B, Almgren P, Tuomi T, et al. Cardiovascular morbidity and mortality associated with the metabolic syndrome. Diabetes Care. 2001;24(4):683-689.
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16.    Ford ES, Giles WH, Dietz WH. Prevalence of the metabolic syndrome among US adults: findings from the third National Health and Nutrition Examination Survey. JAMA. 2002;287(3):356-359.
17.    Ford ES, Giles WH, Mokdad AH. Increasing prevalence of the metabolic syndrome among U.S. adults. Diabetes Care. 2004;27(10):2444-2449.
18.    Kip KE, Marroquin OC, Kelley DE, et al. Clinical importance of obesity versus the metabolic syndrome in cardiovascular risk in women: a report from the Women’s Ischemia Syndrome Evaluation (WISE) study. Circulation. 2004;109(6):706-713.
19.    McNeill AM, Rosamond WD, Girman CJ, et al. The metabolic syndrome and 11-year risk of incident cardiovascular disease in the atherosclerosis risk in communities study. Diabetes Care. 2005;28(2):385-390.
20.    Hunt KJ, Resendez RG, Williams K, et al. National Cholesterol Education Program versus World Health Organization metabolic syndrome in relation to all-cause and cardiovascular mortality in the San Antonio Heart Study. Circulation. 2004;110(10):1251-1257.
21.    Huxley R, Barzi F, Woodward M. Excess risk of fatal coronary heart disease associated with diabetes in men and women: meta-analysis of 37 prospective cohort studies. BMJ. 2006;332(7533):73-78.
22.    Galassi A, Reynolds K, He J. Metabolic syndrome and risk of cardiovascular disease: a meta-analysis. Am J Med. 2006;119(10):812-819.
23.    Gami AS, Witt BJ, Howard DE, et al. Metabolic syndrome and risk of incident cardiovascular events and death: a systematic review and meta-analysis of longitudinal studies. J Am Coll Cardiol. 2007;49(4):403-414.
24.    Kinder LS, Carnethon MR, Palaniappan LP, King AC, Fortmann SP. Depression and the metabolic syndrome in young adults: findings from the Third National Health and Nutrition Examination Survey. Psychosom Med. 2004;66(3):316-322.
25.    Toker S, Shirom A, Melamed S. Depression and the metabolic syndrome: gender-dependent associations. Depress Anxiety. 2008;25(8):661-669.
26.    Gordon T, Kannel WB, Hjortland MC, McNamara PM. Menopause and coronary heart disease. The Framingham Study. Ann Intern Med. 1978;89(2):157-161.
27.    Soares CN, Menopausal transition and depression: who is at risk and how to treat it? Expert Rev Neurother. 2007;7(10):1285-1293.
28.    Ogden CL, Yanovski SZ, Carroll MD, Flegal KM. The epidemiology of obesity. Gastroenterology. 2007;132(6):2087-2102.
29.    Katzmarzyk PT, Ardern CI. Overweight and obesity mortality trends in Canada, 1985-2000. Can J Public Health. 2004;95(1):16-20.
30.    Larsson B, Svärdsudd K, Welin L, Wilhelmsen L, Björntorp P, Tibblin G. Abdominal adipose tissue distribution, obesity, and risk of cardiovascular disease and death: 13 year follow up of participants in the study of men born in 1913. Br Med J (Clin Res Ed). 1984;288(6428):1401-1404.
31.    Lapidus L, Bengtsson C, Larsson B, Pennert K, Rybo E, Sjöström L. Distribution of adipose tissue and risk of cardiovascular disease and death: a 12 year follow up of participants in the population study of women in Gothenburg, Sweden. Br Med J (Clin Res Ed). 1984;289(6454):1257-1261.
32.    Baumgartner RN, Roche AF, Chumlea WC, Siervogel RM, Glueck CJ. Fatness and fat patterns: associations with plasma lipids and blood pressures in adults, 18 to 57 years of age. Am J Epidemiol. 1987;126(4):614-628.
33.    Lee ES, Kim YH, Beck SH, Lee S, Oh SW. Depressive mood and abdominal fat distribution in overweight premenopausal women. Obes Res. 2005;13(2):320-325.
34.    Williams CM. Lipid metabolism in women. Proc Nutr Soc. 2004;63(1):153-160.
35.    Berg AH, Scherer PE. Adipose tissue, inflammation, and cardiovascular disease. Circ Res. 2005;96(9):939-949.
36.    Steinbaum SR. The metabolic syndrome: an emerging health epidemic in women. Prog Cardiovasc Dis. 2004;46(4):321-336.
37.    Wellen KE, Hotamisligil GS. Inflammation, stress, and diabetes. J Clin Invest. 2005;115(5):1111-1119.
38.    Calle EE, Kaaks R. Overweight, obesity and cancer: epidemiological evidence and proposed mechanisms. Nat Rev Cancer. 2004;4(8):579-591.
39.    Mannino DM, Mott J, Ferdinands JM, et al. Boys with high body masses have an increased risk of developing asthma: findings from the National Longitudinal Survey of Youth (NLSY). Int J Obes (Lond). 2006;30(1):6-13.
40.    La Cava A, Matarese G. The weight of leptin in immunity. Nat Rev Immunol. 2004;4(5):371-379.
41.    Weisberg SP, Hunter D, Huber R, et al. CCR2 modulates inflammatory and metabolic effects of high-fat feeding. J Clin Invest. 2006;116(1):115-124. Erratum in: J Clin Invest. 2006;116(5):1457.
42.    Weisberg SP, McCann D, Desai M, Rosenbaum M, Leibel RL, Ferrante AW Jr. Obesity is associated with macrophage accumulation in adipose tissue. J Clin Invest. 2003;112(12):1796-1808.
43.    Libby P, Aikawa M. Stabilization of atherosclerotic plaques: new mechanisms and clinical targets. Nat Med. 2002;8(11):1257-1262.
44.    Mohr WK, Mohr BD. Brain, behavior, connections and implications: psychodynamics no more. Arch Psychiatr Nurs. 2001;15(4):171-181.
45.    Dantzer R. Cytokine-induced sickness behavior: where do we stand? Brain Behav Immun. 2001;15(1):7-24.
46.    Maier SF, Watkins LR. Cytokines for psychologists: implications of bidirectional immune-to-brain communication for understanding behavior, mood, and cognition. Psychol Rev. 1998;105(1):83-107.
47.    Ridker PM, Hennekens CH, Buring JE, Rifai N. C-reactive protein and other markers of inflammation in the prediction of cardiovascular disease in women. N Engl J Med. 2000;342(12):836-843.
48.    Ridker PM, Rifai N, Stampfer MJ, Hennekens CH. Plasma concentration of interleukin-6 and the risk of future myocardial infarction among apparently healthy men. Circulation. 2000;101(15):1767-1772.
49.    Miller GE, Freedland KE, Carney RM, Stetler CA, Banks WA. Pathways linking depression, adiposity, and inflammatory markers in healthy young adults. Brain Behav Immun. 2003;17(4):276-285.
50.    Pai JK, Pischon T, Ma J, et al. Inflammatory markers and the risk of coronary heart disease in men and women. N Engl J Med. 2004;351(25):2599-2610.
51.    Margolis KL, Manson JE, Greenland P, et al. Leukocyte count as a predictor of cardiovascular events and mortality in postmenopausal women: the Women’s Health Initiative Observational Study. Arch Intern Med. 2005;165(5):500-508.
52.    Hansson GK. Inflammation, atherosclerosis, and coronary artery disease. N Engl J Med. 2005;352(16):1685-1695.
53.    Dahlen GH. Lp(a) lipoprotein in cardiovascular disease. Atherosclerosis. 1994;108(2):111-126.
54.    Graham IM, Daly LE, Refsum HM, et al. Plasma homocysteine as a risk foctor for vascular disease. The European Concerted Action Project. JAMA. 1997;277(22):1775-1781.
55.    Hulley S, Grady D, Bush T, et al. Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. Heart and Estrogen/progestin Replacement Study (HERS) Research Group. JAMA. 1998;280(7):605-613.
56.    Cantatore FP, Loverro G, Ingrosso AM, et al. Effect of oestrogen replacement on bone metabolism and cytokines in surgical menopause. Clin Rheumatol. 1995;14(2):157-160.
57.    Lloyd-Jones DM, Leip EP, Larson MG, et al. Prediction of lifetime risk for cardiovascular disease by risk factor burden at 50 years of age. Circulation. 2006;113(6):791-798.
58.    Berger JS, Roncaglioni MC, Avanzini F, Pangrazzi I, Tognoni G, Brown DL. Aspirin for the primary prevention of cardiovascular events in women and men: a sex-specific meta-analysis of randomized controlled trials. JAMA. 2006;295(3):306-313. Erratum in: JAMA. 2006;295(17):2002.
59.    Magliano DJ, Rogers SL, Abramson MJ, Tonkin AM. Hormone therapy and cardiovascular disease: a systematic review and meta-analysis. BJOG. 2006;113(1):5-14.
60.    Stevenson JC, Crook D, Godsland IF. Influence of age and menopause on serum lipids and lipoproteins in healthy women. Atherosclerosis. 1993;98(1):83-90.
61.    Grady D, Herrington D, Bittner V, et al. Cardiovascular disease outcomes during 6.8 years of hormone therapy: Heart and Estrogen/progestin Replacement Study follow-up (HERS II). JAMA. 2002;288(1):49-57. Erratum in: JAMA. 2002;288(9):1064.
62.    Manson JE, Allison MA, Rossouw JE, et al. Estrogen therapy and coronary-artery calcification. N Engl J Med. 2007;356(25):2591-2602.
63.    Berkman LF, Blumenthal J, Burg M, et al. Effects of treating depression and low perceived social support on clinical events after myocardial infarction: the Enhancing Recovery in Coronary Heart Disease Patients (ENRICHD) randomized trial. JAMA. 2003;289(23):3106-3116.
64.    Frasure-Smith N, Lespérance F, Prince RH, et al. Randomised trial of home-based psychosocial nursing intervention for patients recovering from myocardial infarction. Lancet. 1997;350(9076):473-479.
65.    Zhu S, St-Onge MP, Heshka S, Heymsfield SB. Lifestyle behaviors associated with lower risk of having the metabolic syndrome. Metabolism. 2004;53(11):1503-1511.
66.    Fleury J, Keller C, Murdaugh C. Social and contextual etiology of coronary heart disease in women. J Womens Health Gend Based Med. 2000;9(9):967-978.
67.    Schinnar AP, Rothbard AB, Kanter R, Jung YS. An empirical literature review of definitions of severe and persistent mental illness. Am J Psychiatry. 1990;147(12):1602-1608.
68.    Colton CW, Manderscheid RW. Congruencies in increased mortality rates, years of potential life lost, and causes of death among public mental health clients in eight states. Prev Chronic Dis. 2006;3(2):A42.
69.    Cepoiu M, McCusker J, Cole MG, Sewitch M, Belzile E, Ciampi A. Recognition of depression by non-psychiatric physicians–a systematic literature review and meta-analysis. J Gen Intern Med. 2008;23(1):25-36.
70.    Huffman JC, Smith FA, Blais MA, Beiser ME, Januzzi JL, Fricchione GL. Recognition and treatment of depression and anxiety in patients with acute myocardial infarction. Am J Cardiol. 2006;98(3):319-324.
71.    Rumsfeld JS, Ho PM. Depression and cardiovascular disease: a call for recognition. Circulation. 2005;111(3):250-253.

 

Dr. Wilkins is assistant professor and Dr. Warnock is professor of psychiatry in the Department of Psychiatry at the University of Oklahoma in Tulsa.

Disclosure: Dr. Wilkins reports no affiliation with or financial interest in any organization that may pose a conflict of interest. Dr. Warnock has received research support from Boehringer Ingelheim, Forest, and Wyeth.

Acknowledgments: The authors would like to acknowledge the assistance of Ms. Faye Biggs in the preparation of this manuscript.

Please direct all correspondence to: Kirsten M. Wilkins, MD, Assistant Professor, Department of Psychiatry, University of Oklahoma–Tulsa; 4502 E 41st St, Tulsa, OK 74136; Tel: 918-660-3514; Fax: 918-660-3517; E-mail: Kirsten-Wilkins@ouhsc.edu.


 

Focus Points

• Sexual dysfunction in older women is a common yet neglected area of medicine.
• Older women with sexual dysfunction require careful assessment of biologic and psychosocial contributing factors.
• Treatment options for female sexual dysfunction in later life are available but under-utilized.
 

Abstract

The geriatric patient population is anticipated to grow significantly in the coming decades. As individuals are living longer, healthier lives, there is interest in maintaining sexual health throughout the latter decades. The aging female faces many biologic and psychosocial factors which impact sexual functioning and satisfaction. Given this, it is not surprising that ~33% of older women will experience sexual dysfunction. As sexual dysfunction has been strongly associated with quality of life, physicians should be familiar with the assessment and treatment of sexual disorders in older women. This article reviews the effects of aging on the normal female sexual response cycle, as well as the various biologic and psychosocial factors affecting female sexuality in late life. The article then provides an overview of common female sexual disorders of desire, arousal, orgasm, and sexual pain. Finally, the authors discuss assessment and treatment of sexual dysfunction in the older woman.

Introduction

As individuals are living longer, healthier lives, there is a growing interest in maintaining one’s sexual health throughout the latter decades. Previous studies have reported that 70% of healthy 70-year-olds enjoy sex on a regular basis and that 80% of men and women 60–91 years of age are sexually active at least once per month.1,2 A recent study3 concluded that the majority of older adults are engaged in sexual activity and regard sex as an important part of life. However, many biologic and psychosocial factors related to aging impact the quality and quantity of sexual activity an older person experiences. The physical and mental health of the individual as well as their partner, the availability of a willing partner, and the previous level of sexual activity all play an important role in sexuality in aging.

