150 mg per individual dose), nefazodone, and venlafaxine. Table 6 (Table Not Available) lists dosage regimens for antidepressants according to class and type of disorder.BartterSite.org Home | Back to List of Magnesium Articles
Obstetrics and Gynecology Clinics
Volume 28 � Number 2 � June 2001
Copyright � 2001 W. B. Saunders Company
Departments of Pharmacy Practice and Pharmacoeconomics, Obstetrics and Gynecology, and Psychiatry, University of Tennessee Health Science Center, Memphis, Tennessee
A substantial part of the daily work of the obstetrician-gynecologist concerns the care of women with mental health problems. Although the lifetime prevalence for having a psychiatric disorder is about equal in women (30%) and men (36%), gender differences are found in particular disorders.[38] Lifetime prevalence is higher in women compared with men for panic disorder, phobic disorder, generalized anxiety disorder, obsessive-compulsive disorder, and mood disorders (Table 1) (Table Not Available) . Lifetime rates are higher in men compared with women for alcohol abuse and dependence and antisocial personality disorder. No significant gender differences are found in lifetime prevalence rates for schizophrenia or cognitive impairment.
| (Not Available) |
| From Fallon SK, Severino SK: Gender differences in psychopathology. In Wallis LA, et al (eds): Textbook of Women's Health. Philadelphia, Lippincott-Raven, 1998, p 804; with permission. |
This article focuses on depressive and anxiety disorders because of the disproportionate incidence in women as compared with men.
Depressive disorders are characterized by mood swings into protracted periods of low mood that return to normal ("euthymic") functioning. To meet the Diagnostic and Statistical Manual of Mental Disorders, edition 4 (DSM-IV) criteria for major depression, a person must have 2 weeks or more of a depressed mood or loss of interest accompanied by additional symptoms of depression.[8] Dysthymic disorder is characterized by at least 2 years of a depressed mood for more days than not, accompanied by additional depressive symptoms that do not meet criteria for a major depressive episode.[8] Depressive disorder not otherwise specified is a term used for disorders with depressive features that do not meet the criteria for major depression. An example relevant to this discussion is premenstrual dysphoric disorder.
Major depression is a cluster of psychologic and physical symptoms that endure for 2 or more weeks and that interfere with a person's ability to function or enjoy life (Table 2) (Table Not Available) .[8] Epidemiologic studies have generally found higher lifetime prevalence rates of depression[54] and dysthymia[102] in women when compared with men. The National Comorbidity Survey carried out a structured psychiatric interview of a representative sample of the general population and reported a lifetime rate of major depression of 21.3% in women and 12.7% in men,[53] producing a female-to-male ratio of 1.0 to 1.7. The lifetime history of major depression is approximately 1.7 times as common in women compared with men. A gender difference was found beginning in early adolescence and persisting through the mid-50s. Although this increased tendency for depression in women reflects a long-term trend, over the short-term, an increase has also been seen in the rate of depression among young women.[2] The highest rate occurs in adult women aged more than 44 years. The female-to-male ratio may be even higher for particular forms of depression, such as atypical depression, in which depression is accompanied by mood reactivity and at least one of the following: hypersomnia, hyperphagia, leaden paralysis, rejection sensitivity, and seasonal affective disorder.[84]
| (Not Available) |
| From Bhatia SC, Bhatia SK: Depression in women: Diagnostic and treatment considerations. Am Fam Physician 60:226, 1999; with permission. |
Genetic factors responsible for the transmission of depression do not seem to account for the higher prevalence of depression in women,[67] although they may be involved through other mechanisms that influence penetrance (e.g., through endocrine or psychosocial variables). Three different theories have been proposed to explain the predilection for depression in women. The artifact hypotheses,[102] suggests that the finding that depression is more common in women is an artifact, and that women tend to be diagnosed as depressed rather than as sustaining other disorders. It has been postulated that women perceive events to which they are exposed as having a greater impact on their lives than do men and articulate their perceptions in depressive terms. Alternatively, the greater prevalence of alcoholism diagnosed in men may mask their depression; however, alcoholism and major depression have been found to be etiologically independent.[66] Despite the fact that women are more likely to report distressing symptoms and to seek help, Weissman and Klerman[103] have convincingly refuted the premise that the increased prevalence of depression in women can be explained by methodologic error.
