Psychiatric conditions have lagged far behind the more “mainstream” medical conditions in both recognition and treatment. Their effect on people’s lives, however, can be devastating and farreaching. The human costs of depression and anxiety disorders include not just the suffering of the individual but also the effect on the lives of the people around them. Interpersonal stress can manifest itself in work dysfunction and marital and family disruption. Divorce and all of its cosequences are possible outcomes. The economic costs of these conditions are high indeed. Some $40 billion per year is lost in both direct and indirect costs for depression alone.
Unfortunately, the diagnosis of depression and anxiety can be difficult, even elusive, and psychiatric diagnosis remains more art than science. The clinician remains the de facto diagnostic instrument because of the paucity of technology available to playa confirmatory role in the diagnostic process. Blood and neuroimaging tests are useful primarily to exclude or confirm the presence of coexisting processes. Because symptoms such as mild insomnia, irritability, loss of pleasure, and negative thinking patterns are so subjective, they are often missed and may not even be mentioned during visits to a clinician’s office. This is especially true of anxiety disorders. Thus, a high level of suspicion should be maintained when evaluating symptoms that might indicate a mood or anxiety disorder.
Fortunately, ever-improving methods of treatment are available. Seven different classes of antidepressant medications are now available. Psychotherapies have also advanced, now with well-established efficacy of cognitive-behavioral treatments and interpersonal therapy, in addition to the more traditional psychotherapies. However, management of patients with depression or anxiety continues to present a therapeutic challenge. Treatment refractoriness and comorbidity along with the sheer breadth of depression and anxiety symptoms call for the constant need to tailor treatment plans to the broad needs of the patient.
Because depression and anxiety were so poorlY understood and often went unrecognized in the past, patients with these conditions were left with the feeling that their symptoms were “all in their head” or just represented some, Poorly defined “stress.” Patients expenenced an Increased sense of guilt that their symptoms were somehow of heir own making. This approach to diagnosis would often leave patients more demoralized than when they first came to the clinician’s office. prepared now with a more complete understanding of the phenomenology of these disorders, clinicians can be much more precise in their diagnosis. Patients can be educated about the biochemical basis for their symptoms, although care should be taken to avoid creating the impression that the condition will resolve with simple pharmacologic manipulation. Powerful sociocultural forces are often a part of the expression of depression and anxiety, especially for women, and the most effective treatment strategies usually include pharmacotherapy and psychotherapies.
The incidence of major depression in women is substantially higher than that in men. In the 1980s, the National Institutes of Mental Health (NIMH) Epidemiologic Catchment Area (ECA) Program conducted a study of depression in five major cities in the United States. The 1-month prevalence of major depression across all adult age groups was 2.6 to 3.9 percent in women and 1.2 to 2.2 percent for men. The lifetime risk of major depression has been reported as 20 to 26 percent in women and 8 to 12 percent in men. These figures were recently confirmed in the National Comorbidity Survey, the first community study using more recently operationalized criteria from the Diagnostic and Statistical Manual of Mental Disorders-III-R (DSM-III-R).
Many differences in the incidence, presentation, and course of depression appear to exist between women and men. The difference between men and women in the incidence of major depression first begins to appear during adolescence; one study showed that by ages 14 to 16, over 13 percent of girls had suffered depression, compared to 2.7 percent of boys. The age of onset may be earlier and the association with stressful life events and a number of medical and psychiatric conditions is greater. Atypical symptoms such as hypersomnia, hyperphagia, and weight gain are experienced more often among women than men. In addition, the course and self-reported severity of an episode of depression appears to be different for women in that the episode may be of longer duration and greater severity, with more frequent recurrence.
In the elderly, the increased relative risk of depression and depressive symptoms among women versus men continues, although the diagnosis of major depression in the elderly is made less often. Depressive symptoms in the elderly often fall into an area of less specific and sometimes confusing nomenclature. The terms that are used to describe this kind of depression are “minor depression,” “subsyndromal depression,” dysthymia, or depression NOS (not otherwise specified).
Throughout their life span, it is clear that biologic, psychosocial, and cultural factors all play interrelated roles in predisposing adolescent girls and women to depression and anxiety.