Given the many factors related to aging which can impact sexual functioning, it comes as no surprise that the prevalence of sexual dysfunction increases with age.4 While the advertising market and popular media have paid much attention to sexual disorders among older men, these disorders are also common among older women. A recent national sample3 of sexual behaviors and problems in older community-dwelling individuals reported that women 57–64 years of age had the following sexual complaints: lack of interest in sex (44.2%), difficulty with lubrication (35.9%), inability to climax (34%), pain during intercourse (17.8%), and lack of pleasure during sex (24%). Despite the prevalence of sexual complaints, the same study found that women are less likely than men to discuss these matters with their physician. Physicians themselves may fail to assess a patient’s sexual functioning due to personal discomfort, time constraints, placing sexuality low on the priority list, or out of fear of embarrassing the patient or being perceived as too intrusive.5

Given the anticipated increase in the geriatric population and the prevalence of sexual dysfunction with aging, physicians in both primary care and psychiatry should be familiar with common sexual disorders among older women. The purpose of this article is to review the diagnosis, evaluation, and treatment of sexual disorders among older women. The authors begin with a review of the normal sexual response and aging, followed by a discussion of biologic and psychosocial factors associated with changes in sexual functioning in aging. Finally, the article reviews common sexual disorders and their treatments.

Normal Sexual Response and Aging

Before one can accurately diagnose and effectively treat sexual disorders in the older woman, one must understand the effects of aging on the normal sexual response cycle. The normal adult sexual response cycle, as originally described by Masters and Johnson,6 is comprised of four stages: arousal, plateau, orgasm, and resolution. A fifth stage, desire, has been added to include the psychological and physiologic part of sexual functioning which underlies response.7 Any of these stages may be impacted by age-related changes in sexual functioning.

Due to the significant changes in sex steroids that occur during reproductive life events, women are particularly vulnerable to sexual dysfunction during these times.8 Menopause, cessation of menses for >12 months, constitutes the major reproductive life event of the older woman. Perimenopause is defined as the transitional period from the reproductive years to reproductive quiescence.9 Perimenopause and menopause are associated with a decline in ovarian function, resulting in reduction and eventual cessation of estrogen production. Estrogen decline impacts sexual functioning in several ways. The urogenital tissue atrophies and vaginal size is reduced. Vaginal lubrication decreases, which can result in uncomfortable intercourse. The sensitivity of the nipples, clitoris, and vulvar tissue is reduced, and the strength and amount of vaginal contractions during orgasm decrease. In addition, the majority of women undergoing menopause experience other symptoms such as mood lability, fatigue, body aches, and hot flashes.7

In addition to changes in estrogen, the menopausal woman also undergoes a decrease in testosterone production. Androgen deficiency in women is associated with a global loss of sexual desire or libido, decreased production of body oils, thinning of pubic hair, reduced vital energy, and decreased sensitivity of the nipples and clitoris.10

Biological Factors and Sexuality in Aging

In addition to the hormonal changes that occur via menopause, the older woman faces other biologic factors which impact sexual functioning. Many medical and psychiatric illnesses are more prevalent in older adults and are known to impact the quality of sexual activity. These illnesses are often the primary cause of sexual dysfunction in this population.7 Illnesses such as urogenital cancers, cardiovascular disease, arthritis, and chronic obstructive pulmonary disease, as well as many neurologic diseases (stroke, Parkinson’s disease, multiple sclerosis, and others), are associated with sexual dysfunction.

The medical condition itself may directly affect sexual functioning. Diabetes, in particular type II, has been associated with sexual complaints among women, including lack of libido, reduced orgasmic capacity, decreased vaginal lubrication, and reduced sexual satisfaction.11,12 Similarly, studies on the sexual functioning of stroke patients have shown that sexual dysfunction and dissatisfaction are common among women.13 Some illnesses such as arthritis may cause pain or limit flexion and range of motion, leading to uncomfortable intercourse.14 Psychiatric conditions including depression, dementia, and substance abuse can also lead to reduced sexual interest and impaired functioning. Medical illnesses may have an indirect effect on sexual functioning as well. Fear of pain or of exacerbating a medical condition such as angina may lead to an inability to relax and enjoy sexual activity.15 Some illnesses, such as breast cancer or gynecologic malignancies, may result in altered self-image and reduced feelings of sexual attractiveness.14

Various symptoms of sexual dysfunction may arise iatrogenically, as a result of prescription medications. A recent review on medications and sexual function reported that >100 drugs or drug classes have been associated with sexual dysfunction, and that the impact of medications on sexuality increases with age.16 Sexual side effects in women secondary to medications may include loss of libido, reduced capacity for arousal, and difficulty achieving orgasm. Psychiatric medications, including selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants, mood stabilizers, and antipsychotics are known to carry a risk of sexual side effects. Antihypertensive medications, such as beta-blockers, diuretics, and clonidine, among others, have also been associated with sexual side effects. Other medications associated with sexual dysfunction include digoxin, corticosteroids, antihistamines, histamine subtype 2 receptor blockers, opioids, and cancer chemotherapeutic agents.7,16

Psychosocial Factors and Sexuality in Aging

Psychosocial factors also significantly impact sexual activity among older women. The life expectancy of women is greater than that of men; hence, many older women have lost their spouse or partner. As women outnumber men in the latter decades of life, the availability of a willing and functional sexual partner becomes a legitimate issue for heterosexual women. Lesbian women in this age group remain understudied. For those older adults who are able to enter into new sexual relationships, concern about sexually transmitted diseases has been reported as a reason for lack of sexual activity.3

One’s social environment can also play a role in the expression of sexuality. Some older women will find themselves living with their adult children and their families or in assisted living or long-term care facilities, where opportunity and/or privacy for sexual activity is lacking. On the other hand, many older women will continue to live independently. Some couples may even enjoy increased time for intimacy due to retirement or “the empty nest.” Among postmenopausal women, the elimination of concern about the possibility of pregnancy may result in decreased anxiety and increased ability to enjoy sex.7

Psychological and cultural factors are also important. Our culture is notoriously geared toward the notion that sex is for the young and, therefore, older adults are often not seen as sexually desirable or capable.17 This view is not always bestowed equally upon the genders. Movies and television frequently pair younger, attractive women with older men. Such ageist stereotypes about sexuality are unfortunately accepted by many older individuals, who may see sexual activity as inappropriate or dangerous.7

Sexual Disorders in Older Women

Hypoactive Sexual Desire Disorder

Sexual desire comprises a critical portion of the human sexual response cycle, and includes sexual fantasies and thoughts as well as motivation and receptivity to sexual activity. This phase has been postulated to include biologic, motivational-affective, and cognitive components.18 Basson19 suggested that a woman’s sexual response arises not from a biologic neediness or urge, but rather from intimacy. Motivation to participate in sexual activity is theorized to derive not only from sexual pleasure, but also from closeness and tenderness. Therefore, a woman may choose to experience sexual activity in order to have intimate relationship needs met.

Female hypoactive sexual desire disorder (HSDD) may occur in up to 33% of adult women in the United States. The complaint of low sexual desire alone does not meet criteria for the diagnosis of HSDD. However, such a complaint is not uncommon among older women. The prevalence of lack of interest in sex for women in the US 50–59 years of age has been reported as 27%, slightly lower than rates in younger women.20 A more recent study,3 however, reported prevalence rates of 38% to 49% for women 57–85 years of age. It is important to note that not all women are distressed by a decrease in sexual desire. In 2007, Hayes and colleagues21 reported that while the proportion of women with low sexual desire increases with age, the proportion of women distressed about their low desire actually decreases with age.

The diagnosis of HSDD is made when the patient has persistently or recurrently deficient (or absent) sexual fantasies and desire for sexual activity, which cause marked distress or interpersonal difficulty and are not better accounted for by another Axis I disorder, general medical condition, or substance.22 Frequently, in women, HSDD and the physiologic effects of a general medical condition are both present. Thus, HSDD due to combined factors is diagnosed. HSDD may be lifelong (eg, patients with history of sexual trauma or abuse) or acquired (as in the case of a general medical condition). It may be generalized or situational and is frequently associated with dysfunction in sexual arousal and orgasm.23 An extreme version of HSDD, sexual aversion disorder, consists of persistent or recurrent extreme aversion to, and avoidance of, all genital sexual contact, which causes marked distress or interpersonal difficulty.22

Female sexual desire in later life may be impacted by numerous factors. As reviewed above, these factors may include medical or psychiatric illnesses, medications, and psychosocial factors such as availability of a partner or marital harmony. Hormonal fluctuations associated with surgical or natural menopause and endocrine disorders such as diabetes mellitus may affect desire. Psychiatric conditions such as major depressive disorder or panic disorder may also contribute to lack of desire or even aversion to and avoidance of sexual activity.24 Medications, including psychotropics, antihypertensives, tamoxifen, and antiepileptics, may result in decreased libido.

Female Sexual Arousal Disorder

Female sexual arousal disorder (FSAD), as defined by the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition–Text Revision,22 includes a persistent or recurrent inability to attain, or maintain until completion of sexual activity, an adequate lubrication-swelling response of sexual excitement. As in HSDD, the symptoms cause marked distress or difficulty with interpersonal functioning and may not be better accounted for by another Axis I diagnosis, general medical condition, or substance.22 Approximately 36% to 43% of women 57–85 years of age report difficulty with vaginal lubrication during sexual activity.3 The clinician should make the distinction between difficult lubrication due to physiologic changes during menopause versus a symptom of FSAD. In the older woman, this distinction may be challenging as estradiol deficiency prevents an adequate lubrication response. Gathering an adequate medical and sexual history, including the timing of onset of the arousal difficulties, may help the clinician make this distinction.

FSAD is commonly associated with other sexual disorders. For example, a woman who is not able to maintain her arousal response may complain of low desire. The clinician should assess the onset of her decreased sexual interest as it may correlate to her delayed arousal response. If so, her primary difficulty is FSAD, with a secondary HSDD. That is, since her arousal response is significantly diminished, she may “report” low sexual desire. This is an important distinction for the clinician to make as the diagnosis and treatment may vary.

Arousal difficulties may have underlying psychological, vascular, neurologic, or endocrinologic etiologies.25 The most notable endocrinologic etiology for the older woman is, of course, menopause. Estrogen decline results in vaginal dryness and difficulty attaining adequate lubrication for sexual activity. With regard to vascular etiologies, atherosclerosis may result in decreased vaginal and clitoral blood flow. Traumatic injury to the pelvic arterial bed from fractures, trauma, surgical disruption, or chronic perineal pressure from activities such as bicycle riding can result in diminished vaginal and clitoral blood flow.26 Spinal cord injuries and peripheral and central nervous system disorders may inhibit sexual arousal as well. As in HSDD, psychological factors (eg, self-esteem issues, presence of a mood or anxiety disorder) and relationship problems may also contribute to difficulties in female arousal. Medications with antihistaminic and anticholinergic properties may prevent adequate lubrication and arousal.

Female Orgasmic Disorder

Among women, there is significant variability in the type and intensity of sexual stimulation that results in orgasm. In addition, orgasm may vary within an individual over her life cycle. Female orgasmic disorder (FOD) is defined by the DSM-IV-TR as a persistent or recurrent delay in, or absence of, orgasm following a normal sexual excitement phase. Given the variability of sexual response among women, the DSM-IV-TR dictates that the diagnosis of FOD should be based on the clinician’s judgment that the patient’s orgasmic capacity is less than would be expected for her age, sexual experience, and adequacy of sexual stimulation.22 As in the other sexual disorders, inability to achieve orgasm may be a problem she has had all of her life or one that has developed due a wide variety of biopsychosocial issues including relationship issues, the normal process of aging, general medical conditions, or any of a variety of possible medications.

Up to 38% of women >57 years of age report an inability to climax.3 Some women have never experienced orgasm, possibly the result of inexperience, religious inhibitions, or emotional or sexual trauma. Others acquire FOD after previously enjoying a satisfying sex life. As with the other female sexual disorders, if a women “had it, lost it, and wants it back” for herself, treatment will generally have a more favorable outcome.27 FOD is more common among unmarried women and those without a college degree.20 Psychosocial factors including relationship quality, self-esteem, and attitudes toward sex may also contribute to FOD. Medical etiologies of anorgasmia include medications, substance abuse, hormonal deficiency, surgery, or trauma.

Sexual Pain Disorders

Eleven percent to 18% of women 57–85 years of age report pain during intercourse.3 Sexual pain disorders include dyspareunia and vaginismus. The two disorders are characterized by difficulty with vaginal penetration. The DSM-IV-TR defines dyspareunia as recurrent or persistent genital pain associated with sexual intercourse. Vaginismus is defined by the DSM-IV-TR as recurrent or persistent involuntary spasm of the musculature of the outer third of the vagina that interferes with sexual intercourse, though some authors have proposed reconceptualizing this disorder as either an aversion/phobia of genital penetration or a genital pain disorder.28 In order to make either diagnosis, the symptoms must cause marked distress and interpersonal difficulty and are not better accounted for by another Axis I disorder (eg, somatization disorder) or a general medical condition or substance.22

Dyspareunia may be due to psychological factors or a combination of psychological factors plus a general medical condition. DeUgarte and colleagues25 suggested dividing dyspareunia into three categories for ease of diagnosis: pain with intromission (often secondary to vestibulitis, vaginismus, or superficial vaginal lesions), mid-vaginal pain (often secondary to vaginal dryness, surgical scars, etc), and deep-thrust dyspareunia (secondary to endometriosis, pelvic adhesions, neoplasm, or interstitial cystitis).

Vaginismus may be so severe that penetration of the vagina by any means (tampon, speculum, or penis) may be impossible. Vaginismus may be primary, wherein no penetration has ever been achieved, or secondary, wherein penetration has been achieved in the past. There is often a negative feedback cycle, wherein the discomfort and humiliation of attempted penetration leads to a phobic avoidance of any sexual contact at all.29 Proposed psychological factors contributing to vaginismus may include psychosexual conflicts, strict religious upbringing which associates sex with sin, a history of sexual abuse or rape, or emotional disconnect between sexual partners.30

Assessment and Treatment of Sexual Disorders in the Older Woman

Assessment

The evaluation of the older women who presents with a sexual complaint requires careful consideration of the patient and the multitude of factors that impact on the various components of the sexual response cycle (Table 1).23 A comprehensive medical and psychiatric history must be obtained, with special attention paid to any psychiatric or medical condition which may impact sexual functioning (eg, depression, anxiety, substance abuse, menopause, diabetes). A complete sexual history is imperative and includes attitudes toward sexuality, level of sexual knowledge of the patient and partner, relationship with the current partner, past sexual behaviors, and current and past sexual levels of functioning (ie, desire, arousal, and orgasm).