According to the biologic hypothesis, gender-related biologic differences explain the increased prevalence of major depression in women. As females move from girlhood through the life cycle, they are subjected to changing hormones that modulate the expression of emotions. They also experience constant internal hormonal changes over the course of the menstrual cycle and with pregnancy and delivery and in the postpartum, breastfeeding, and weaning periods. According to the biologic hypothesis, shifting hormonal levels drive affective states in women and are responsible for disorders such as premenstrual dysphoric disorder and postpartum depression. The changing levels may heighten a woman's vulnerability to depression across her lifetime.[74] No specific endocrinologic abnormality has been identified consistently in women with premenstrual symptoms, postpartum disorders, or oral contraceptive-induced mood changes, although estrogen may have an antidepressant effect, presumably by enhancing serotonin activity. Reports supporting this hypothesis include the finding that pharmacologic doses of estrogen in women with severe refractory depressions lead to significant improvement in mood.[57]
Evidence abounds for depressive disorders or symptoms occurring at low estrogen times (e.g., postpartum or premenstrually).[72] A role for female reproductive hormones in mood regulation is also suggested by the finding that gender differences in rates of depression first arise at puberty.[48] Premenstrual mood symptoms have been reported to disappear with ovariectomy[18] but not with hysterectomy alone.[11] In menopausal women, circulating higher estradiol levels have been positively associated with higher mood scores.[93]
The psychologic hypothesis suggests that sex role stresses may explain the higher prevalence of depression in women,[104] although gender differences in rates of depression emerge in early adolescence before adult sex roles are fully established.[53] This theory suggests that the intergenerational and chronic social disadvantages to which women are exposed cause them to be more depressed than men. Poorer job opportunities, lower wages, and the pressure to fulfill familial as well as career or vocational responsibilities undoubtedly contribute to depression in women. Rape, domestic violence, and sexual molestation in childhood have been associated with enduring physical and psychologic sequelae.[24] Violence against women reduces self-esteem, impairs interpersonal functioning, and is often associated with recurrent depression.[2] Additionally, according to the psychosocial hypothesis, from early childhood, girls are taught to be more psychologically dependent and docile; therefore, they internalize stress rather than act out their objections.[90]
Women are significantly more likely than men to experience seasonal affective disorder, a syndrome characterized by recurrent depressive episodes that occur most commonly in winter and that are characterized by features such as overeating, oversleeping, carbohydrate craving, and weight gain.[2] The prevalence of seasonal affective disorder in the general population is not well established, but a rate of 4.3% to 10%[49] has been suggested, with a female-to-male ratio of 6.3 to 1.[84] In patients receiving treatment for recurrent depression, a prevalence of seasonal changes of as much as 38% has been reported.[39] A large proportion of patients with seasonal affective disorder may have bipolar affective disorder.[84]
Most women who present to obstetrician-gynecologists with complaints of premenstrual syndrome have other disorders. Medical, gynecologic, and psychiatric screening, as well as 2 months of prospective charting of symptoms, are required to diagnose accurately the woman's problem or disorder. Premenstrual dysphoric disorder occurs in 3% to 8% of ovulating women.[60] The DSM-IV criteria emphasize distressing emotional symptoms (depression, irritability, mood swings) in the luteal phase only that severely affect lifestyle.[8] A pattern of less severe luteal symptoms, mainly physical complaints, is diagnosed as premenstrual syndrome. The key diagnostic point in differentiating premenstrual syndrome and premenstrual dysphoric disorder from other disorders is that the follicular chart is clear of symptoms. Women can also be diagnosed with premenstrual magnification, which occurs when symptoms of a concurrent psychiatric or medical disorder are magnified during the premenstrum.[60] The current etiologic hypothesis of premenstrual dysphoric disorder is that normal ovarian function is the cyclic trigger for biochemical events that involve the serotonin system.[60]
Traditionally, pregnancy has been viewed as a period of well-being that makes women feel biologically "complete" and that provides "protection" against psychiatric disorder; however, the prevalence rates of depression are now known to be similar in pregnant and nongravid women.[3] Factors such as a history of depression or premenstrual dysphoric disorder, younger age, limited social support, living alone, a greater number of children, marital conflict, and ambivalence about pregnancy increase the risk for depression during pregnancy and the postpartum.[3] A history of depression during the antenatal phase remains one of the strongest predictors of future depression during pregnancy and the purpureum.
Between 30% and 75% of women experience mild postpartum "blues" lasting 4 to 10 days.[14] This postpartum depression is characterized by labile mood, tearfulness, irritability, anxiety, and sleep and appetite disturbances. If physical symptoms and depressed mood persist for 2 weeks, patients should be evaluated for postpartum depression, particularly if they have a history of depression.
Postpartum major depression is relatively common, with a prevalence rate approximately the same as for major depression in nonpregnant women.[14] Symptoms usually begin during the third trimester and are similar to the symptoms of major depression. The risk of postpartum depression is increased in women with pregravid depression, a history of premenstrual dysphoric disorder, primiparous status, negative life events during pregnancy, an inadequate social support system, and marital problems.[14]
Community surveys show that anxiety disorders are some of the most common medical illnesses. It is estimated that 10% to 20% of patients in general medical settings have an anxiety or depressive disorder.[13] [56] Nevertheless, half the time, these disorders are missed by primary care physicians.[88] The tendency for patients to emphasize somatic complaints contributes to this underrecognition, although the greater likelihood for women to identify emotional material makes recognition in women somewhat more successful.[56] The need to detect anxiety disorders in general medical settings is underscored by the long-term morbidity associated with these illnesses. A 3-year follow-up study of patients with anxiety disorder in a primary care setting found that only one-third of patients fully recovered.[73] For patients who did not completely recover, functional disability continued and exceeded the disability experienced by patients who sustained depression in the absence of anxiety.[73] Recognition and treatment of anxiety disorders are important issues for women because community rates of anxiety disorders in women generally exceed those for men by a factor of at least two[54] (Table 3) (Table Not Available) .
| (Not Available) |
| From Yonkers KA: Recognition and treatment of anxiety disorders in women. In Wallis LA, et al (eds): Textbook of Women's Health. Philadelphia, Lippincott-Raven, 1998, p 820; with permission. |
The symptom criteria for the anxiety disorders are described in the DSM-IV.[8] This article focuses on the symptom criteria and prevalence of anxiety disorders in women, including social phobia, panic disorder with or without agoraphobia, generalized anxiety disorder, obsessive-compulsive disorder, and posttraumatic stress disorder (PTSD). Gender-relevant risk factors and pathophysiolgic findings are also outlined. Common clinical presentations, treatment, and referral issues are addressed. Table 4 (Table Not Available) describes the core fears and common triggers associated with each of the major anxiety disorders.