Relationship to Female Hormones The connection between depressive symptoms and female sex hormones has been extensively investigated. Supporting evidence includes the increase in incidence of depression with the onset of puberty,s the development of depressive symptoms during the postpartum period, and the link between depressive symptoms and the menstrual cycle, pecifically the late luteal phase? In addition, women who have previously established depression often note an increase in depressive symptoms or their intensity during the premenstrual period? Finally, depressive symptoms canoccur during the use of oral contraceptives, but the relationship between depression and the use of combined oral contraceptives is controversial. Depressive symptoms can occur with use of progestin-only contraceptives.
The biochemical synthesis, metabolism, and turnover of the putative neurotransmitters thought to be germane to depression (serotonin, norepinephrine, and dopamine) are known to be affected by estrogens The biogenic amine theory holds that it is under activity in serotonin and norepinephrine transmission that leads to depression, whereas overactivity can lead to mania. The synaptic effects of antidepressants on these neurotransmitters has led to significant success in treating depression.
Biochemical Markers Of Depression To date, finding biochemical markers with clinical utility has been elusive. In research settings, measurement of the urinary metabolites of norepinephrine, 3-methoxy-4-hydroxyphenylglycol and 3-methoxy-4-hydroxymandelic acid; the cerebrospinal fluid (CSF) metabolite of dopamine, homovanillic acid; and the CSF metabolite of serotonin, 5-hydroxyindoleacetic acid (5-HIAA), appear to have a role in depression, but they have not proven helpful in clinical settings. Research findings have corroborated the theoretical prediction of the biogenic amine theory that these metabolites of norepinephrine, serotonin, and dopamine all are present in reduced concentrations in both urine and CSF. However, these findings are not reliable enough to be clinically useful.
Extreme caution must be used in ascribing gender differences in mood and anxiety disorders to sex hormones alone. Sociocultural influences affect boys and girls as well as men and women, and it seems certain that they playa critical role in the development of depression and anxiety. The work of Carol Gilligan and others has been enlightening in identifying the tasks facing girls growing up in our culture. In preadolescence, the self-esteem of boys and girls appears equal, but with the onset of adolescence, girls show a predisposition to a loss of self-esteem and a belief that they can no longer influence the course of events in their lives. At the same time, boys become increasingly aggressive, in part due to increasing testosterone levels. Girls may react to this aggressiveness with interpersonal withdrawal, because a large proportion of self-esteem in girls is based on relationships. Boys, in distinction, usually have their self-esteem tied to a sense of achievement in work, activities, and sports.
Physical ChangesThe physical changes in girls’ bodies also playa role in the development of mood and anxiety disorders. Preadolescent girls are unencumbered with concerns about menstruation, birth control, pregnancy, and the effect of these concerns on their life choices. Intrapsychic conflict can occur, however, with girls’ changing bodies and the implications of these changes. This transition into womanhood coincides with an increase not only in depression and anxiety but also in eating disorders, substance abuse, and educational difficulties ranging from poorer grades to outright academic failure. Western cultural norms, and particularly American culture, reinforce problems with self-esteem and body image, plaguing girls incessantly with messages from magazines, books, television shows, movies, and popular music.
Family of Origin A girl’s family may complicate the difficulty she has in understanding herself sexually. The attitudes of parents serve as a template on which the girl’s own identity starts to grow and develop. Both the female role models in a girl’s life and the way in which the men and boys in her life react to women in general are of significant consequence to her sense of emerging self.
Challenges of AdulthoodAdulthood presents similar challenges for women. Balancing roles of career and motherhood in adulthood can be. extremely stressful. The issues of birth control, marriage, parenthood, and family affect women in fundamentally different ways than men. Women still take primary responsibility for contraception, and once pregnant, they confront an enormous array of physical changes. The changes that attend pregnancy in terms of their relationship with their mate and their work life provide additional challenges. Developing effective strategies of compromise and balance in their life becomes of paramount importance in achieving and maintaining emotional equilibrium. The costs of achieving this equilibrium, unfortunately, can be high. Lack of life satisfaction and interpersonal conflict with significant people in their lives are common. A paternally oriented work and cultural environment may provide little understanding or empathy for the difficult processes women confront. In marriage, an unenlightened and unresponsive spouse may have great difficulty in adequately responding to the issues women face on a daily basis, leading to marital conflict and sometimes divorce.
As life progresses, women continue to confront different psychological challenges. As a consequence of greater involvement in child-rearing and family cohesiveness, they may suffer a sense of loss as their children grow and leave home.