 

Equally as important as assessing the patient’s current level of sexual functioning is assessing her level of distress due to her symptoms. Shifren and colleagues31 recently reported that while sexual problems are greatest in elderly women, sexual problems causing distress are least prevalent in this age group. They noted that the reasons for this are unclear, but may include changes in partner status or partner’s health, significance of other medical conditions, or other factors important to relationships of long duration. Clinicians should be able to identify relevant age-appropriate issues with older couples; it may be helpful to interview partners alone and together.17 Accurate assessment of sexual dysfunction in late life is contingent upon a trusting, secure doctor-patient relationship in which both parties feel comfortable discussing these sensitive topics.7

The use of a simple intra-individual assessment tool such as the Sexual Energy Scale (SES) may be helpful in providing an objective means of measuring the patient’s report of their subjective experience of vitality/sexual energy.32 The patient is educated that sexual energy is not comprised merely of the frequency of intercourse or masturbation, but also includes sexual dreams, fantasies, genital sensations, and sexual appetite. The patient rates her current sexual energy on a scale of 1–10, with 1 being the lowest sexual energy she has experienced in her adult life, and 10 being the highest (Figure). The SES may be repeated at subsequent visits. The busy primary care physician can use this simple, one-item scale to track symptomatic improvement over time as the patient is being treated. The scale may help both patient and physician evaluate response to treatment.

 

A thorough medication inventory, including over-the-counter medications, is essential. As discussed above, many medications carry risk of sexual side effects and may impact all components of the sexual response cycle. Physical examination, including gynecologic examination, may help identify medical factors impacting sexual functioning (eg, vaginal atrophy, cystocoele, leakage). Laboratory testing may include complete blood count, electrolyte levels, lipid panel, and thyroid function tests as well as levels of prolactin, follicle-stimulating hormone, estrogen, and free and total testosterone.

Treatment

Treatment for the older woman with sexual dysfunction depends in part on whether the problem is considered a sexual disorder that she has had all of her life or one that has developed more recently (Table 2).23 If the problem has developed more recently, assuming that there is no significant change in her health, then the clinical prognosis is likely to be more optimistic. In either case, the patient should be encouraged to cultivate a positive attitude toward sexuality in late life and avoid unrealistic expectations, such as that sex must be the same as when she was younger.7 Education may be required as to what constitutes normal and dysfunctional sexuality as well as how to modify sexual activity in the face of fatigue and pain. Maintaining open and honest communication between partners is essential. Lifestyle adjustments are likely to be beneficial. Patients should be instructed to cease smoking and avoid alcohol or illicit drugs. Regular exercise, as tolerated, including pelvic floor exercises, proper nutrition, and sleep hygiene techniques should be encouraged, in addition to stress management techniques and social and partnership skills training.23

 

 
If the disorder is due to a substance such as a prescription or over-the-counter medication, one could wait to see if tolerance will develop and the sexual side effect will attenuate, though this does not commonly occur.33 Attempts to reduce or eliminate that medication may be undertaken, if feasible. If the patient is felt to require the medication, consideration may be given to switching to another class which may have lower likelihood of sexual side effects (eg, switching from fluoxetine to bupropion for treatment of depression). An alternative strategy is to utilize antidotes to reverse sexual side effects (eg, bupropion or sildenafil for SSRI-induced sexual dysfunction). Of note, no medication is Food and Drug Administration-approved for the treatment of sexual disorders in women.

If the sexual dysfunction is due to a medical or psychiatric condition, treatment for that condition (eg, hypothyroidism, depression, vulvitis) should be optimized first. Postmenopausal women should be assessed for signs and symptoms of estrogen deficiency (ie, hot flashes, vaginal dryness) and androgen deficiency (ie, global loss of sexual desire, decreased genital sensitivity). Hormone replacement therapy (estrogen and/or testosterone) may be considered and is available in a variety of routes of administration (oral, transdermal, injection or topical). The use of estrogen replacement has been controversial in the US because of its reported association with breast cancer, stroke, and ovarian cancer. In selecting patients for estrogen replacement, the clinician should carefully consider the individual’s medical history, including history of smoking, migraine headaches, breast cancer, or stroke.

The testosterone patch is currently available for women with HSDD in Australia, Canada, and Europe. While it is known that testosterone can improve sexual desire in postmenopausal women on estrogen therapy, the question has been raised as to whether or not the testosterone patch is effective for HSDD in postmenopausal women who are not on estrogen. To answer this question, Davis and colleagues34 conducted a randomized, double-blind, placebo-controlled multisite trial. They found that for postmenopausal women with HSDD not on estrogen, 300 mcg/day of testosterone had a significantly greater improvement in the 4-week frequency of satisfying sexual episodes than those using placebo. In the US, physicians may prescribe physiologic replacement levels of testosterone for women using low doses of products that are approved for men or by referring patients to compounding pharmacies. Prior to beginning testosterone replacement, clinicians should engage patients in a thorough discussion of the risks and benefits. Potential long-term risks may include hyperlipidemia, hirsutism, clitoromegaly, voice changes, liver tumors, and transaminase dysfunction, although these side effects are generally considered dose dependent. Physiologic replacement levels of testosterone in women do not appear to have significant adverse events. A clinician may want to order a baseline fasting lipid profile before initiating testosterone, with a repeat panel in several months. Women in this age group are at increased risk of hyperlipidemia, and if these studies have not been done within the last year, then it is prudent to obtain these studies.

While many medications have been tried in the treatment of female sexual disorders, randomized controlled trials are limited, particularly in older women. Agents such as sildenafil, bupropion, prostaglandin E1, phentolamine, and others have been reported as possible treatments for female sexual disorders, in addition to medical devices such as vacuum therapy and electronic stimulation.25 Currently, there are non-hormonal medications for the treatment of low sexual desire in ongoing phase III clinical trials in the US (ie, flibanserin).

For the older woman whose sexual disorder is felt to be related to psychological issues, sex and/or marital therapy should be considered. Cognitive-behavioral techniques are replacing previously used psychodynamic models of therapy.35 Therapy often begins with psychoeducation and support, to help cultivate more positive attitudes toward sexuality in late life. The therapist may help correct “all or nothing” cognitive distortions, wherein the patient feels that if orgasm is not achieved, sex is worthless. Patients may be educated on techniques such as self-stimulation, sensate focus, and foreplay, so that the focus of sexual activity is not exclusively intercourse. For the older woman with vaginismus, psychoeducation and cognitive-behavioral therapy may be accompanied by the use of vaginal dilators of graduated sizes, allowing the woman to be in control while extinguishing the involuntary muscle contraction.29

Conclusion

As women are living longer, healthier lives, they seek to maintain sexual health and satisfaction throughout the latter decades. Many biologic and psychosocial factors uniquely affect the older woman and place her at risk for sexual dysfunction. She must overcome hormonal fluctuations, medical conditions, necessary medications, changes in intimate relationships, and a culture which equates sexiness and vitality with youth. Physicians who treat older women should be familiar with the effects of aging on the normal female sexual response cycle, as well as the biologic and psychosocial factors which impact female sexual functioning in late life. Physicians should routinely inquire about patients’ sexual functioning and satisfaction and provide an open, supportive environment in which to discuss such concerns.

Older women may experience disorders of sexual desire, arousal, orgasm, and pain. Identifying the biologic and psychosocial contributors is essential in the treatment of these disorders. Treatment in all cases should include psychoeducation and lifestyle adjustments, such as exercise, proper nutrition, sleep hygiene, elimination of alcohol and drugs, and improving communication skills among partners. Treatment should also include optimizing treatment of underlying medical and psychiatric conditions, reduction or elimination of problematic medications, and referral for sex therapy, as clinically indicated. Medications for the treatment of various sexual disorders in women are currently under investigation. Given the strong association between sexual dysfunction and quality of life,20 further research is needed in this area. Sexual dysfunction is a common, but neglected area in medicine, in particular for the older woman. PP

References

1.    Kaplan HS. Sex, intimacy, and the aging process. J Am Acad Psychoanal. 1990;18(2):185-205.
2.    Starr BD, Weiner MB. The Starr-Weiner Report on Sex and Sexuality in the Mature Years. New York, NY: McGraw-Hill; 1981.
3.    Lindau ST, Schumm LP, Laumann EO, Levinson W, O’Muircheartaigh CA, Waite LJ. A study of sexuality and health among older adults in the United States. N Engl J Med. 2007;357(8):762-774.
4.    Spector IP, Rosen RC, Leiblum SR. Sexuality. In: Reichman WE, Katz PR, eds. Psychiatric Care in the Nursing Home. New York, NY: Oxford University Press; 1996:133-150.
5.    Clayton AH. Sexual function and dysfunction in women. Psychiatr Clinics of N Am. 2003;26(3):673-682.
6.    Masters WH, Johnson VE. Human Sexual Response. Boston, MA: Little, Brown; 1966.
7.    Agronin ME. Sexual disorders. In: Blazer DG, Steffens DC, Busse EW, eds. Textbook of Geriatric Psychiatry. Washington, DC: American Psychiatric Publishing, Inc; 2004:303-317.
8.    Warnock JK. Impact of medical illness and reproductive transitions on sexual functioning in women. Mental Fitness. 2004;3(4):34-39.
9.    Altshuler LL, Cohen LS, Moline ML, et al. The Expert Consensus Guidelines. Treatment of depression in women. Postgrad Med. 2001;(Spec No):1-107.
10.    Sarrel PM. Sexuality and menopause. Obstet Gynecol. 1990;75(suppl):26S-30S.
11.    Schreiner-Engel P, Schiavi RC, Vietorisz D, Smith H. The differential impact of diabetes type on female sexuality. J Psychosom Res. 1987;31(1):22-33.
12.    Erol B, Tefekli A, Ozbey I, et al. Sexual dysfunction in type II diabetic females: a comparative study. J Sex Marital Ther. 2002;28(s):55-62.
13.    Korpelainen JT, Nieminen P, Myllyla VV. Sexual functioning among stroke patients and their spouses. Stroke. 1999;30(4):715-719.
14.    Kaiser FE. Sexual function in the older woman. Clin Geriatr Med. 2003;19(3):463-472.
15.    Addis IB, Ireland CC, Vittinghoff E, Lin F, Stuenkel CA, Hulley S. Sexual activity and function in postmenopausal women with heart disease. Obstet Gynecol. 2005;106(1):121-127.
16.    Thomas DR. Medications and sexual function. Clin Geriatr Med. 2003;19(3):553-562.
17. Sbrocco T, Weisberg RB, Barlow DH. Sexual dysfunction in the older adult: assessment of psychosocial factors. Sex Disabil. 1995;13(3):201-218.
18.    Graziottin A. The biological basis of female sexuality. Int Clin Psychopharmacol. 1998;13(suppl 6):S15-S22.
19.    Basson R. The female sexual response: a different model. J Sex Marital Ther. 2000;26(1):51-65.
20.    Laumann EO, Paik A, Rosen RC. Sexual dysfunction in the United States: prevalence and predictors. JAMA. 1999;281(6):537-544.
21.    Hayes RD, Dennerstein L, Bennett CM, Koochaki PE, Leiblum SR, Graziottin A. Relationship between hypoactive sexual desire disorder and aging. Fertil Steril. 2007;87(1):107-112.
22.    Diagnostic and Statistical Manual of Mental Disorders. 4th ed, text rev. Washington, DC: American Psychiatric Association; 2000.
23.    Warnock JK. Female hypoactive sexual desire disorder: epidemiology, diagnosis, and treatment. CNS Drugs. 2002;16(11):745-753.
24.    Figueira I, Possidente E, Marques C, Hayes K. Sexual dysfunction: a neglected complication of panic disorder and social phobia. Arch Sex Behav. 2001;30(4):369-377.
25.    DeUgarte CM, Berman L, Berman J. Female sexual dysfunction: from diagnosis to treatment. Sexuality, Reproduction, and Menopause. 2004;2(3):139-145.
26.    Berman JR, Goldstein I. Female sexual dysfunction. Urol Clin North Am. 2001;28(2):405-416.
27.    Warnock JK. Acquired, generalized, female hypoactive sexual desire disorder: I had it, I lost it, I want it back. Psychiatric Times. 2005;22(9):45-52.
28.    Reissing ED, Binik YM, Khalifé S. Does vaginismus exist? A critical review of the literature. J Nerv Ment Dis. 1999;187(5):261-274.
29.    Butcher J. ABC of sexual health: female sexual problems II: sexual pain and sexual fears. BMJ. 1999;318(7176):110-12.
30.    Sadock VA. Normal human sexuality. In: Sadock BJ, Sadock VA, eds. Comprehensive Textbook of Psychiatry. 7th ed. Philadelphia, PA: Lippincott Williams and Wilkins; 2000:1577-1631.
31.    Shifren JL, Monz BU, Russo PA, Segreti A, Johannes CB. Sexual problems and distress in United States women: prevalence and correlates. Obstet Gynecol. 2008;112(5):970-978.
32.    Warnock JK, Bundren C, Morris DW. Female hypoactive sexual desire disorder due to androgen deficiency: clinical and psychometric issues. Psychopharm Bull. 1997;33(4):761-66.
33.    Rothschild AJ. Sexual side effects of antidepressants. J Clin Psych. 2000;61(suppl 11):28-36.
34.    Davis SR, Moreau M, Kroll R, et al. Testosterone for low libido in postmenopausal women not taking estrogen. N Engl J Med. 2008;359(19):2005-2017.
35.    Rosen RC, Leiblum SR. Principles and Practice of Sex Therapy: Update for the 1990s. New York, NY: Guilford Press; 1988.

Return

 

Dr. Wilkins is assistant professor and Dr. Warnock is professor of psychiatry in the Department of Psychiatry at the University of Oklahoma in Tulsa.

Disclosure: Dr. Wilkins reports no affiliation with or financial interest in any organization that may pose a conflict of interest. Dr. Warnock has received research support from Boehringer Ingelheim, Forest, and Wyeth.

Acknowledgments: The authors would like to acknowledge the assistance of Ms. Faye Biggs in the preparation of this manuscript.

Please direct all correspondence to: Kirsten M. Wilkins, MD, Assistant Professor, Department of Psychiatry, University of Oklahoma–Tulsa; 4502 E 41st St, Tulsa, OK 74136; Tel: 918-660-3514; Fax: 918-660-3517; E-mail: Kirsten-Wilkins@ouhsc.edu.