| (Not Available) |
| From Pigott TA: Obsessive-compulsive disorder: Symptom overview and epidemiology. Bulletin of the Menninger Clinic 62(4, suppl A):A24, 1998; with permission. |
An anxiety disorder frequently seen in primary care settings is panic disorder. As is true for other anxiety disorders, women are more likely to sustain panic disorder than are men. Lifetime prevalence of uncomplicated panic is 2% in men versus 5% in women.[54] Typical age of onset for panic disorder is between adolescence and 30 years.[105] Patients with panic disorder are five times as likely to rate their physical health as poor, twice as likely to have a general medical visit, and 30 times more likely to use an emergency room than are patients without a psychiatric illness.[58] Numerous environmental factors, including drugs,[21] may induce or worsen panic symptoms, as shown below:
Environmental Factors That Induce or Worsen Panic Attacks *
In women, exogenous progesterone,[100] triphasic oral contraceptives,[31] and sexual abuse have been associated with panic disorder.
The essential feature is a panic attack, which patients frequently refer to as an "anxiety attack." Panic attacks occur suddenly, with a crescendolike pattern over the course of several minutes, and are characterized by a variety of physical sensations and cognitions, the most common of which are shortness of breath, hyperventilation, palpitations, trembling and shaking, and a sense that one is "out of control" or about to die.[105] Diagnostic criteria for the disorder require that an individual has recurrent attacks with no identifiable precipitants that lead to persistent concern about a subsequent attack, worry about the implications of the attack (i.e., going crazy), or a change in behavior for at least 2 months' duration. [8] Patients who have several attacks but who do not worry or have a change in behavior have less impairment and usually a more benign course. Commonly, patients also have attacks that are precipitated by stressful or traumatizing events. Although these panic attacks technically do not qualify for panic disorder, it is unclear whether the prognosis for individuals with these attacks differs.[105] In clinical populations, no difference is found between the symptoms noted by men and women.[20] [97]
In some instances, anxiety associated with the panic attacks can become generalized and can lead to agoraphobia. Agoraphobia is the fear of being in a place from which escape may be difficult or help unavailable if, for example, an individual has a panic attack.[105] Eventually, this fear causes a patient to avoid potentially problematic places (crowded malls, cars) or to endure them with severe discomfort. The most extreme example is when a patient becomes virtually house-bound because of his or her fears. Approximately 7% of women sustain agoraphobia, and community studies show that it occurs twice as often in women.[83] Agoraphobia is unlike social phobia in that agoraphobics fear a variety of places and are not concerned with being noticed or drawing attention. Social phobics feel more comfortable in situations where they will not be noticed, even if this includes a large crowd.
In comparing male and female agoraphobic patients, one study found that women were slightly more avoidant than men and that the degree of avoidance was inversely correlated with scores on a scale of masculinity.[20] Such scales measure assertiveness and self-actuating behaviors. These findings coincide with psychosocial theories suggesting that women are reared to be dependent rather than assertive and receive less encouragement for task mastery.[105]
The outcome for agoraphobia, or panic with agoraphobia, is less promising than the outcome for uncomplicated panic,[52] suggesting that if women are more likely to sustain agoraphobia, they are more likely to have a worse overall clinical course.
Generalized anxiety disorder is probably the most common anxiety disorder seen in the primary care setting. The lifetime prevalence rate is nearly 7% in women versus approximately 4% in men (See Table 3 (Table Not Available) ). Generalized anxiety disorder is characterized by anxiety and worry experienced most of the time for at least 6 months.[8] Anxiety and worry typically are associated with common day-to-day circumstances (job, health of friends or family, finances, and so forth) and are excessive. Individuals sustaining generalized anxiety disorder find it difficult to control the worry. These psychologic features are associated with at least three of the following symptoms: restlessness, fatigue, difficulty concentrating, irritability, muscle tension, and difficulty sleeping.[8] One study of generalized anxiety disorder in women found that patients could be differentiated from controls by their heightened muscular tension, but they did not necessarily have different autonomic responses.[45] A study comparing the impact of stressful life events on the development of generalized anxiety disorder found that four or more stressful life events increased the risk for the disorder in men eightfold, whereas, in women, four or more total life events increased the risk less than twofold.[15] A serious unexpected life event increased the risk for generalized anxiety disorder threefold in all subjects.
In terms of predictors, men and women also differ. Men with less education and women with more education who experience a negative important life event are at greater risk for generalized anxiety disorder. In addition, urban women but rural men have a higher risk for the disorder. An additional finding from the previous study was the high degree of comorbidity detected; approximately one third of all patients had a concurrent anxiety or depressive disorder.[15]
Social phobia, also known as social anxiety disorder, is a persistent fear of one or more situations that may lead to embarrassing scrutiny by others, such as speaking, eating, or writing in front of other people.[8] Commonly, patients avoid social settings where they feel others may notice them, such as classroom settings, parties, or group activities. Patients are reluctant to admit to their social phobia, and the entity may come to the attention of a primary care physician when a patient presents for treatment of another general medical or gynecologic problem. Adolescents with social phobia may be identified by school absences.