Menopause and all of its attendant features must be addressed and managed. In late adulthood, increasing physical frailty and the potential loss of a life partner accompanies a longer life span.
Subtypes of Depression
One of the newer trends in conceptualizing depression is the further subclassification of the disorder. The primary interest in subtyping depression is to optimize treatment approaches.
Atypical Depression Atypical depression is actually the most common form of depression seen among outpatients. The symptoms of depression that characterize this subtype include mood reactivity (i.e., the capacity to be cheered up temporarily by positive interactions or events), hypersomnia (increased sleepiness), “leaden paralysis” (severe fatigue), hyperphagia (increased eating), and rejection sensitivity (an increased sensitivity to interpersonal rejection and conflict). Patients with atypical depression tend to have an earlier age at onset of their first depressive episode, and women seem to be more often affected by this type than men. The episodes appear to be of shorter duration than those of melancholic depression, but more frequent. Patients with coexisting obsessive compulsive, avoidant, and passive-aggressive personalities are more prone to this type of depression. The importance of recognizing this particular subtype is that monoamine oxidase inhibitors (MAOIs) have the greatest efficacy in treatment. Tricyclic antidepressants (TCAs) are less effective. Selective serotonin reuptake inhibitors (SSRIs) are also effective treatments and may be considered as first-line therapy because of their high safety and low risk of side effects.
Anxious Depression Anxiety and depression are often considered to be two separate entities; however, it is now clear that there is significant overlap of these disorders. In fact, the majority of patients diagnosed with either a depressive or anxiety disorder will actually have both conditions. The anxiety disorders that are more likely to coexist with major depression are panic disorder, social phobia, obsessive-compulsive disorder, posttraumatic stress disorder, and generalized anxiety disorder. When significant coexisting anxiety is identified, care must be directed toward its treatment as well. In the cases of panic disorder, social phobia, and obsessive-compulsive disorders, for example, the recommendation to seek cognitive behavioral treatments to a patient would be a great importance.
Bipolar Depression To help distinguish unipolar from bipolar depression, it is helpful to recognize the different symptomatology of these disorders. Patients with unipolar depression are more physically and mentally active and have complaints of somatic and sleep disturbances as well as anxiety and anger. Bipolar patients tend, in contrast, to be more quietly withdrawn, with psychomotor slowing and hypersomnia. They also tend to have fewer signs and symptoms of anxiety, fewer physical complaints, and less reported anger. Bipolar patients are also less likely to identify and complain of depression and are, as a result, at increased risk for undertreatment and suicide. Although bipolar disorder has the same incidence in both men and women, so-called “rapid-cycling” (at least four episodes of a mood disturbance in the previous 12 months meeting the criteria for a major depressive, manic, mixed, or hypomanic episode) more commonly affects women. Menopause is a risk factor for developing rapid cycling; sex hormone influences likely play a role.
The recognition of bipolar depression is of critical importance because treating this subtype of depression with an antidepressant without the coadministration of a mood stabilizer (e.g., lithium) can lead to a manic episode. Manic episodes can be difficult enough to treat in their own right, but are especially difficult to treat when they are precipitated by an antidepressant. The treatment of bipolar depression is somewhat complicated, in that a number of different types of approaches are possible, including the use of lithium, anticonvulsants, antidepressants, atypical antipsychotics, and electroconvulsive therapy.
Depression With Anger Attacks This newly identified subtype is characterized by sudden episodes of anger accompanied by symptoms of autonomic activation, such as tachycardia, sweating, flushing, and tightness of the chest. Depressed patients affected this way experience these attacks as uncharacteristic of themselves and inappropriate to the situations in which they occur. About one-third of depressed patients will present with such attacks; coexisting anxiety and somatic symptomS are relatively common. This subtype appears to have a predilection for affecting patients with avoidant, dependent, borderline, narcissistic, and antisocial personality disorders. Anger attacks improve with antidepressant treatment, although there is insufficient evidence to indicate a differential response to different types of antidepressants.
Seasonal Affective Disorder This subtype of depression is characterized by the onset and remission of major depressive episodes at recurrent and distinct, regular times of the year. It is greater at higher latitudes, in younger people, and in women. The symptom profile of SAD consists of increased appetite, carbohydrate craving, weight gain, and hypersomnia. Treatment for SAD includes full-spectrum bright light at an intensity of 10,000 lux for 30 min, preferably administered in the morning. However, light is often not sufficient for treating SAD because nearly two-thirds of patients also require supplemental treatment with antidepressants.