 

Focus Points

• Sexual dysfunction in older women is a common yet neglected area of medicine.
• Older women with sexual dysfunction require careful assessment of biologic and psychosocial contributing factors.
• Treatment options for female sexual dysfunction in later life are available but under-utilized.
 

Abstract

The geriatric patient population is anticipated to grow significantly in the coming decades. As individuals are living longer, healthier lives, there is interest in maintaining sexual health throughout the latter decades. The aging female faces many biologic and psychosocial factors which impact sexual functioning and satisfaction. Given this, it is not surprising that ~33% of older women will experience sexual dysfunction. As sexual dysfunction has been strongly associated with quality of life, physicians should be familiar with the assessment and treatment of sexual disorders in older women. This article reviews the effects of aging on the normal female sexual response cycle, as well as the various biologic and psychosocial factors affecting female sexuality in late life. The article then provides an overview of common female sexual disorders of desire, arousal, orgasm, and sexual pain. Finally, the authors discuss assessment and treatment of sexual dysfunction in the older woman.

Introduction

As individuals are living longer, healthier lives, there is a growing interest in maintaining one’s sexual health throughout the latter decades. Previous studies have reported that 70% of healthy 70-year-olds enjoy sex on a regular basis and that 80% of men and women 60–91 years of age are sexually active at least once per month.1,2 A recent study3 concluded that the majority of older adults are engaged in sexual activity and regard sex as an important part of life. However, many biologic and psychosocial factors related to aging impact the quality and quantity of sexual activity an older person experiences. The physical and mental health of the individual as well as their partner, the availability of a willing partner, and the previous level of sexual activity all play an important role in sexuality in aging.

Given the many factors related to aging which can impact sexual functioning, it comes as no surprise that the prevalence of sexual dysfunction increases with age.4 While the advertising market and popular media have paid much attention to sexual disorders among older men, these disorders are also common among older women. A recent national sample3 of sexual behaviors and problems in older community-dwelling individuals reported that women 57–64 years of age had the following sexual complaints: lack of interest in sex (44.2%), difficulty with lubrication (35.9%), inability to climax (34%), pain during intercourse (17.8%), and lack of pleasure during sex (24%). Despite the prevalence of sexual complaints, the same study found that women are less likely than men to discuss these matters with their physician. Physicians themselves may fail to assess a patient’s sexual functioning due to personal discomfort, time constraints, placing sexuality low on the priority list, or out of fear of embarrassing the patient or being perceived as too intrusive.5

Given the anticipated increase in the geriatric population and the prevalence of sexual dysfunction with aging, physicians in both primary care and psychiatry should be familiar with common sexual disorders among older women. The purpose of this article is to review the diagnosis, evaluation, and treatment of sexual disorders among older women. The authors begin with a review of the normal sexual response and aging, followed by a discussion of biologic and psychosocial factors associated with changes in sexual functioning in aging. Finally, the article reviews common sexual disorders and their treatments.

Normal Sexual Response and Aging

Before one can accurately diagnose and effectively treat sexual disorders in the older woman, one must understand the effects of aging on the normal sexual response cycle. The normal adult sexual response cycle, as originally described by Masters and Johnson,6 is comprised of four stages: arousal, plateau, orgasm, and resolution. A fifth stage, desire, has been added to include the psychological and physiologic part of sexual functioning which underlies response.7 Any of these stages may be impacted by age-related changes in sexual functioning.

Due to the significant changes in sex steroids that occur during reproductive life events, women are particularly vulnerable to sexual dysfunction during these times.8 Menopause, cessation of menses for >12 months, constitutes the major reproductive life event of the older woman. Perimenopause is defined as the transitional period from the reproductive years to reproductive quiescence.9 Perimenopause and menopause are associated with a decline in ovarian function, resulting in reduction and eventual cessation of estrogen production. Estrogen decline impacts sexual functioning in several ways. The urogenital tissue atrophies and vaginal size is reduced. Vaginal lubrication decreases, which can result in uncomfortable intercourse. The sensitivity of the nipples, clitoris, and vulvar tissue is reduced, and the strength and amount of vaginal contractions during orgasm decrease. In addition, the majority of women undergoing menopause experience other symptoms such as mood lability, fatigue, body aches, and hot flashes.7

In addition to changes in estrogen, the menopausal woman also undergoes a decrease in testosterone production. Androgen deficiency in women is associated with a global loss of sexual desire or libido, decreased production of body oils, thinning of pubic hair, reduced vital energy, and decreased sensitivity of the nipples and clitoris.10

Biological Factors and Sexuality in Aging

In addition to the hormonal changes that occur via menopause, the older woman faces other biologic factors which impact sexual functioning. Many medical and psychiatric illnesses are more prevalent in older adults and are known to impact the quality of sexual activity. These illnesses are often the primary cause of sexual dysfunction in this population.7 Illnesses such as urogenital cancers, cardiovascular disease, arthritis, and chronic obstructive pulmonary disease, as well as many neurologic diseases (stroke, Parkinson’s disease, multiple sclerosis, and others), are associated with sexual dysfunction.

The medical condition itself may directly affect sexual functioning. Diabetes, in particular type II, has been associated with sexual complaints among women, including lack of libido, reduced orgasmic capacity, decreased vaginal lubrication, and reduced sexual satisfaction.11,12 Similarly, studies on the sexual functioning of stroke patients have shown that sexual dysfunction and dissatisfaction are common among women.13 Some illnesses such as arthritis may cause pain or limit flexion and range of motion, leading to uncomfortable intercourse.14 Psychiatric conditions including depression, dementia, and substance abuse can also lead to reduced sexual interest and impaired functioning. Medical illnesses may have an indirect effect on sexual functioning as well. Fear of pain or of exacerbating a medical condition such as angina may lead to an inability to relax and enjoy sexual activity.15 Some illnesses, such as breast cancer or gynecologic malignancies, may result in altered self-image and reduced feelings of sexual attractiveness.14

Various symptoms of sexual dysfunction may arise iatrogenically, as a result of prescription medications. A recent review on medications and sexual function reported that >100 drugs or drug classes have been associated with sexual dysfunction, and that the impact of medications on sexuality increases with age.16 Sexual side effects in women secondary to medications may include loss of libido, reduced capacity for arousal, and difficulty achieving orgasm. Psychiatric medications, including selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants, mood stabilizers, and antipsychotics are known to carry a risk of sexual side effects. Antihypertensive medications, such as beta-blockers, diuretics, and clonidine, among others, have also been associated with sexual side effects. Other medications associated with sexual dysfunction include digoxin, corticosteroids, antihistamines, histamine subtype 2 receptor blockers, opioids, and cancer chemotherapeutic agents.7,16

Psychosocial Factors and Sexuality in Aging

Psychosocial factors also significantly impact sexual activity among older women. The life expectancy of women is greater than that of men; hence, many older women have lost their spouse or partner. As women outnumber men in the latter decades of life, the availability of a willing and functional sexual partner becomes a legitimate issue for heterosexual women. Lesbian women in this age group remain understudied. For those older adults who are able to enter into new sexual relationships, concern about sexually transmitted diseases has been reported as a reason for lack of sexual activity.3

One’s social environment can also play a role in the expression of sexuality. Some older women will find themselves living with their adult children and their families or in assisted living or long-term care facilities, where opportunity and/or privacy for sexual activity is lacking. On the other hand, many older women will continue to live independently. Some couples may even enjoy increased time for intimacy due to retirement or “the empty nest.” Among postmenopausal women, the elimination of concern about the possibility of pregnancy may result in decreased anxiety and increased ability to enjoy sex.7

Psychological and cultural factors are also important. Our culture is notoriously geared toward the notion that sex is for the young and, therefore, older adults are often not seen as sexually desirable or capable.17 This view is not always bestowed equally upon the genders. Movies and television frequently pair younger, attractive women with older men. Such ageist stereotypes about sexuality are unfortunately accepted by many older individuals, who may see sexual activity as inappropriate or dangerous.7

Sexual Disorders in Older Women

Hypoactive Sexual Desire Disorder

Sexual desire comprises a critical portion of the human sexual response cycle, and includes sexual fantasies and thoughts as well as motivation and receptivity to sexual activity. This phase has been postulated to include biologic, motivational-affective, and cognitive components.18 Basson19 suggested that a woman’s sexual response arises not from a biologic neediness or urge, but rather from intimacy. Motivation to participate in sexual activity is theorized to derive not only from sexual pleasure, but also from closeness and tenderness. Therefore, a woman may choose to experience sexual activity in order to have intimate relationship needs met.

Female hypoactive sexual desire disorder (HSDD) may occur in up to 33% of adult women in the United States. The complaint of low sexual desire alone does not meet criteria for the diagnosis of HSDD. However, such a complaint is not uncommon among older women. The prevalence of lack of interest in sex for women in the US 50–59 years of age has been reported as 27%, slightly lower than rates in younger women.20 A more recent study,3 however, reported prevalence rates of 38% to 49% for women 57–85 years of age. It is important to note that not all women are distressed by a decrease in sexual desire. In 2007, Hayes and colleagues21 reported that while the proportion of women with low sexual desire increases with age, the proportion of women distressed about their low desire actually decreases with age.

The diagnosis of HSDD is made when the patient has persistently or recurrently deficient (or absent) sexual fantasies and desire for sexual activity, which cause marked distress or interpersonal difficulty and are not better accounted for by another Axis I disorder, general medical condition, or substance.22 Frequently, in women, HSDD and the physiologic effects of a general medical condition are both present. Thus, HSDD due to combined factors is diagnosed. HSDD may be lifelong (eg, patients with history of sexual trauma or abuse) or acquired (as in the case of a general medical condition). It may be generalized or situational and is frequently associated with dysfunction in sexual arousal and orgasm.23 An extreme version of HSDD, sexual aversion disorder, consists of persistent or recurrent extreme aversion to, and avoidance of, all genital sexual contact, which causes marked distress or interpersonal difficulty.22

Female sexual desire in later life may be impacted by numerous factors. As reviewed above, these factors may include medical or psychiatric illnesses, medications, and psychosocial factors such as availability of a partner or marital harmony. Hormonal fluctuations associated with surgical or natural menopause and endocrine disorders such as diabetes mellitus may affect desire. Psychiatric conditions such as major depressive disorder or panic disorder may also contribute to lack of desire or even aversion to and avoidance of sexual activity.24 Medications, including psychotropics, antihypertensives, tamoxifen, and antiepileptics, may result in decreased libido.

Female Sexual Arousal Disorder

Female sexual arousal disorder (FSAD), as defined by the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition–Text Revision,22 includes a persistent or recurrent inability to attain, or maintain until completion of sexual activity, an adequate lubrication-swelling response of sexual excitement. As in HSDD, the symptoms cause marked distress or difficulty with interpersonal functioning and may not be better accounted for by another Axis I diagnosis, general medical condition, or substance.22 Approximately 36% to 43% of women 57–85 years of age report difficulty with vaginal lubrication during sexual activity.3 The clinician should make the distinction between difficult lubrication due to physiologic changes during menopause versus a symptom of FSAD. In the older woman, this distinction may be challenging as estradiol deficiency prevents an adequate lubrication response. Gathering an adequate medical and sexual history, including the timing of onset of the arousal difficulties, may help the clinician make this distinction.

FSAD is commonly associated with other sexual disorders. For example, a woman who is not able to maintain her arousal response may complain of low desire. The clinician should assess the onset of her decreased sexual interest as it may correlate to her delayed arousal response. If so, her primary difficulty is FSAD, with a secondary HSDD. That is, since her arousal response is significantly diminished, she may “report” low sexual desire. This is an important distinction for the clinician to make as the diagnosis and treatment may vary.

Arousal difficulties may have underlying psychological, vascular, neurologic, or endocrinologic etiologies.25 The most notable endocrinologic etiology for the older woman is, of course, menopause. Estrogen decline results in vaginal dryness and difficulty attaining adequate lubrication for sexual activity. With regard to vascular etiologies, atherosclerosis may result in decreased vaginal and clitoral blood flow. Traumatic injury to the pelvic arterial bed from fractures, trauma, surgical disruption, or chronic perineal pressure from activities such as bicycle riding can result in diminished vaginal and clitoral blood flow.26 Spinal cord injuries and peripheral and central nervous system disorders may inhibit sexual arousal as well. As in HSDD, psychological factors (eg, self-esteem issues, presence of a mood or anxiety disorder) and relationship problems may also contribute to difficulties in female arousal. Medications with antihistaminic and anticholinergic properties may prevent adequate lubrication and arousal.

Female Orgasmic Disorder

Among women, there is significant variability in the type and intensity of sexual stimulation that results in orgasm. In addition, orgasm may vary within an individual over her life cycle. Female orgasmic disorder (FOD) is defined by the DSM-IV-TR as a persistent or recurrent delay in, or absence of, orgasm following a normal sexual excitement phase. Given the variability of sexual response among women, the DSM-IV-TR dictates that the diagnosis of FOD should be based on the clinician’s judgment that the patient’s orgasmic capacity is less than would be expected for her age, sexual experience, and adequacy of sexual stimulation.22 As in the other sexual disorders, inability to achieve orgasm may be a problem she has had all of her life or one that has developed due a wide variety of biopsychosocial issues including relationship issues, the normal process of aging, general medical conditions, or any of a variety of possible medications.

Up to 38% of women >57 years of age report an inability to climax.3 Some women have never experienced orgasm, possibly the result of inexperience, religious inhibitions, or emotional or sexual trauma. Others acquire FOD after previously enjoying a satisfying sex life. As with the other female sexual disorders, if a women “had it, lost it, and wants it back” for herself, treatment will generally have a more favorable outcome.27 FOD is more common among unmarried women and those without a college degree.20 Psychosocial factors including relationship quality, self-esteem, and attitudes toward sex may also contribute to FOD. Medical etiologies of anorgasmia include medications, substance abuse, hormonal deficiency, surgery, or trauma.