In adults and adolescents, the fear of speaking in public (limited social phobia) occurs at a high frequency; the more generalized form of the disorder when an individual is fearful of many social situations is seen less often.[105] Initial studies suggested that the rate of social phobia was higher in men than women; however, data from the Epidemiological Catchment Area Study[87] and National Comorbidity Study[105] suggest that social phobia occurs more often in women. In fact, risk factors for development of social phobia include female gender, single status, young age, and low socioeconomic status.[87] One study found that women were more likely to have a fear of speaking or performing in public, whereas men were more likely to be distressed by writing or eating in public.[79] Social phobia is frequently accompanied by other psychiatric disorders; in particular, the rates for depression, suicide, and alcohol abuse are high.[87] Some researchers suggest that the high rate of alcohol abuse (estimated to be nearly 40%) is an individual's attempt to "self-medicate" and ameliorate the anxiety associated with the disorder.[87]
Obsessive-compulsive disorder is found in approximately 3% of women and 2% of men (Table 3) (Table Not Available) . As is true for social phobia, early clinical studies suggested a higher prevalence in men, but this observation was made because men presented for treatment more frequently than women.[77] Diagnostic features of obsessive-compulsive disorder include obsessions or compulsions that are excessive and unreasonable and that lead to marked distress and functional impairment.[8] Obsessions are recurrent thoughts or images that are intrusive and inappropriate and are not simply about real-life problems.[8] The patient attempts to suppress them or neutralize them. Compulsions are repetitive behaviors (hand washing or checking) that an individual is driven to repeat to decrease anxiety.[8]
Obsessive-compulsive disorder seems to have an earlier age of onset than many of the other anxiety disorders, and it is frequently noted in children.[77] The age of onset differs according to gender, with an earlier age of onset (5 to 15 years) in males and a later onset (26 to 35 years) in females.[77] A comorbid history of depression is likely in women and frequently precedes the onset of obsessive-compulsive disorder.[77] Differences appear in terms of the type of compulsions men and women are most likely to have. One study found that women tended to be compulsive washers, whereas men were more likely to have checking rituals.[73] Bulimia and anorexia, possibly related disorders that involve obsessions about food and weight, are seen more frequently in women.[50] In terms of the course of illness, some researchers suggest that males may be more treatment resistant than females; the duration of illness is longer in males, and they receive treatment for a longer period of time.[82]
Posttraumatic stress disorder is an anxiety disorder that develops after exposure to a traumatic stressor that involves actual or threatened death or serious injury to oneself or to others.[8] Exposure triggers several reactions, including reexperiencing the traumatic event, for example, by having recurrent intrusive images or dreams or feelings that an event is recurring. An avoidance of stimuli associated or reminiscent of the event is another characteristic.[8] Symptoms of arousal are part of the diagnostic criteria and include difficulty sleeping, hypervigilance, trouble concentrating, and an exaggerated startle response.[8] Events that are likely to trigger PTSD include combat exposure, sexual assault, physical assault, natural disasters, and severe accidents.[105] In female patients, PTSD can occur as the result of sexual assault or early childhood abuse.[105] Breslau and co-workers [17] found the prevalence of PTSD in a large Detroit-based health maintenance organization to be 11% in women and 6% in men. PTSD develops in nearly 25% of individuals exposed to severe trauma, but a gender difference in risk is found such that 31% of women but only 19% of men have PTSD after exposure to a trauma. In addition to female sex, other predictors for the development of PTSD include neuroticism and a family history of anxiety or depression.[17] The high rate of PTSD in women is particularly notable because males tend to be exposed to trauma at higher rate than females.[17] Some authorities suggest that women are exposed to greater "network events" (i.e., trauma befalling people in their network to whom they are intimate).[55] This theory is supported by the work of others[105] who stress that, for women, a premium is placed on staying in "connection with other people," and trauma occurs when those valuable connections are lost.
For some women, chronic PTSD presents as a personality disorder, such as borderline personality disorder.[105] This condition typically occurs in patients who have been exposed to severe early sexual and physical trauma. Estimates of trauma in patients with borderline personality disorder are as high as 80%.[44] In this patient population, additional symptoms such as dissociative experiences, anger, depression, self-abusive behavior, multiple suicide attempts, and polysubstance abuse can occur. Worsening of PTSD symptoms during the premenstrual phase of the menstrual cycle has been noted.[105]
Data for panic disorder suggest that some pregnant patients can remain well after medication discontinuation.[3] The postpartum period seems to be a time of increased vulnerability to recurrent panic symptoms. Women with obsessive-compulsive disorder may have an exacerbation of symptoms during pregnancy. As is true for panic disorder, the postpartum period marks a time of increased vulnerability to obsessive-compulsive disorder even if attempts at medication discontinuation are successful during pregnancy. The course of the other anxiety disorders during pregnancy and lactation remains unknown.
In addition to confirming the diagnosis of a depressive or anxiety disorder, the physician should identify any relationship between the disorder and menstruation, pregnancy, the perinatal period, or the perimenopausal period. A possible relationship between depression or anxiety and medications such as birth control pills or agents used in hormone replacement therapy must be explored. If there is a link to any treatable cause of the disorder, it should be addressed first. If the patient's depressive or anxiety disorder does not respond to this intervention, further treatment is required.
Patients with depressive disorders or anxiety disorders (with coexisting depression) are at high risk for suicide. Factors to be considered in determining the nature and intensity of treatment include the availability and adequacy of social supports, access to and lethality of suicide means, and past history of suicidal behavior. The risk for suicide in some patients recovering from depression increases transiently as they develop the energy and capacity to act on self-destructive plans made earlier in the course of their illness.[2]
Cognitive behavioral therapy is usually administered by a psychologist or psychiatrist with special training in this modality. Treatment usually lasts 3 to 6 months and entails psychoeducation regarding the illness and treatment procedure and exploration of catastrophic thoughts and negative thinking.[30] Patients complete assignments that enable them to identify and correct negative cognitions and dysfunctional and avoidant behaviors. Techniques useful in obsessive-compulsive disorder include thought stopping, which teaches a patient how to stop obsessive thoughts.[40] Patients with PTSD respond to graded exposure to the avoided stressor.[27] Social skills training is particular effective in patients who have social phobia.[62] Deep breathing and relaxation training are particularly effective for patients with generalized anxiety disorder and panic disorder.[78] [86] Patients can be taught basic techniques in the office and can be instructed to purchase books and tapes. If the patient fails to improve, more intensive psychotherapy is warranted. In these instances, the patient may benefit from referral to a psychiatrist.