Psychotic DepressionThe diagnosis of psychotic depression requires the presence of hallucinations or delusions in the presence of depressive symptoms. These psychotic symptoms can be either “mood-congruent,” such as delusions of guilt or deserved punishment, or “mood-incongruent,” such as persecutory delusions and delusions of thought insertion (the belief that someone or something is inserting thoughts into one’s mind) or thought broadcasting (the belief that other people can hear one’s thoughts as if they were being broadcast). Psychotic depression is present in about 15 percent of patients with major depression and is more common in bipolar depression than unipolar depression. This subtype of depression, compared to all the other subtypes, is the most dangerous, because it is the one most frequently associated with suicide. It does not respond to antidepressant therapy alone; antipsychotics are necessary in combination with antidepressant therapy, and electroconvulsive therapy is frequently needed.
Depression in Pregnancy
Pregnancy does not confer any protection against depression; it appears that there is no significant difference in the prevalence of depression when comparing pregnant with nonpregnant women. Risk factors for depression during pregnancy include a prior history of depression, ambivalent or negative attitudes about being pregnant, limited or absent social and family support, living alone, having a higher number of children, the presence of significant marital conflict, and a younger age. The evidence is conflicting about the course of depression during pregnancy, with some studies showing general improvement as pregnancy progresses and other studies suggesting the opposite. However, the presence of depression during pregnancy raises the specter of higher risk for prematurity and lower Apgar scores for the infant and mood instability in the mother.
Treatment with medication should be considered for pregnant women if the symptoms of depression are moderate to severe or if they persist into the second trimester. Despite the desire of most women and their physicians to avoid medication in the first trimester, if a patient has a history of recurrent moderate to severe depression with multiple failed attempts at antidepressant discontinuation, maintaining antidepressant treatment during conception attempts and pregnancy is preferable. Antidepressant medication is usually well tolerated during pregnancy. Further information on treatment is discussed below.
Postpartum depression affects 5 to 20 percent of women. True postpartum depression must be distinguished from a milder form of depression, sometimes referred to as the “postpartum blues.” This milder form of depression is characterized by typical depressive symptoms (e.g., depressed mood, loss of energy, loss of appetite, and decreased libido) accompanied by feelings of being overwhelmed and interpersonally sensitive to the feelings and comments of others. This condition can affect up 85 percent of women in the first week after the infant’s birth. To be distinguished from nonpregnancy depression, postpartum depression must begin within 6 months of giving birth. Among women who have experienced postpartum depression previously, the risk increases up to 50 to 60 percent. Other factors that increase the risk of this type of depression include marital conflict, the emotional state of the father, stressful life events, ambivalent or negative feelings regarding the pregnancy and child, and the temperament of the child. Hormonal influences are thought to provide the biologic substrate for the subsequent development of depression; rapidly falling levels of estrogen are thought to contribute. Less well known is the potential contribution of thyroid dysfunction in the postpartum period. Hypothyroidism is more common in the first 6 months after giving birth, and the rates of thyroid dysfunction can be as high as 9 percent after pregnancy compared to 3 to 4 percent in the population at large.
Assessing the Risk of Suicide
Suicide merits special mention because up to 15 percent of untreated or inadequately treated patients with depression will commit suicide. Suicide is a major public health issue in the United States, representing the ninth leading cause of death in the country overall. In people under 45 years of age, suicide is the fifth most common cause of death, more common than homicide and only slightly less frequent than coronary heart disease. Women are more likely than men to attempt suicide, usually choosing drug overdose as the preferred method. Men, however, choose more lethal methods and, as a result, men are four times more likely to die than women.
The risk of suicide for an individual must be aggressively defined during the patient evaluation through skillful and detailed questioning, while being mindful that patients will often find thoughts of suicide to be the most distressing and painful. Presents an algorithm that may be used for assessing the risk of suicide. Inquiry should include assessment of associated demographic risk factors, psychosocial stressors, comorbid anxiety or agitation symptoms, and substance abuse.
The pharmacology of treating depression has become significantly more complicated. There are now three identified neurotransmitter receptor systems (norepinephrine, dopamine, and serotonin) and seven distinct mechanisms of action. Medication options In Considering initial medication treatment, side-effect profiles and potential drug interactions should be considered.