Sexual Pain Disorders

Eleven percent to 18% of women 57–85 years of age report pain during intercourse.3 Sexual pain disorders include dyspareunia and vaginismus. The two disorders are characterized by difficulty with vaginal penetration. The DSM-IV-TR defines dyspareunia as recurrent or persistent genital pain associated with sexual intercourse. Vaginismus is defined by the DSM-IV-TR as recurrent or persistent involuntary spasm of the musculature of the outer third of the vagina that interferes with sexual intercourse, though some authors have proposed reconceptualizing this disorder as either an aversion/phobia of genital penetration or a genital pain disorder.28 In order to make either diagnosis, the symptoms must cause marked distress and interpersonal difficulty and are not better accounted for by another Axis I disorder (eg, somatization disorder) or a general medical condition or substance.22

Dyspareunia may be due to psychological factors or a combination of psychological factors plus a general medical condition. DeUgarte and colleagues25 suggested dividing dyspareunia into three categories for ease of diagnosis: pain with intromission (often secondary to vestibulitis, vaginismus, or superficial vaginal lesions), mid-vaginal pain (often secondary to vaginal dryness, surgical scars, etc), and deep-thrust dyspareunia (secondary to endometriosis, pelvic adhesions, neoplasm, or interstitial cystitis).

Vaginismus may be so severe that penetration of the vagina by any means (tampon, speculum, or penis) may be impossible. Vaginismus may be primary, wherein no penetration has ever been achieved, or secondary, wherein penetration has been achieved in the past. There is often a negative feedback cycle, wherein the discomfort and humiliation of attempted penetration leads to a phobic avoidance of any sexual contact at all.29 Proposed psychological factors contributing to vaginismus may include psychosexual conflicts, strict religious upbringing which associates sex with sin, a history of sexual abuse or rape, or emotional disconnect between sexual partners.30

Assessment and Treatment of Sexual Disorders in the Older Woman

Assessment

The evaluation of the older women who presents with a sexual complaint requires careful consideration of the patient and the multitude of factors that impact on the various components of the sexual response cycle (Table 1).23 A comprehensive medical and psychiatric history must be obtained, with special attention paid to any psychiatric or medical condition which may impact sexual functioning (eg, depression, anxiety, substance abuse, menopause, diabetes). A complete sexual history is imperative and includes attitudes toward sexuality, level of sexual knowledge of the patient and partner, relationship with the current partner, past sexual behaviors, and current and past sexual levels of functioning (ie, desire, arousal, and orgasm).

 

Equally as important as assessing the patient’s current level of sexual functioning is assessing her level of distress due to her symptoms. Shifren and colleagues31 recently reported that while sexual problems are greatest in elderly women, sexual problems causing distress are least prevalent in this age group. They noted that the reasons for this are unclear, but may include changes in partner status or partner’s health, significance of other medical conditions, or other factors important to relationships of long duration. Clinicians should be able to identify relevant age-appropriate issues with older couples; it may be helpful to interview partners alone and together.17 Accurate assessment of sexual dysfunction in late life is contingent upon a trusting, secure doctor-patient relationship in which both parties feel comfortable discussing these sensitive topics.7

The use of a simple intra-individual assessment tool such as the Sexual Energy Scale (SES) may be helpful in providing an objective means of measuring the patient’s report of their subjective experience of vitality/sexual energy.32 The patient is educated that sexual energy is not comprised merely of the frequency of intercourse or masturbation, but also includes sexual dreams, fantasies, genital sensations, and sexual appetite. The patient rates her current sexual energy on a scale of 1–10, with 1 being the lowest sexual energy she has experienced in her adult life, and 10 being the highest (Figure). The SES may be repeated at subsequent visits. The busy primary care physician can use this simple, one-item scale to track symptomatic improvement over time as the patient is being treated. The scale may help both patient and physician evaluate response to treatment.

 

A thorough medication inventory, including over-the-counter medications, is essential. As discussed above, many medications carry risk of sexual side effects and may impact all components of the sexual response cycle. Physical examination, including gynecologic examination, may help identify medical factors impacting sexual functioning (eg, vaginal atrophy, cystocoele, leakage). Laboratory testing may include complete blood count, electrolyte levels, lipid panel, and thyroid function tests as well as levels of prolactin, follicle-stimulating hormone, estrogen, and free and total testosterone.

Treatment

Treatment for the older woman with sexual dysfunction depends in part on whether the problem is considered a sexual disorder that she has had all of her life or one that has developed more recently (Table 2).23 If the problem has developed more recently, assuming that there is no significant change in her health, then the clinical prognosis is likely to be more optimistic. In either case, the patient should be encouraged to cultivate a positive attitude toward sexuality in late life and avoid unrealistic expectations, such as that sex must be the same as when she was younger.7 Education may be required as to what constitutes normal and dysfunctional sexuality as well as how to modify sexual activity in the face of fatigue and pain. Maintaining open and honest communication between partners is essential. Lifestyle adjustments are likely to be beneficial. Patients should be instructed to cease smoking and avoid alcohol or illicit drugs. Regular exercise, as tolerated, including pelvic floor exercises, proper nutrition, and sleep hygiene techniques should be encouraged, in addition to stress management techniques and social and partnership skills training.23

 

 
If the disorder is due to a substance such as a prescription or over-the-counter medication, one could wait to see if tolerance will develop and the sexual side effect will attenuate, though this does not commonly occur.33 Attempts to reduce or eliminate that medication may be undertaken, if feasible. If the patient is felt to require the medication, consideration may be given to switching to another class which may have lower likelihood of sexual side effects (eg, switching from fluoxetine to bupropion for treatment of depression). An alternative strategy is to utilize antidotes to reverse sexual side effects (eg, bupropion or sildenafil for SSRI-induced sexual dysfunction). Of note, no medication is Food and Drug Administration-approved for the treatment of sexual disorders in women.

If the sexual dysfunction is due to a medical or psychiatric condition, treatment for that condition (eg, hypothyroidism, depression, vulvitis) should be optimized first. Postmenopausal women should be assessed for signs and symptoms of estrogen deficiency (ie, hot flashes, vaginal dryness) and androgen deficiency (ie, global loss of sexual desire, decreased genital sensitivity). Hormone replacement therapy (estrogen and/or testosterone) may be considered and is available in a variety of routes of administration (oral, transdermal, injection or topical). The use of estrogen replacement has been controversial in the US because of its reported association with breast cancer, stroke, and ovarian cancer. In selecting patients for estrogen replacement, the clinician should carefully consider the individual’s medical history, including history of smoking, migraine headaches, breast cancer, or stroke.

The testosterone patch is currently available for women with HSDD in Australia, Canada, and Europe. While it is known that testosterone can improve sexual desire in postmenopausal women on estrogen therapy, the question has been raised as to whether or not the testosterone patch is effective for HSDD in postmenopausal women who are not on estrogen. To answer this question, Davis and colleagues34 conducted a randomized, double-blind, placebo-controlled multisite trial. They found that for postmenopausal women with HSDD not on estrogen, 300 mcg/day of testosterone had a significantly greater improvement in the 4-week frequency of satisfying sexual episodes than those using placebo. In the US, physicians may prescribe physiologic replacement levels of testosterone for women using low doses of products that are approved for men or by referring patients to compounding pharmacies. Prior to beginning testosterone replacement, clinicians should engage patients in a thorough discussion of the risks and benefits. Potential long-term risks may include hyperlipidemia, hirsutism, clitoromegaly, voice changes, liver tumors, and transaminase dysfunction, although these side effects are generally considered dose dependent. Physiologic replacement levels of testosterone in women do not appear to have significant adverse events. A clinician may want to order a baseline fasting lipid profile before initiating testosterone, with a repeat panel in several months. Women in this age group are at increased risk of hyperlipidemia, and if these studies have not been done within the last year, then it is prudent to obtain these studies.

While many medications have been tried in the treatment of female sexual disorders, randomized controlled trials are limited, particularly in older women. Agents such as sildenafil, bupropion, prostaglandin E1, phentolamine, and others have been reported as possible treatments for female sexual disorders, in addition to medical devices such as vacuum therapy and electronic stimulation.25 Currently, there are non-hormonal medications for the treatment of low sexual desire in ongoing phase III clinical trials in the US (ie, flibanserin).

For the older woman whose sexual disorder is felt to be related to psychological issues, sex and/or marital therapy should be considered. Cognitive-behavioral techniques are replacing previously used psychodynamic models of therapy.35 Therapy often begins with psychoeducation and support, to help cultivate more positive attitudes toward sexuality in late life. The therapist may help correct “all or nothing” cognitive distortions, wherein the patient feels that if orgasm is not achieved, sex is worthless. Patients may be educated on techniques such as self-stimulation, sensate focus, and foreplay, so that the focus of sexual activity is not exclusively intercourse. For the older woman with vaginismus, psychoeducation and cognitive-behavioral therapy may be accompanied by the use of vaginal dilators of graduated sizes, allowing the woman to be in control while extinguishing the involuntary muscle contraction.29

Conclusion

As women are living longer, healthier lives, they seek to maintain sexual health and satisfaction throughout the latter decades. Many biologic and psychosocial factors uniquely affect the older woman and place her at risk for sexual dysfunction. She must overcome hormonal fluctuations, medical conditions, necessary medications, changes in intimate relationships, and a culture which equates sexiness and vitality with youth. Physicians who treat older women should be familiar with the effects of aging on the normal female sexual response cycle, as well as the biologic and psychosocial factors which impact female sexual functioning in late life. Physicians should routinely inquire about patients’ sexual functioning and satisfaction and provide an open, supportive environment in which to discuss such concerns.

Older women may experience disorders of sexual desire, arousal, orgasm, and pain. Identifying the biologic and psychosocial contributors is essential in the treatment of these disorders. Treatment in all cases should include psychoeducation and lifestyle adjustments, such as exercise, proper nutrition, sleep hygiene, elimination of alcohol and drugs, and improving communication skills among partners. Treatment should also include optimizing treatment of underlying medical and psychiatric conditions, reduction or elimination of problematic medications, and referral for sex therapy, as clinically indicated. Medications for the treatment of various sexual disorders in women are currently under investigation. Given the strong association between sexual dysfunction and quality of life,20 further research is needed in this area. Sexual dysfunction is a common, but neglected area in medicine, in particular for the older woman. PP

References

1.    Kaplan HS. Sex, intimacy, and the aging process. J Am Acad Psychoanal. 1990;18(2):185-205.
2.    Starr BD, Weiner MB. The Starr-Weiner Report on Sex and Sexuality in the Mature Years. New York, NY: McGraw-Hill; 1981.
3.    Lindau ST, Schumm LP, Laumann EO, Levinson W, O’Muircheartaigh CA, Waite LJ. A study of sexuality and health among older adults in the United States. N Engl J Med. 2007;357(8):762-774.
4.    Spector IP, Rosen RC, Leiblum SR. Sexuality. In: Reichman WE, Katz PR, eds. Psychiatric Care in the Nursing Home. New York, NY: Oxford University Press; 1996:133-150.
5.    Clayton AH. Sexual function and dysfunction in women. Psychiatr Clinics of N Am. 2003;26(3):673-682.
6.    Masters WH, Johnson VE. Human Sexual Response. Boston, MA: Little, Brown; 1966.
7.    Agronin ME. Sexual disorders. In: Blazer DG, Steffens DC, Busse EW, eds. Textbook of Geriatric Psychiatry. Washington, DC: American Psychiatric Publishing, Inc; 2004:303-317.
8.    Warnock JK. Impact of medical illness and reproductive transitions on sexual functioning in women. Mental Fitness. 2004;3(4):34-39.
9.    Altshuler LL, Cohen LS, Moline ML, et al. The Expert Consensus Guidelines. Treatment of depression in women. Postgrad Med. 2001;(Spec No):1-107.
10.    Sarrel PM. Sexuality and menopause. Obstet Gynecol. 1990;75(suppl):26S-30S.
11.    Schreiner-Engel P, Schiavi RC, Vietorisz D, Smith H. The differential impact of diabetes type on female sexuality. J Psychosom Res. 1987;31(1):22-33.
12.    Erol B, Tefekli A, Ozbey I, et al. Sexual dysfunction in type II diabetic females: a comparative study. J Sex Marital Ther. 2002;28(s):55-62.
13.    Korpelainen JT, Nieminen P, Myllyla VV. Sexual functioning among stroke patients and their spouses. Stroke. 1999;30(4):715-719.
14.    Kaiser FE. Sexual function in the older woman. Clin Geriatr Med. 2003;19(3):463-472.
15.    Addis IB, Ireland CC, Vittinghoff E, Lin F, Stuenkel CA, Hulley S. Sexual activity and function in postmenopausal women with heart disease. Obstet Gynecol. 2005;106(1):121-127.
16.    Thomas DR. Medications and sexual function. Clin Geriatr Med. 2003;19(3):553-562.
17. Sbrocco T, Weisberg RB, Barlow DH. Sexual dysfunction in the older adult: assessment of psychosocial factors. Sex Disabil. 1995;13(3):201-218.
18.    Graziottin A. The biological basis of female sexuality. Int Clin Psychopharmacol. 1998;13(suppl 6):S15-S22.
19.    Basson R. The female sexual response: a different model. J Sex Marital Ther. 2000;26(1):51-65.
20.    Laumann EO, Paik A, Rosen RC. Sexual dysfunction in the United States: prevalence and predictors. JAMA. 1999;281(6):537-544.
21.    Hayes RD, Dennerstein L, Bennett CM, Koochaki PE, Leiblum SR, Graziottin A. Relationship between hypoactive sexual desire disorder and aging. Fertil Steril. 2007;87(1):107-112.
22.    Diagnostic and Statistical Manual of Mental Disorders. 4th ed, text rev. Washington, DC: American Psychiatric Association; 2000.
23.    Warnock JK. Female hypoactive sexual desire disorder: epidemiology, diagnosis, and treatment. CNS Drugs. 2002;16(11):745-753.
24.    Figueira I, Possidente E, Marques C, Hayes K. Sexual dysfunction: a neglected complication of panic disorder and social phobia. Arch Sex Behav. 2001;30(4):369-377.
25.    DeUgarte CM, Berman L, Berman J. Female sexual dysfunction: from diagnosis to treatment. Sexuality, Reproduction, and Menopause. 2004;2(3):139-145.
26.    Berman JR, Goldstein I. Female sexual dysfunction. Urol Clin North Am. 2001;28(2):405-416.
27.    Warnock JK. Acquired, generalized, female hypoactive sexual desire disorder: I had it, I lost it, I want it back. Psychiatric Times. 2005;22(9):45-52.
28.    Reissing ED, Binik YM, Khalifé S. Does vaginismus exist? A critical review of the literature. J Nerv Ment Dis. 1999;187(5):261-274.
29.    Butcher J. ABC of sexual health: female sexual problems II: sexual pain and sexual fears. BMJ. 1999;318(7176):110-12.
30.    Sadock VA. Normal human sexuality. In: Sadock BJ, Sadock VA, eds. Comprehensive Textbook of Psychiatry. 7th ed. Philadelphia, PA: Lippincott Williams and Wilkins; 2000:1577-1631.
31.    Shifren JL, Monz BU, Russo PA, Segreti A, Johannes CB. Sexual problems and distress in United States women: prevalence and correlates. Obstet Gynecol. 2008;112(5):970-978.
32.    Warnock JK, Bundren C, Morris DW. Female hypoactive sexual desire disorder due to androgen deficiency: clinical and psychometric issues. Psychopharm Bull. 1997;33(4):761-66.
33.    Rothschild AJ. Sexual side effects of antidepressants. J Clin Psych. 2000;61(suppl 11):28-36.
34.    Davis SR, Moreau M, Kroll R, et al. Testosterone for low libido in postmenopausal women not taking estrogen. N Engl J Med. 2008;359(19):2005-2017.
35.    Rosen RC, Leiblum SR. Principles and Practice of Sex Therapy: Update for the 1990s. New York, NY: Guilford Press; 1988.