Because no antidepressant is more clearly effective than another and because no single medication results in remission for all patients, the medication to be prescribed for a particular patient depends on various factors. These factors include side effects of the drug, the patient's preference, prior response to the drug, concurrent nonpsychiatric medical illnesses, concomitant use of nonpsychotropic medications, likelihood of compliance with the drug regimen, and the drug's cost.[4] [9] [30] [89] Support and education optimize adherence. Patients with more severe illness should optimally be seen weekly during the initial 6 to 8 weeks of acute treatment.[4] [9] [25] If the patient has no response or only minimal symptomatic response by 6 weeks, the adequacy of the diagnosis and treatment should be reassessed, possibly in consultation with a mental health specialist.[4] [9] [25]
Patients who have improved symptomatically at 6 weeks may nevertheless have impaired psychosocial functioning.[14] Because many patients are likely to improve in this domain as well over the next 6 weeks, neither the dosage nor the medication type should be changed.[14] If normal functioning has returned by 12 weeks, continuation pharmacologic treatment should be begun.[4] [9] [14] If psychosocial difficulties persist, psychotherapy focused on the residual impairment may be beneficial.
In the last decade, clinical practice has shifted away from tricyclic antidepressants and monoamine oxidase inhibitors toward serotonergic reuptake inhibitors (SSRIs) and other newer agents. The older antidepressants are unquestionably effective, and their safety and side-effect profiles are well known; however, their adverse effects present greater problems, particularly in patients with coexisting medical illnesses.[32] Several case series have documented tricyclic antidepressant discontinuation rates as high as one-third in medically ill patients because of adverse effects.[37] [80]
The SSRIs and the newer antidepressants, such as nefazodone (Serzone), venlafaxine (Effexor), and mirtazapine (Remeron), have proved effective in the treatment of major depression and many anxiety disorders. These newer antidepressants resemble tricyclic antidepressants, many of which have similar dual action on serotonergic and noradrenergic reuptake.[32] Fortunately, the newer drugs are almost entirely devoid of the anticholinergic and cardiovascular adverse effects of the tricyclics and allow modification of the serotonergic and noradrenergic systems without producing the toxicity common to the tricyclics.[32]
A detailed history of present illness, past psychiatric history, medical history, medication history, family history, and social occupational information should be obtained. Laboratory data should include thyroid function tests (e.g., hypothyroidism may present as depression) and other tests as indicated by the patient history (e.g., complete blood counts with differential, liver function test, electrolytes).[4] [9] [94] Nearly 15% of cases of depressive disorders are related to general medical or other conditions, including substance abuse, concurrent medications, general medical disorders, and nonmood psychiatric disorders (e.g., eating disorders, obsessive-compulsive disorder, and panic disorders).[29] [30] These underlying conditions must be managed before treating the depressive disorder.
The following medications have been reported to cause or exacerbate depressive symptoms[4] :
A relationship must be established between initiation of the medication and the onset of depressive symptoms. It may be necessary to alter the dose or to change the medication to resolve the depressive symptoms. The patient should return for further assessment if the depression is not resolved.
Patients with mild depression can be treated with psychotherapy alone or with a combination of medication and psychotherapy.[9] [30] If nonresponsive to psychotherapy, even mild depression should be considered for antidepressant medication therapy. As severity increases, antidepressants become progressively indicated; in the most severe cases, electroconvulsive therapy has a greater role as a primary treatment.[9] [30]
Treatment of major depression consists of an acute phase, a continuation phase, and a maintenance phase.[9] [30] The acute phase seeks to remove all signs and symptoms of the current episode and to restore psychosocial and occupational functioning.[9] A remission is declared when these goals are achieved. Should symptoms return within the following 6 months, the person is considered to have relapsed. The continuation phase seeks to prevent relapse by extending the intervention for approximately 6 months after remission.[9] If the person remains asymptomatic for 6 to 8 months after the episode's onset, a recovery may be declared. Because persons with three or more previous depressive episodes are at high risk for additional episodes, maintenance intervention is provided for a year to lifetime with the goal of preventing another recurrence.[9] All patients should go through the first two phases; maintenance therapy is not likely to be indicated in the patient's first diagnosis of depression.[9] [30] The antidepressant should be prescribed at the full dose during the continuation and maintenance phases.[9]
The SSRIs are recommended as first-line therapy for major depression because of data supporting their efficacy in the acute and maintenance phases, the minimal need for dosage titration, the overall favorable side-effect profile, and the length of available clinical experience.[69] In addition, women seem to respond better to SSRIs than to tricyclics.[35] If a patient does not respond to or is intolerant to an SSRI, a different SSRI, bupropion (Wellbutrin), nefazodone (Serzone), or venlafaxine (Effexor) may be considered. Potential advantages of bupropion or nefazodone include a significantly lower incidence of sexual dysfunction as compared with the SSRIs, a favorable effect on insomnia and anxiety (nefazodone), [34] a favorable effect on sleep architecture (nefazodone), [34] and minimal drug interactions (bupropion). [36] Table 5 (Table Not Available) compares the adverse effect profiles of the newer antidepressants.