 

Dr. Kornstein is professor of Psychiatry and Obstetrics/Gynecology, executive director of the Institute for Women’s Health, and executive director of the Mood Disorders Institute at Virginia Commonwealth University in Richmond.

Disclosure: Dr. Kornstein has received research support from AstraZeneca, Boehringer-Ingelheim, Bristol-Myers Squibb, the Department of Health and Human Services, Eli Lilly, Forest, the National Institute of Mental Health, Novartis, Pfizer, sanofi-aventis, Sepracor, Takeda, and Wyeth; has served on the advisory boards of Bristol-Myers Squibb, Eli Lilly, Endo Pharmaceuticals, Forest, Neurocrine, Pfizer, Sepracor, Takeda, and Wyeth; and has received book royalties from the Guilford Press.

Please direct all correspondence to: Susan G. Kornstein, MD, Virginia Commonwealth University, Department of Psychiatry, PO Box 980710, Richmond, VA 23298-0710; Tel: 804-828-5637; Fax: 804-828-5644; E-mail: skornste@vcu.edu.


 

This issue highlights various clinical concerns in women’s mental health. The articles encompass a broad range of topics in women’s health across the life span, from obesity and psychotropic medication use during lactation in reproductive-age women to the comorbidity of depression and cardiovascular disease and management of sexual dysfunction in older women.

Almost 50% of American women are obese. Obesity has detrimental effects on fertility as well as pregnancy outcomes. Psychiatric disorders, such as eating disorders and mood disorders, often have effects on weight, including weight gain and nutritional status during pregnancy and postpartum weight retention. Kelly C. Allison, PhD, and colleagues review the relationship between obesity, psychopathology, and reproductive functioning—including fertility, pregnancy, and the postpartum period—as well as psychological aspects of polycystic ovarian syndrome.

Clinicians are often asked to assist postpartum women with decisions regarding the use of psychotropic medications while breastfeeding. The United States Food and Drug Administration is proposing changes to the pregnancy and lactation subsections of medication labeling that will eliminate the five pregnancy categories (A, B, C, D, and X) and replace them with a summary of the risks in pregnancy and lactation and a discussion of the data to support those risks. Madeleine A. Becker, MD, and colleagues provide a review of postpartum psychiatric conditions and summarize the existing safety data for the most commonly used psychotropics during lactation, including antidepressants, antipsychotics, benzodiazepines, and mood stabilizers.

Cardiovascular disease is the most common cause of death among women and represents an additional vulnerability and a compounded burden of illness for women with chronic mental illness. Valerie H. Taylor, MD, PhD, FRCPC, and Claudio N. Soares, MD, PhD, FRCPC, explore issues in the management of cardiovascular disease in women with depression. They examine the increased risk for cardiovascular disease in depressed women and the potential mechanisms by which hormonal factors, obesity, metabolic syndrome, and inflammatory processes may contribute to this risk. They also discuss the negative impact of depression on both risk and long-term outcome of cardiovascular disease.

An often neglected area in the care of older women is that of sexual dysfunction, which occurs in >30% of women and can significantly impact quality of life. Kirsten M. Wilkins, MD, and Julia K. Warnock, MD, PhD, discuss the assessment and treatment of female sexual dysfunction in late life. They review the effects of aging on the normal female sexual response cycle, as well as biologic and psychosocial factors that affect female sexuality. They also provide an overview of common female sexual disorders, including hypoactive sexual desire disorder, female sexual arousal disorder, female orgasmic disorder, and sexual pain disorders such as dyspareunia and vaginismus. They stress how important it is for clinicians to routinely ask their patients about sexual functioning and satisfaction, and note that several new medications for the treatment of sexual disorders in women are currently under investigation.

I want to express my appreciation to the authors for their contributions to this issue and for their work in expanding our knowledge of women’s mental health. I hope that clinicians will find these articles useful in their practice as they evaluate and treat women patients and that they will be stimulated to develop further interest in the field. PP

 

Dr. Taylor is assistant professor in the Department of Psychiatry and Behavioral Neuroscience at McMaster University in Hamilton, Ontario, Canada. Dr. Soares is academic head of the Mood Disorders Division and associate professor in the Department of Psychiatry and Behavioural Neurosciences at McMaster University, as well as director of the Women’s Health Concerns Clinic at St. Joseph’s Healthcare Hamilton.

Disclosure: Dr. Taylor is a consultant to sanofi-aventis; is on the speaker’s bureaus of Allergan, AstraZeneca, and sanofi-aventis; has received grant support from the Canadian Institute of Health Research, the Center for Minimally Invasive Surgery, the Community Health, Education, and Research Fund, the National Alliance for Research on Schizophrenia and Depression, the Ontario Mental Health Foundation, and the Society of American Gastrointestinal and Endoscopic Surgeons; and has received funding from Novartis and sanofi-aventis. Dr. Soares is a consultant to Bayer, Concert, Sepracor, and Wyeth; is on the speaker’s bureaus of AstraZeneca, Lundbeck, and Wyeth; and receives research support from Allergen, NCE, AstraZeneca, the Canadian Institute of Health Research, Eli Lilly, the Hamilton Community Foundation, the National Alliance for Research on Schizophrenia and Depression, and Physicians Service Incorporated.

Please direct all correspondence to: Valerie H. Taylor, MD, PhD, FRCPC, Assistant Professor, Department of Psychiatry and Behavioral Neuroscience, McMaster University, 1280 Main St West, Hamilton, Ontario L8S4L8, Canada; Tel: 905-522-1155, ext. 35410; Fax: 905-575-6029; E-mail: taylorv@mcmaster.ca.


 

Focus Points

• Women are more likely to suffer from major depressive disorder (MDD) than men; cardiovascular disease (CVD) is the largest single cause of death among women, accounting for 33% of all deaths.
• The heightened prevalence of MDD and CVD result in a compounded burden of illness among women; nonetheless, few studies have explored the potential role of gender differences for the development and management of CVD among depressed patients.
• The prevalence of CVD in MDD female patients appears to be modulated by hormone changes and different inflammatory response across the reproductive life cycle.
 

Abstract

Worldwide, cardiovascular disease (CVD) is the largest single cause of death among women, accounting for 33% of all deaths. In many countries, more women than men die every year of CVD, highlighting the unique aspects of risk factor management of CVD in women. Major depressive disorder is also an illness that affects women more often than men; thus, cardiovascular conditions among patients with chronic mental illness such as depression represent an additional vulnerability and a compounded burden of illness for women. Clinical and hormonal changes that occur during pregnancy and the postmenopausal period also represent life events that require specific attention and represent a time of heightened vulnerability for both mood disorders and CVD risk. This article addresses the role of gender in risk stratification and in the responsiveness to preventive interventions for CVD in women with depression. Moreover, it reviews existing evidence on sex hormones as modulators of biomarkers and clinical measures of CVD in depressed patients.

Introduction

Coronary heart disease (CHD), stroke, and peripheral vascular disease all contribute to overall mortality rates attributed to cardiovascular disease (CVD); despite significant efforts in disease prevention, CVD remains a major health concern in the developed world. It kills one in every five individuals1 and remains the leading cause of death in the United States and most developed western countries. CVD is also the largest single cause of death among women.2 In many countries, including the US, more women than men die every year of CVD.2,3 While most of the attention remains focused on more “traditional” female diseases such as breast cancer, many more women die from CVD than from breast cancer (1 in 2.6 versus 1 in 30, respectively).

Major depressive disorder (MDD) is more commonly diagnosed in women.4 The occurrence of cardiovascular events in patients with chronic mental illness such as depression may, therefore, represent a compounded burden for women both in terms of disease prevalence and access to treatment. Gender seems not only to predispose women with depression to the development of CVD, but also to influence the occurrence of MDD in women with heart disease. For example, recent data suggest that young women may be at particularly high risk for depression after an acute myocardial infarction.5

Overall, patients with MDD die earlier than those without mood disorders from a variety of physical illnesses, and mortality data among patients with mood disorders from as early as 1916 has documented this increase.6,7 A 4-decade study found excess mortality for manic and depressed patients of both genders, with the increase in mortality being most prominent in the first 10 years post admission due to a mood episode. A population-based study of the specific mortality ratios (SMRs) for patients with MDD or bipolar disorder from 1973–1995 found that SMRs for all natural causes of death were 1.9 for males and 2.1 for females with bipolar disorder, and 1.5 and 1.6 for MDD, respectively.8 A meta-analysis that examined excess mortality in MDD found an increased relative risk for depressed subjects to die compared to non-depressed subjects (1.81, 95% CI: 1.58–2.07).9 A large component of this increased mortality risk is attributed to CVD.8 Among women with MDD, CVD is responsible for more deaths than suicide.8 Existing data suggest that the pathophysiology of the mood disorders and its contribution to the relative risk of cardiovascular events and heart failure may be affected by gender, which might be of potential relevance for the prevention, diagnosis, and therapy of these conditions.

Metabolic Syndrome in Women with MDD

A partial explanation for increased CVD in women in general and in particular among women with mood disorders is the heightened vulnerability in this population for the development of metabolic syndrome (MeS). MeS is defined by a cluster of risk factors that ultimately contribute to CHD.10 By definition, MeS requires the presence of any three of the following five criteria: central obesity (waist circumference >102 cm [>40 in] in men, >88 cm [>35 in] in women); elevated triglycerides (>150 mg/dL [>1.7 mmol/L] or specific treatment for this lipid abnormality); raised blood pressure (BP; systolic BP >130 or diastolic BP >85 mm Hg, or treatment of previously diagnosed hypertension); raised fasting glucose (>100 mg/dL [>5.6 mmol/L] or treatment for type 2 diabetes); and reduced high density lipoprotein (HDL) cholesterol (<40 mg/dL [<1.03 mmol/L] in males, <50 mg/dL [<1.3 mmol/L] in females or specific treatment for this lipid abnormality).11 People with MeS are twice as likely to die from, and three times as likely to suffer, a heart attack or stroke. They have up to a nine-fold greater risk of developing type 2 diabetes, compared with people without the syndrome.12-14 Given that up to 80% of the 200 million people with diabetes globally will possibly die of CHD, MeS and diabetes now rank ahead of HIV/AIDS in worldwide morbidity and mortality.15

Approximately 40% of the adult population in the US meets diagnostic criteria for MeS.16 A closer look at the National Health and Nutrition Examination (NHANES) III data that was obtained between 1984–1998, compared to the NHANES 1999–2000 results, reveals a greater increase in MeS prevalence in women. Young women (20–39 years of age) seem especially vulnerable, with a 78% increase in prevalence, compared to a non-significant 5% increase in men in this age group.17 Data on 728 women from the Women’s Ischemic Syndrome Evaluation study18 showed that MeS was strongly associated with angiographic coronary artery disease and conferred an approximate two-fold adjusted risk of death and major adverse cardiac events.

In the Atherosclerosis Risk in Communities study,19 a total of 12,809 individuals who did not have diabetes or CVD at baseline were followed for an average of 11 years. Men and women with MeS were 1.5–2.0 times more likely to develop CHD than individuals who did not have MeS after adjustment for age, smoking status, low-density lipoprotein cholesterol, and race. In addition, the risk of CHD associated with the MeS was significantly higher in women (crude hazard ratios [HRs]=2.55) than in men (HRs=1.51).

In the San Antonio Heart Study,20 the cardiovascular mortality risk in subjects who had MeS was also shown to be significantly higher in women than in men, although the gender differences seen in cardiovascular mortality were only significant in individuals who had both MeS and type 2 diabetes. This association between type 2 diabetes and fatal CHD was also examined in a recent meta-analysis21 that showed a relative higher risk in women compared to men. The subgroup analysis of two recently published meta-analyses22,23 also indicate that the MeS might be a stronger risk factor for CVD in women than in men (relative risk=2.10 vs. 1.57,22 and 2.63 vs. 1.98,23 respectively).

Many of the physical illnesses linked to MeS occur at high rates in patients with mood disorders and may represent the expression of overlapping pathophysiologies linking these illnesses. The association between MeS and mood disorders, however, remains controversial due to conflicting data.24,25 These discrepancies might be due to differences in methodology (longitudinal vs. cross-sectional), or type of population studied (age, presence or absence of associated cardiovascular risk factors, history of MDD). A potential confounder appears to be the role of gender differences. While the majority of studies addressing the association between mood disorders and MeS indicated a relationship between the two conditions, those that were unable to find a correlation between the two conditions did find a relationship between women with mood disorders and MeS when populations were divided by gender.24,25

This highlights the need to explore the potential role of gender differences for the development and management of CVD among depressed patients and to target female sub-populations during periods of heightened vulnerability for both CVD and MDD (eg, the menopausal transition).26,27

The Contribution of Obesity to CVD in Women with MDD

A key variable linking mood disorders with CVD is obesity. Obesity is associated with increased risk of all-cause mortality and, in the general population, obesity and its associated metabolic and cardiovascular complications represent a significant contribution to premature death.28,29 This relationship is especially relevant to the field of mental health. People with mood disorders are at higher risk for obesity in part due to a complex interplay of factors that include unhealthy lifestyle choices, reduced energy expenditure and increase in consumption of palatable energy-dense foods, unwanted effects of pharmacotherapy, and, ultimately, poorly understood biologic factors.