| (Not Available) |
| From Sachs GS, Guille C: Weight gain associated with use of psychotropic medications. J Clin Psychiatry 60(suppl 21):19, 1999; with permission. |
Potential advantages of venlafaxine include relatively few documented drug interactions and the suggestion of enhanced efficacy for severe and treatment-resistant depression.[70] Increased efficacy rates are found with increasing doses of bupropion, nefazodone, and venlafaxine, whereas SSRIs have a relatively flat dose-response curve.[70] SSRIs are usually given in once-daily doses, whereas twice-daily dosing is recommended for bupropion (150 mg per individual dose), nefazodone, and venlafaxine. Table 6 (Table Not Available) lists dosage regimens for antidepressants according to class and type of disorder.
| (Not Available) |
| Adapted from Drug Treatment Protocols Washington, DC, American Pharmaceutical Association, 1999, pp 263, 305; and Korzekwa MI, Steiner M: Assessment and treatment of premenstrual syndromes. Prim Care Update Ob/Gyn 6:156, 1999; with permission. |
Many of the side effects of the SSRIs and venlafaxine are similar, except that venlafaxine has also been reported to elevate blood pressure in some patients (especially with doses >225 mg/day).[22] Nefazodone may be a preferable choice as an alternative antidepressant for the patient who does not tolerate the side effects (e.g., nausea, sexual dysfunction, insomnia) commonly associated with the SSRIs or venlafaxine.[34] Because of the potential for drug interactions, changing from an SSRI to nefazodone should be performed cautiously.[32]
Tricyclic antidepressants are not recommended as first-line agents because of their relatively less favorable side-effect profile, higher patient attrition rate when compared with SSRIs and other newer agents, and high risk of toxicity, including lethality in overdose.[25] Pharmacoeconomic data indicate that SSRIs, at least in the primary care environment, may be associated with overall treatment costs at least as low as with tricyclic antidepressants.[95]
Conservative treatment options, such as dietary changes, exercise, stress management, and progressive relaxation, are recommended for all women with premenstrual symptoms. Women should eat small, frequent, complex carbohydrates, and be encouraged to reduce salt, chocolate, caffeine, and alcohol during the luteal phase.[60] Women diagnosed with premenstrual syndrome may respond to oral contraceptives and specific vitamins, such as calcium (1000 mg daily), magnesium (360 mg daily), vitamin E (400 IU daily), and pyridoxine (100 mg daily).[60] Women with premenstrual dysphoric disorder generally find these treatments insufficient. Results from several randomized, placebo-controlled trials in women with premenstrual dysphoric disorder have demonstrated that the SSRIs have excellent efficacy and minimal side effects. Recent studies indicate that low-dose, intermittent (luteal phase only) treatment with SSRIs is effective.[60] There is also randomized, placebo-controlled evidence for the efficacy of clomipramine (Anafranil), buspirone (Buspar), alprazolam (Xanax), mefenamic acid (Ponstel), and various ovulation-suppression regimens, but these agents tend to have more side effects than the SSRIs.[60]
For all patients with anxiety disorders, potential underlying general medical illnesses should be investigated. Electrolyte levels and thyroid function should be tested and a history regarding caffeine and concurrent drug use obtained.[10] After general medical illnesses are corrected or potentially aggravating substances stopped, the patient should be reassessed because she may still require psychotropic or psychologic treatment for an anxiety disorder. In terms of therapeutic options, patients may require pharmacotherapy, cognitive behavioral therapy, or both.[10] A substantial number of patients with an anxiety disorder are found to have coexisting medical conditions, as listed previously.
The SSRIs, including fluoxetine, fluvoxamine, paroxetine, citalopram, and sertaline, have been evaluated for the treatment of panic disorder and have well-established efficacy and safety profiles.[92] Some of the newer antidepressants, such as nefazodone and venlafaxine, also seem effective.[6] [92] All of the newer antidepressants are well tolerated and are not associated with cardiovascular effects, orthostatic hypotension, or physical dependence[6] ; consequently, many clinicians consider these agents first-line therapy for the management of panic disorder.
Because the SSRIs and the other newer antidepressants can initially produce increased anxiety in patients with panic disorder, it is recommended that doses approximately half of those given to depressed patients be administered at the beginning of treatment.[6] [10] The dose is then slowly titrated upward over several weeks to standard antidepressant doses. Response does not usually occur for at least 4 weeks, and some patients do not realize full response for 8 to 12 weeks.[10] Short-term benzodiazepine use may be beneficial to relieve any initial anxiety and to provide some symptom relief before antidepressant response occurs.[10] After 12 weeks of acute treatment, therapy should be maintained for at least 1 year, followed by an attempt at discontinuation.[10] Many patients partially or fully relapse when medication is discontinued and may benefit from a prolonged period of treatment. Patients who show no improvement after 12 weeks at therapeutic doses should be referred to a mental health specialist.
Currently, there are no large class-to-class drug studies comparing the SSRIs with other classes of antipanic medications; however, a meta-analysis of 32 randomized, prospective, double-blind, placebo-controlled studies involving more than 2348 patients with panic disorder found that SSRIs were significantly superior to imipramine and alprazolam.[16]
Short-term treatment with benzodiazepines is helpful for many patients with generalized anxiety disorder. As is true for panic disorder, discontinuation of benzodiazepines is associated with anxiety return.[2] Given the fact that generalized anxiety disorder is chronic, patients who respond to benzodiazepines are likely to require them for extended periods of time. Because this class of medication is associated with abuse and tolerance, the newer antidepressants offer an attractive alternative.[2] The SSRIs have been shown to be effective in treating anxiety with comorbid depression, and venlafaxine has recently been approved for generalized anxiety disorder.[7]
Starting doses of SSRIs are similar for generalized anxiety disorder and depression alone. Paroxetine (Paxil) has the advantage of requiring no initial dosage titration, and its more sedating profile provides more immediate relief (See Table 5 (Table Not Available) ). Agitation may be a side effect of fluoxetine (Prozac) and sertraline (Zoloft). Patients with panic symptoms may tolerate these medications better at initial daily doses of 10 mg or 25 mg, respectively. Although patients with generalized anxiety disorder often have sleep disturbances, most SSRIs lack significant sedative effects and may fail to relieve insomnia.[7] Low-dose trazodone (Desyrel, 50 mg) is a safe effective hypnotic in women taking antidepressants and generally should be used on an as needed basis.[7]
Target symptoms of anxiety should be assessed at baseline and every 2 to 4 weeks. If after 4 weeks of therapy at usual therapeutic doses there is no improvement, the dose should be increased as tolerated and assessed in another 4 weeks.[7] If the anxiety is adequately improved, maintenance therapy should be begun for 2 to 6 months before giving consideration to halting medication on a trial basis.[7] Medication withdrawal should be gradual and guided by the patient's ability to function, response to nonpharmacologic therapy, and ability to tolerate the taper. Most patients who have generalized anxiety disorder do not require long-term medication treatment, but patients who relapse should be allowed to continue effective pharmacotherapy. Patients who do not respond to therapy should be referred to a mental health specialist to reconfirm the diagnosis and monitor therapy.
The SSRIs are effective for the treatment of obsessive-compulsive disorder and are safe and well tolerated.[5] [33] [41] [106] SSRIs have fewer anticholinergic adverse effects when compared with clomipramine and are safe when taken in overdose. Paroxetine, fluoxetine, fluvoxamine, and sertraline have proven efficacy in the treatment of obsessive-compulsive disorder, and all four agents have been approved by the US Food and Drug Administration (FDA) for use in patients with this disorder.[5] [42] [43] [98] [106] Although there are no data to suggest that one agent is more effective than another,[68] some patients may respond specifically to one agent.[81]
Few studies have compared the SSRIs in the treatment of obsessive-compulsive disorder.[68] Studies comparing SSRIs and clomipramine have shown that clomipramine may be slightly more effective than the SSRIs, but it is also associated with an increased incidence of adverse effects.[47] [106]
When initiating SSRI therapy, medications should be titrated gradually. The standard pharmacologic regimen is a 10- to 12-week trial with an SSRI in adequate doses before initiating alternative therapy.[81] In many cases, the adequate dose is the maximum tolerated amount, because doses needed for the treatment of obsessive-compulsive disorder may be higher than those for other anxiety disorders or depression (Table 6) (Table Not Available) . Even with maximum pharmacotherapy, some patients do not experience complete relief of symptoms.[40] Full remission is rare, and as many as 25% of patients fail initial therapy.[40]
After response to acute treatment, maintenance therapy is recommended for a period of at least 1 year before gradual discontinuation of medication is considered.[81] Medications should be tapered slowly during discontinuation and should be restarted if symptoms reappear.[40] Because the symptomatology in these patients is difficult to treat, they may often need to be referred to a psychiatrist for management.
The SSRIs, including paroxetine, fluvoxamine, sertraline, and fluoxetine, have shown substantial acute efficacy in clinical trials and are emerging as first-line treatment for social phobia.[51] [62] [96] [99] The SSRIs are easily administered once daily and have a favorable side-effect profile (See Table 5 (Table Not Available) ). Paroxetine is the most well-studied SSRI to date in social phobia and is the only SSRI approved by the FDA for this disorder. In a double-blind, placebo-controlled study, the efficacy of paroxetine compared with placebo was evaluated in 187 patients with generalized social phobia. More than half of the patients taking paroxetine (55%) were considered therapeutic responders compared with 24% of patients treated with placebo.[96] These findings suggest that the SSRIs should be considered first-line therapy for patients with social phobia.
On the basis of the current level of clinical evidence and the data from controlled studies under review, SSRIs are the first-line drug therapy for PTSD. With their spectrum of activity, they are most effective in meeting the defined treatment goals for the condition in that they reduce symptoms and disability, improve functionality and resilience to stress, and treat comorbid depression and anxiety.[12]
Sertraline has been shown to be effective in rape victims[85] and is the only SSRI approved by the FDA for PTSD. Fluoxetine,[91] fluvoxamine,[28] and paroxetine[64] have also been shown to be effective in PTSD.
An SSRI should be started in patients with no improvement in their acute stress response, or alternatively, they should be referred to a mental health specialist.[12] Therapy should be initiated with a low dose and titrated gradually to the same or a higher level of drug used to treat depression (Table 6) (Table Not Available) . An appropriate trial of initial therapy is 3 months.[26] If there is no substantial response to treatment, the most appropriate form of management is referral to a specialist. Referral may be made sooner if the patient's condition is severe or complicated by comorbid psychiatric disorders. Effective pharmacotherapy should be continued for 12 months or longer, depending on the severity and duration of illness.[26]
There is no invariable rule to determine appropriate referral to psychiatric services. Such referral depends on the availability of mental health professions in a particular location, the ease of access to these professions, and the skills available in the primary care team. In many parts of the world, primary care services are the only medical services available, and primary care teams must necessarily deal with all problems. In large cities of industrialized nations, where there are typically many suitable professionals available, referral will depend on whether the patient can pay for any necessary treatment and on whether the indicated treatment can be supplied by the primary care team.