The amount of weight gain in patients with a mood disorder may not be the only factor linked to an increase in morbidity from obesity-related diseases; another factor may be the increased amount of centrally deposited adipose tissue. Abdominal fat distribution consists of two discrete depots, subcutaneous adipose tissue (SAT) and visceral (intra-abdominal) adipose tissue (VAT). These patterns of body fat distribution predict CVD better than total body fat volume.30,31 A measure of VAT, the waist to hip ratio, is positively associated with increased blood pressure, increased triglycerides, and decreased HDL cholesterol.32 This association is of particular relevance for women with mood disorders as a recent study that investigated this relationship in premenopausal women showed that the depression was associated with VAT, not SAT.33 It has been speculated that these findings may, in part, explain the association between depression and CVD in this population as the reduced tendency to accumulate fat within the intra-abdominal sites may be one of the primary metabolic differences underlying the reduced risk of cardiovascular disease, metabolic syndrome, and diabetes in women.34 Normally, premenopausal women more frequently develop peripheral obesity with SAT, whereas men and postmenopausal women are more prone to VAT. After menopause, concentrations of lipoproteins as well as body fat distribution shifts to a more male pattern. Postmenopausal women have an increased tendency of visceral fat deposition, which by virtue of its proinflammatory and prothrombotic properties, contribute to their risk of developing MeS and CVD.35

The Role of Inflammation

Women are more susceptible than men to obesity in general; presently, 2 million more women than men have a body mass index >30.36 Obesity predisposes individuals to an increased risk of developing many diseases, including atherosclerosis, diabetes, non-alcoholic fatty liver disease, certain cancers, and immune-mediated disorders such as asthma.37-39 Part of this increased vulnerability is related to the ability of adipose tissue to function as an endocrine organ and secrete a wide range of hormones. Among the soluble mediators derived from adipocytes (fat cells) are leptin, adiponectin, and resistin, all of which are considered to play a role in the regulation of energy metabolism.40-42 Obesity is also associated with a chronic inflammatory response characterized by abnormal cytokine and adipokine production, increased synthesis of acute-phase reactants, and the activation of pro-inflammatory signaling pathways. Inflammation plays an essential role in the development of insulin resistance and type 2 diabetes, the initiation and progression of atherosclerotic lesions, and plaque disruption.43

Mood disorders are also associated with the production of pro-inflammatory cytokines that influence CVD, and some studies suggest that depression promotes an inflammatory process. The most compelling evidence of this derives from studies that have ameliorated depressive symptoms through psychotherapy and found corresponding declines in the magnitude of inflammation markers.44 Conversely, inflammatory processes contribute to depression and exposure to inflammatory mediators produces a constellation of behaviors (eg, hyposomnia, anhedonia, anorexia) that resemble depressive symptoms.45,46 Existing literature links mood disorders and inflammatory markers; several cytokines that are elevated in individuals with MDD and bipolar disorder, including IL-6 and C-reactive protein (CRP), predict cardiac morbidity and mortality,47,48 while an association between adiposity and elevated Il-6 and CRP levels has been suggested in clinically depressed individuals.49 Woman seem especially vulnerable to the risks posed by inflammation. In an analysis of women participating in the Nurses’ Health Study, high levels of Il-6, tumor necrosis factor-a, and CRP were significantly related to an increased risk of CHD.50 These findings supported the results from the Women’s Health Initiative study, demonstrating white cell count and CRP as the strongest predictors for cardiovascular morbidity and mortality in postmenopausal women.51 The combination of increased central obesity and chronic low-grade inflammation appears to be a mechanism for the pathogenesis of CVD.52

Variables other than weight also play a role in inflammation in women. Sex steroids may influence inflammatory processes and hence modify cardiovascular risk. Raised levels of CRP, homocysteine, lipoprotein(a) (Lp-a), and IL-6 are each independently associated with increased risk for cardiovascular events in women. While changes in these parameters across the menopausal transition cannot clearly be attributed solely to hormonal changes, endogenous sex steroid levels and exogenous hormone therapy seem to exert a modulatory effect. Elevations of the amino acid homocysteine, which is associated with arterial and venous thromboembolic disease, and Lp-a, a known independent risk factor for the development of atherosclerosis, occur with age and/or menopause,53,54 while CRP and IL-6 appear to be influenced by endogenous sex steroid levels and exogenous hormone therapy.55,56

Prevention

It was noted with the recently updated guidelines on prevention of CHD in women that healthcare professionals should focus on women’s lifetime heart disease risk and not just on short-term risk.2 The guidelines emphasized that prevalence of CHD in women is such that nearly all women should be considered at risk for atherosclerosis. Prevention of CVD is paramount to the health of women and even modest control can have significant impact. Fortunately, most CVD in women is preventable, if recognized. Even the presence of a single risk factor at 50 years of age is associated with a substantially increased lifetime absolute risk for CVD and shorter duration of survival.57 With few exceptions, such as the use of aspirin for primary prevention of heart disease in women >65 years of age,58 recommendations to prevent CVD in women do not differ from men.2 However, there are certain circumstances in which prevention strategies or interventions should be individualized.

Hormone replacement therapy (HRT) is not recommended for either primary or secondary prevention of CVD, particularly in women in their late postmenopausal years.59 Estrogen deficiency leads to an unfavorable lipid profile,60 which until recently had been considered the main pathologic phenomenon responsible for development of atherosclerosis and CHD. However, improvement in lipid profile with HRT does not reduce cardiac disease events in clinical studies.61,62 It remains controversial whether different estrogen therapies would offer a better risks/benefit ratio when administered via different pathways or to younger versus older sub-populations of menopausal women.62

The efficacy of non-pharmacologically based treatments in women also needs further evaluation. Data suggest that women with CVD respond differently than men to psychological treatments. Subgroup analyses of the Enhancing Recovery in Coronary Heart Disease Patients trial showed a significant treatment by sex interaction on cardiovascular outcomes, suggesting a protective effect of cognitive-behavioral therapy in men, but a tendency for harm in women.63 These results mirrored those of an earlier study, the Montreal Heart Attack Readjustment Trial (M-HART), which tested the effect of a nurse-based psychosocial support intervention at home for distressed patients after myocardial infarction.64 The M-HART program had no overall impact on cardiac or all-cause mortality over the year. However, separate preplanned comparisons in men and women revealed two times the odds of cardiac and all-cause mortality in treated women compared with control women, while there was no impact in men. Altogether, these data suggest that women and men respond differently to psychological interventions and highlight the importance of performing gender-specific analyses. At the very least, gender-based stratification should be better planned in future studies to allow sufficient power to examine gender-related differences. A more targeted emphasis could also be placed on prevention programs based on gender. In a US study65 designed to examine the extent to which modifiable lifestyle behaviors are associated with the risk of having MeS, MeS was associated with physical inactivity in overweight men and in normal weight and overweight women, suggesting a high protective value of physical exercise in women.

Gender biases in the diagnosis and management of women with CVD also plays a role in the outcome of this illness,66 and this is compounded by the stigma associated with mental illness. During the past several decades, CVD mortality has markedly declined in the US, from >50% to approximately 36% as the underlying cause of death.1 Recent data suggest that the decline is largely due to improved diagnosis and treatment rather than to major successes in primary prevention. In contrast, patients with severe mental illnesses,67 lose ≥25 years of life expectancy, with the majority of the excess premature deaths due to CVD.68 There is now a sufficient consensus that depression is a risk factor for CHD as well as an important prognostic factor in cardiac patients. Nonetheless, <50% of depressed medical patients are recognized by their physicians, and recognition has only mildly increased in the last 10 years.69 During an admission for acute myocardial infarction, <15% of patients with depression are identified,70 and evaluation and treatment of depression continue to be mostly ignored during routine cardiac care.71

Conclusion

Knowledge of the unique aspects associated with the management and occurrence of CVD in women has improved significantly in the last few years, and there is now acknowledgement that gender is a confounder that needs to be addressed appropriately (Figure).

 

 

 

 

The additional risk conferred by MDD both to CVD risk and its impact on long-term outcome also needs to play a role in risk stratification and management. This way, we may hope to decrease the mortality attributed to this illness in women. PP

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This interview took place on December 17, 2008, and was conducted by Norman Sussman, MD.

 

This interview is also available as an audio PsychCastTM at http://psychcast.mblcommunications.com.

Disclosure: Dr. Alexopoulos receives research support from Dainippon Sumitomo Pharma and UCB S.A.; and is on the speaker’s bureau of Pfizer.


 

Dr. Alexopoulos is staff physician in the Epilepsy Center of the Neurological Institute at the Cleveland Clinic in Ohio. Previously, he served as chief resident in adult neurology at the Mount Sinai School of Medicine in New York City. Dr. Alexopoulos has twice received the Cleveland Clinic’s World Class Service Recognition Award. He is a member of the American Epilepsy Society, the Society of Neuroscience, and the American Clinical Neurophysiology Society, among others. His specialty interests include epilepsy, clinical neurophysiology, and translational research in epilepsy.

 

Why did you focus your clinical and research work on epilepsy?

Epilepsy is a unique model disease that allows us to examine human brain function on different levels. While I understand this statement now, it was an intuitive attraction thought led me to the field early on. Epilepsy stands exactly at the border between neurology and psychiatry; the study of it unifies two of my main interests in brain and behavior relationship. My other two interests are in neuroimaging and neurophysiology of the central nervous system, subspecialties that also play a central role in the practice of epileptology and related research work.

What are the biggest changes in our understanding of epilepsy and its treatment?

In terms of diagnostic developments that can help us in treatment, there is a tremendous advancement in technology. High-resolution imaging with post processing of magnetic resonance imaging is very helpful for studying the brain of patients with epilepsy. Digital long-term video electroencephalograph (EEG) monitoring has become increasingly available. Functional imaging studies and advanced neurophysiologic techniques are in development or in use now. Patients with medically refractory epilepsy may be candidates for surgical therapy. Epilepsy surgery itself has become more widely accepted as an effective and potentially curative means of treatment.

Currently available medications more or less suppress seizures and are targeted toward relieving symptoms. However, we do not yet have disease-modifying therapies for epilepsy. Therefore, understanding the pathophysiology and mechanisms of epileptogenesis is extremely important. Much work is being conducted in the laboratory, including using in vitro and in vivo models in animal studies, that needs to be translated to the human condition.

The other aspect is better understanding of pharmaco-resistance in intractability. Why do people present or develop intractable epilepsy in the course of their disease? Interestingly, intractability is not particular to epilepsy; there is intractability in psychiatry, with treatment-resistant depression (TRD) and treatment-resistant psychosis, as well as in other medical diseases. Thus, shared mechanisms have been postulated. We are developing animal models that are specifically geared toward intractable epilepsies, because the way we have been screening antiepileptic medications so far has not taken into account the sizeable and challenging population of patients with medically refractory epilepsies. Clearly, this is an area where we need to focus more.

There have also been developments in the public health of epilepsy, ie, in dissolving the stigma, educating the public mind, and disseminating knowledge about the condition. There is also more understanding in areas that border epilepsy, such as psychogenic non-epileptic seizures. The National Institutes of Health (NIH) organized two meetings in the last decade to review and update needed benchmarks for epilepsy research. The most recent 2007 benchmarks for epilepsy research are accessible at the NIH Website.1

Is there a delay in some people being diagnosed with epilepsy?

Yes, there is a significant delay. Excellent psychiatrists and neurologists may miss the diagnosis. Epileptologists, however, have the advantage of access to a surrogate clinical marker­—the EEG. More importantly, now we have access to continuous video EEG recordings, which are geared toward capturing the patient’s typical spell and characterizing the correlate on the EEG at the same time. That helps diagnostically, especially with atypical spells and other paroxysmal behaviors that cannot be classified based on history alone.

Depending on the type of seizures, the delay to the diagnosis is variable. Patients with more commonly understood seizures, such as generalized tonic-clonic seizures, usually receive proper diagnosis early on. However, delay in diagnosis can be significant for complex partial or simple partial seizures. Often, families, caretakers, or even patients are not aware of the patient’s seizures. Episodes in children may be misconstrued as daydreaming. The same applies for the elderly, who may present with new-onset seizures. In fact, the incidence of epilepsy has a bimodal distribution in the very young and the very old. Spells in the elderly may be difficult to diagnose. They do not exactly follow the book. It may take several months (on average 1–2 years) to identify these cases of epilepsy.

Once the diagnosis is made, appropriate treatment must be instituted. Unfortunately, in approximately one-third of patients diagnosed with epilepsy, medications will not work well or will be associated with unacceptable side effects. Therefore, seizures are not well controlled, even if the patient is quite adherent to the prescribed treatment. There is a tremendous delay from the time of the diagnosis to the time that intractability is recognized. Thus, it is important to identify these patients early on. These patients need to be referred to fourth-level epilepsy centers where comprehensive evaluations can be conducted. If they are surgical candidates, epilepsy surgery can be offered early on in the course of the patient’s epilepsy. This is important because of the detrimental effects of uncontrolled seizures, in terms of quality of life, lack of independence, and progression of disease.

Other common type of spells, the so-called “psychogenic nonepileptic seizures,” are often mistaken for seizure-like activity. However, the pathophysiology between psychogenic seizure and epileptic seizure is fundamentally different. Misdiagnosis is quite common, and patients are often subjected to long-term treatment with antiepileptic medications and unneeded side effects. Potentially harmful interventions, including intubation and pharmacologically induced coma, have also been reported in a subset of these patients for so-called non-epileptic seizures.

When a patient is evaluated with an EEG or continuous monitoring, is diagnosis based exclusively on clinical aspects?

When confronted with a potential diagnosis of psychogenic nonepileptic seizures, the gold standard is to refer the patient early on for video EEG recording. This is cost effective as it can avoid many years of unnecessary treatment. Video EEG is useful in making the correct diagnosis, but there may be uncertainty at times. For example, if the patient comes into the monitoring unit and stays there for 1 week and the typical episode is not captured, the physician must go by the history and available information. If the patient has episodes that lead to loss of consciousness, even if these are really nonepileptic, restrictions in the patient’s lifestyle related to seizure precautions must be applied, including driving restrictions.