In major depression, treatment-resistant patients are defined as persons not responding after 6 to 8 weeks of antidepressant treatment at an adequate dose or persons who do not respond to successive doses of two different agents given at adequate doses.[4] [9] Usually, such patients, including those with a severe risk of self-harm, are referred to a mental health professional. Patients with psychotic forms of depression and patients with agitated depression and bipolar illness are also usually referred to mental health services, at least for initial assessment. Indications for the referral of patients with depressive and anxiety disorders include the following[94] :
Women with depression and anxiety disorders who wish to become pregnant are faced with difficult decisions regarding the use of antidepressants. Several issues must be addressed. Risks of fetal exposure to medications, including congenital anomalies, neurodevelopmental sequelae, and perinatal syndromes, must be weighed against the risks of untreated maternal disorder.[23]
Whenever possible, behavioral techniques such as cognitive behavioral therapy should be employed for the treatment of women with depressive and anxiety disorders during pregnancy and lactation.[65] If medication must be used during pregnancy, it is best to prescribe drugs that have been researched and evaluated for possible adverse effects and to use the lowest possible dose for the shortest length of time.[65]
The SSRIs have been well studied in pregnancy. Numerous studies have suggested that in utero exposure to fluoxetine is not associated with an increased risk of major malformations.[19] [75] A registry containing more than 1500 cases of prenatal exposure to fluoxetine failed to show increased rates of congenital anomalies.[1] A preliminary study of neurobehavioral functioning in children exposed to fluoxetine in utero also failed to show adverse effects associated with prenatal exposure to the drug.[71]
Data regarding safety of the other SSRIs are similar but less extensive. Kulin and colleagues[61] matched 267 women who took paroxetine, sertraline, or fluvoxamine during pregnancy with an equal number of controls. There were a total of 222 live births, including 9 major malformations in women who had taken SSRIs, and 235 births and 9 major malformations in controls. The rates of miscarriage and stillbirth were similar in both groups, and mean birth weight and gestational age were also similar. Based on these data, paroxetine, sertraline, or fluvoxamine did not increase the risk of congenital anomalies when used during pregnancy; however, given the low overall number of patients in the study, more data are necessary to confirm that these drugs do not harm the developing fetus. An additional small study of 63 infants exposed to paroxetine during the first trimester failed to show evidence of congenital anomalies.[46]
The shorter half-lives of paroxetine, sertraline, and fluvoxamine make these SSRIs a better choice for treating the patient who does not wish to take medication during pregnancy but who is not yet pregnant. Because fetoplacental circulation is established 18 to 21 days after conception, a patient who has regular menstrual cycles has a "window" of 4 to 7 days after the first day of a missed menstruation before fetoplacental circulation is established.[3] Such a patient may elect to remain on an SSRI with a short half-life while trying to conceive. She could discontinue the SSRI on the day of missed menstruation, and, theoretically, the medication would be cleared before fetoplacental circulation was established. The different SSRIs can be used in different scenarios depending on the severity of the psychiatric illness and the situation of the patient.
In addition to safe use during pregnancy, these agents have favorable side-effect profiles and may be considered first-line therapy for depression severe enough to justify the use of medication during pregnancy.[1] [3] This recommendation is not consistent with the pregnancy ratings from the FDA[76] ; however, experts in the field of teratology consider these ratings inadequate for determining safety in pregnancy.[59]
The most successful treatment strategies for postpartum depression are multifactorial, including education, psychotherapy, group support, and referrals to self-help and national organizations (Postpartum Support International Depression After Delivery).[3] Few controlled studies have investigated the pharmacologic treatment of postpartum depression, but fluoxetine and nortriptyline have been reported to be beneficial.[3] For women with a history of postpartum depression, prophylactic antidepressants initiated at the time of delivery reduced the rate of depression from 67% in an untreated sample to 6% in the treated sample.[3] The choice of antidepressant should take into consideration whether the patient will be breastfeeding.
Like most antidepressants, the SSRIs are excreted into breast milk.[2] In the studies that have assessed infant serum concentrations, the values have typically been below the limits of detection of the assay, and few adverse events have been described.[63] Table 7 (Table Not Available) describes the newer antidepressants by FDA pregnancy category and the adverse effects associated with breastfeeding.
| (Not Available) |
| Adapted from Bhatia SC, Bhatia SK: Depression in women: Diagnostic and treatment considerations.Am Fam Physician 60:232, 1999; with permission. |
Depressive and anxiety disorders are common problems facing obstetrician-gynecologists. Although psychiatric disorders are equally common in men and women, women are at least twice as likely to present with depressive disorders and most anxiety disorders. The depressive disorders include major depression, dysthymia, seasonal affective disorder, and premenstrual dysphoric disorder. The anxiety disorders are panic disorder (with and without agoraphobia), generalized anxiety disorder, social phobia, obsessive compulsive disorder, and PTSD. One must diagnose and manage depressive and anxiety disorders during pregnancy, the purpureum, and while breastfeeding.
General treatment principles include assessing suicide risk, psychotherapy, pharmacologic treatment, and an appropriate medical work-up for depressive and anxiety disorders. The SSRIs are the first-line treatment for most depressive and anxiety disorders because of data supporting their efficacy, the minimal need for dosage titration, the overall favorable side-effect profile, and the length of available clinical experience. Newer antidepressants, such as venlafaxine, bupropion, nefazodone, and mirtazapine, are options for patients unresponsive to, or intolerant of, the SSRIs. Treatment considerations include acute, maintenance, and continuation therapy, dosage regimens, adverse effects, and drug interactions. Specific guidelines are available for referring patients to a mental health specialist.