On other occasions, a patient may exhibit a paroxysmal behavior but there is no signature of seizure activity on the EEG. Then the behavior has to be analyzed systematically by looking at the video of the episode, which can either be recorded in the hospital or at home. These videos must be reviewed by experienced interpreters, who will focus on the pathophysiologic underpinnings and evolution of recorded manifestations. Thus, documentation of seizures can be made even in the absence of any EEG abnormalities or when EEG is inconclusive. It is important to remember here that the diagnosis of epilepsy is first and foremost a clinical one that relies heavily on a careful history and description of the  patient’s spells. EEG is a quite helpful tool, but needs to always be viewed from within the clinical context. In addition, we are interested in developing screening questionnaires that can be available to primary care physicians so that they are attuned to the possibility of nonepileptic seizures. These screening instruments would also suggest when a patient should be referred for video EEG evaluation.

Is there a scientific basis for the United States Food and Drug Administration labeling all antiepileptic drugs with a suicide warning?
I think there are several criticisms about the methodology and results of the meta-analysis conducted by the FDA, pooling data from 200 clinical studies of several antiepileptic medications, which were studied not only in patients with epilepsy, but rather in a number of heterogeneous conditions (eg, treatment of chronic pain, migraine, and psychiatric indications such as anxiety and bipolar disorder). Currently, I believe the FDA is trying to come up with a class warning for all antiepileptics because some were not included in their initial warning in 2008.

However, the issue is more complex than what appears at the surface. For example, psychiatrists are also familiar with warnings that relate to the initial introduction of antidepressants and the relationship to suicide. Depression is a very common comorbidity in patients who have epilepsy. Depression and epilepsy share common pathophysiologic mechanisms. In adults, epilepsy commonly arises from the limbic system, which is at the center of mechanisms that control emotions and that may underlie depression. In addition, uncontrolled seizures, their unpredictability, and restrictions related to seizures also create a significant burden and frustration in patients. There is also the stigma associated with epilepsy that can have major psychosocial implications.

I would think that ~50% or more of our patients attending the outpatient epilepsy clinic at a tertiary epilepsy center have comorbid mood disorders. Recently, we have instituted screening methods where all of our patients are asked to complete questionnaires, including a suicide screen, a patient healthcare questionnaire, and a depression severity questionnaire. This occurs before medication is prescribed. Rarely a full day at the epilepsy clinic goes by without encountering a patient with a moderate to severe depression based on these measures. Ever so often one of these patients will present with a high risk of suicide, as assessed by suicidal ideation in the past 3 months or prior suicide attempt at any time, and positive responses to emotional items that are consistent with serious depression. Thus, screening for suicide and discussing it openly with patients is extremely important. In this respect, I think that the FDA warning may in fact help clinicians pay more attention to this important facet of epilepsy care. It is increasingly recognized that the impact of comorbid psychiatric conditions like depression and anxiety on quality of life can be worse than the effect of epilepsy. Lastly, I should emphasize that non-adherence to antiepileptic drug therapy can lead to a significant increase in accidents and deaths. This fact is well-documented, and therefore treatment with antiepileptic medications should not be withheld even in patients with suicidal risks. Rather, these patients should be managed closely by both neurology and psychiatry. Good communication between the treating neurologist and psychiatrist is essential.

Is suicide screening as a mode for suicide prevention effective?

I wish it were. However, it does make clinicians more sensitive to the existence of an underlying mood disorder in patients who voice their frustration and feelings about suicide. Being acutely suicidal upon screening merits immediate referral to a psychiatrist who initiates appropriate treatment. Many of our patients with epilepsy also receive treatment with antidepressants. It is of course important to understand the need for concurrent antidepressant therapy because even if the seizures are controlled, the quality of life, in general, is not improved unless the mood is also improved.

Given that several of the anticonvulsants are also effective in treating bipolar disorder, do bipolar disorder and epilepsy share a common pathophysiology?

One possibility why these medications have efficacy in both conditions is that these conditions have a shared underlying pathophysiology. Further, the biochemistry, neurotransmitter, or network abnormalities in both conditions can be modified by the same medical interventions. Take electrical stimulation, for example, which is being explored not only for epilepsy but also for mood disorders and other psychiatric and neurologic conditions. Organic psychiatry plays an important role in understanding and treating these conditions.

However, It should also be remembered that medications that are effective in the treatment of epilepsy have a variety of mechanisms of action. Few, if any, antiepileptics have a single well-characterized action that targets the expression of abnormal hyperexcitability and/or hypersynchrony. Although rational development of antiepileptics is a desirable goal, it should be recognized that most medications currently on the market are not the product of rational drug design. Most available antiepileptics have multiple and unknown mechanisms of action. Even in cases where we have been able to identify the relevant molecular target or pathway, we still cannot exactly explain how modulation of this pathway can result in seizure suppression.

Is vagus nerve stimulation (VNS) effective in treating epilepsy?

When seizures are not well controlled we often rely on combination therapy. By increasing doses and adding more medication the burden of side effects is inevitably high. Thus, development of nonpharmacologic treatments is important. VNS has been a welcome addition to our armamentarium in treating epilepsy, though it is intended for the treatment of medically refractory epilepsy. The premarketing data that led to FDA approval of VNS were fairly convincing, though more systemic and control studies are needed for VNS treatment in TRD.

Approximately one-third of patients with epilepsy will derive an appreciable benefit from VNS, but it has not been possible to predict, before implantation, which patients will benefit. Therefore, prior to VNS implantation, it is important to conduct a thorough preimplantation workup. This should be done by physicians who are used to evaluating treatment-resistant epilepsy. The same should apply for patients with TRD, and I would think that a similar approach would be necessary for patients with TRD, although I have no personal experience with the use of VNS in this patient population.

In our practice, we first need to confirm that the diagnosis of epilepsy is correct. I sometimes see patients with nonepileptic seizures who have already had a VNS implanted. This is, of course, inappropriate and results in poor utilization of our resources. Before implanting the VNS we need to establish that there are no other curative options available for this patient. For example, the a patient may be a candidate for potentially curative resective epilepsy surgery. VNS, in contrast, may be beneficial but rarely eliminates seizures long-term; therefore, it is considered more of a palliative intervention. There may be an additional benefit in terms of mood, attentiveness, and overall cognitive function, independent of seizure control. Lastly, VNS for the treatment of epilepsy is attractive because it is less invasive compared to direct or deep brain stimulation. At this time, studies are ongoing to examine the utility of electrically stimulating other brain targets for the treatment of intractable epilepsy, as well as TRD. Deep brain stimulation for epilepsy may be around the corner.

At the recent annual meeting of the American Epilepsy Society in December 2008, the results of a prospective, randomized, double-blind study2 examining the effectiveness of bilateral deep brain stimulation of the anterior nucleus of the thalamus were released. The Stimulation of the Anterior Nucleus of the Thalamus in Epilepsy study showed that stimulating the left and right anterior nucleus of the thalamus produced a modest, but statistically significant median percent reduction in seizures compared to a no stimulation control group at the end of the blinded phase of observation. These results have not yet been published.

Another device-based trial for the treatment of epilepsy is currently ongoing. This study utilizes a responsive brain stimulation approach to directly target/stimulate the putative epileptogenic focus. Enrollment in this study was just completed; results should be anticipated sometime in 2010 after completion of the blinded period of observation for all enrolled subjects.

What are the major side effects of VNS?

Stimulation-related side effects occur only at the time of stimulation, such as hoarseness, discomfort in the throat, shortness of breath, changes in speech, and coughing. These are usually self-limited and can also be modified by changing the parameters of stimulation. There are no known major side effects. However, it should be pointed out that long-term studies are lacking because VNS for epilepsy was only approved in the US the past decade.

There are situations where VNS may not be ideal. For one, VNS may worsen obstructive sleep apnea; the manufacturer also recommends that the device should be used with caution in patients with underlying pulmonary diseases like chronic obstructive airway disease. There are also safety issues related to MRI, where the VNS scan must only be conducted under specific conditions, with the device turned off, and with the use of specific coils and MRI sequences, which are known to be safe in this setting. This remains a problematic issue, especially for patients who have a chronic condition and may need sequential imaging. That is a mojor issue; that is, at least until the technology advances and MRI-compatible devices become available. PP

References

1.    National Institute of Neurological Disorders and Stroke. 2007 NINDS Epilepsy Research Benchmarks. Available at: www.ninds.nih.gov/research/epilepsyweb/2007_benchmarks.htm. Accessed January 13, 2009.
2.    ClinicalTrials.gov. SANTE – Stimulation of the Anterior Nucleus of the Thalamus for Epilepsy. Available at: http://www.clinicaltrials.gov/ct2/show/NCT00101933?term=sante=2. Accessed February 4, 2009.

 

Dr. Richa is psychiatrist at the Psychiatric Hospital of the Cross in Lebanon. Dr. Baylé is professeur des Universités-Praticien Hospitalier at Paris-Descartes University in France. Dr. Loo is professor at Sainte-Anne Hospital at Paris-Descartes University.

Disclosure: The authors report no affiliation with or financial interest in any organization that may pose a conflict of interest.

Please direct all correspondence to: Sami Richa, MD, Hôpital Psychiatrique de la Croix, PO Box 60096, Jall-Eddib – Metn, Lebanon; Tel: 011-9613225960; Fax: 011-9611892700; E-mail: samiric@idm.net.lb.


 

Focus Points

• Niemann-Pick disease (NPD) could be associated with a psychiatric disorder.
• Psychiatric symptoms without neurologic impairment may be a manifestation of NPD.
• Psychiatric disorder found in NPD type B could be schizophrenia.
• The mechanisms underlying psychiatric disturbance are unknown.

 

Abstract

The following is a case of Niemann-Pick disease (NPD) type B associated with a psychiatric disorder. A 27-year-old male was admitted to the hospital with Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition–Text Revision criteria for paranoid schizophrenia. He was ameliorated after initiation of treatment by amisulpiride 400 mg/day. Auditory hallucinations, persecutory delusions, depersonalization, and derealisation regressed and was able to work. He was followed up for >10 years. The patient had typical history of NPD type B (hepatosplenomegaly and pulmonary infiltrates) diagnosed at 3 years of age.

Introduction

Niemann-Pick disease (NPD) is an inborn error of lipids metabolism. In types A and B, there is a clear deficiency of sphingomyelinase, resulting in widespread lysosomal deposition of sphingomyelin liquid crystals. The most common disorder (type A) begins shortly after birth with hepatosplenomegaly, failure to thrive, neurologic impairment, and early death. The adult form (type B) is a relatively benign disorder with hepatosplenomegaly and pulmonary infiltrates, and is characterized by the sparing of brain involvement.1

Some authors report adult cases of NPD type B with neurologic and/or psychiatric symptoms. Patients with neurologic impairment (mental retardation, cerebellar ataxia, extrapyramidal signs, or cherry red-spots) have intermediate forms between type A and type B. Sometimes, brain storage is inapparent (found at autopsy). Patients with psychiatric disorder and with NPD, without any neurologic symptoms, are excessively rare—only two cases2,3 could be found in the literature. These two cases most likely belong to type B and there could be a chance association of schizophrenia and NPD.
NPD type C is a secondary cholesterol storage disorder without sphingomyelinase deficiency. Neurologic signs are often pointed out (juvenile form) and psychosis may be the only clinical manifestation of this disease (adult form). Hepatosplenomegaly is often mild.1

Case Report

The following is a case report of NPD type B associated with a psychiatric disorder. A 27-year-old male was admitted to the hospital. He met Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition–Text Revision4 criteria for paranoid schizophrenia. He had auditory hallucinations and persecutory delusions. He also had feelings of strong depersonnalization and derealization. Since 3 years of age, he had magical thinking and ideas of reference and had reduced his social activity. There were no neurologic or intellectual impairments. He had no history of developmental disorder. There was no drug abuse. The patient had a typical history of NPD type B (hepatosplenomegaly and pulmonary infiltrates) diagnosed at 3 years of age. The sphingomyelinase activity in leucocyte extracts was at 0.10 μKat/Kg proteins (normal at 0.67±0.25). Computed tomography scan and magnetic resonance imaging revealed a slight ventricular enlargment. An electroencephalograph indicated no abnormalities. There was no ocular abormality. Motor nerves  conduction velocities were normal.

He was ameliorated after initiation of treatment by amisulpiride 400 mg/day. Auditory hallucinations, persecutory delusions, depersonnalization, and derealisation regressed and he was able to work. The patient has been followed up for >10 years.  He worsened every time he discontinued amisulpiride or reduced the posology of 400 mg/day; the relapse was on the same mode, including delusions, hallucinations, and behavioural disturbance.

This is the third case of NPD type B associated with a psychiatric disorder,3 the first which presented NPD before schizophrenia. Hepatosplenomegaly had developped before the onset of psychiatric symptoms. Complete exploration of the central nervous system revealed no abnormality. The mechanisms underlying psychiatric disturbance are unknown. The authors of this case report could make no correlation between brain damage and psychiatric symptoms.

Conclusion

Psychiatric symptoms without neurologic impairment may be a manifestation of NPD (intermediate type AB) or a chance association (type B). In this case presented, the presence of enzyme protein in fibroblasts revealed an intermediate type AB. PP

References

1.    Spence MW, Callahan JW. Sphingomyelin-cholesterol lipidoses : The Niemann-Pick Group of  Diseases. In: Scriver C, Beaudet AL, Sly WS, Valle D, eds. The Metabolic Basis of  Inherited Diseases. 6th ed. New York, NY: McGraw-Hill; 1989:1655-1676.
2.    Dubois G, Mussini JM, Auclair M, et al. Adult sphingomyelinase deficiency: report of 2 patients who  initially presented with psychiatric disorders. Neurology. 1990;40(1):132-136.
3.    Sogawa H, Horino K, Nakumara F, et al. Chronic Niemann-Pick disease with sphingomyelinase deficiency in  two brothers with mental retardation. Eur J Pediatr. 1978;128(4):235-240.
4.    Diagnostic and Statistical Maual of Mental Disorders. 4th ed, text rev. Washington, DC: American Psychiatric Association; 2000.