Monoamine Oxidase Inhibitors The MAOIs are the oldest class of antidepressants. MAOIs act by increasing the neurotransmission of serotonin dopamine, and norepinephrine by inhibiting thei; metabolism in the synapse. In general, the MAOIs have unsurpassed efficacy in the treatment of depression, comparable to that observed with the TCAs. They are especially effective in depression complicated by anxiety and in atypical depression.
Adverse Effects. The chief drawback to the use of MAOIs is the potential tyramine reaction. This reaction, characterized by headache and acute hypertension, is precipitated by tyramine acting as a false transmitter and displacing norepinephrine from presynaptic storage granules. As a result, large amounts of dietary tyramine can cause a hypertensive crisis by displacing large amounts of norepinephrine into the circulation. Tyramine is found in a number of foods, such as aged cheeses and soy sauce. Some drugs with sympathomimetic activity, such as diet medications, ephedrine, and phenylephrine, can also provoke a hypertensive crisis because their metabolism will also be impaired by the presence of an MAOI.
Another potential danger of using MAOIs is the emergence of the serotonin syndrome. Although this syndrome can also appear with the use of SSRls, it is potentially deadly in the case of the MAOls. The syndrome is characterized by lethargy, restlessness, confusion, flushing, diaphoresis, tremor, and myoclonic jerking. In its full expression, the syndrome can progress to hyperthermia, hypertonicity, myoclonus, and death. The deadliest interaction that can produce the serotonin syndrome is the combination of a MAOI and meperidine (Demerol). Thus, patients taking an MAOI must never be given meperidine. It is advisable for patients taking MAOls to wear a Medic Alert bracelet indicating that they cannot be given meperidine. If a patient is in need of a narcotic analgesic, it is safe to use codeine or morphine.
Common Side Effects. Other potential side effects of MAOIs . The most common side effects are orthostatic hypotension and insomnia.
Tricyclic Antidepressants These medications act as both serotonin and norepinephrine reuptake inhibitors. Their actions at three other receptors result in anticholinergic antimuscarinic effects (e.g., side effects of dry mouth, blurred vision, and constipation), receptor antagonism (e.g., potential for hypotension), and antihistamine effects (e.g., possible drowsiness). The varying intensity of the medication effects at these receptors provides a differential side-effect profile for these agents. These medications also inhibit sodium channels conferring a risk of cardiac arrhythmias, particularly in the case of overdose.
A major benefit of use of the TCAs is the availability of accurate and clinically usable serum plasma levels to monitor therapy. Plasma levels of nortriptyline, desipramine, and imipramine can all be followed to optimize dosing. Monitoring drug levels is also helpful if a patient has not responded to what should be a therapeutic dose, if the patient is at higher risk of drug side effects because of age or medical illness, if the patient requires rapid increases in medication because of high risk of suicide, if compliance is in question, to document the optimal therapeutic level for a patient, and to monitor potential drug interactions when TCAs are given with medication known to increase blood concentration (e.g., cimetidin SSRIs).
Dosing Regimens. The starting dose for nortriptyline is usually 25 mg! d and can be increased to 75 mg/d over 7 to 14 days, depending On the patient’s response and the emergence of side effects. The maximum dose of nortriptyline should not exceed 150 mg/d. Starting doses for most of these medications is 25 mg with gradual increases to the therapeutic ranges. The therapeutic range for imipramine is calculated as the sum of the concentration of both imipramine itself and its metabolite, desipramine. The total concentration of both imipramine and desipramine should be 200 to 250 ng/mg. In the case of using desipramine alone, the concentration should not exceed 125 ng/mL. For clomipramine (Anafranil), a TCA with additional effectiveness in the treatment of obsessive-compulsive disorder, the maximum dose should not exceed 250 mg/d to avoid the risk of seizures encountered at higher doses.
Adverse Effects and Common Side Effects. The major adverse effect is the risk of cardiac arrhythmias, particularly in the case of overdose. These medications also commonly cause dry mouth, blurred vision, and sedation.
Selective Serotonin Reuptake Inhibitors Five SSRIs are now available commercially in the United States: fluoxetine (Prozac), sertraline (Zoloft), paroxetine (PaxiD, fluvoxamine (Luvox), and citalopram (Celexa). The mechanism of action is complex and includes inhibition of serotOnin neurotransmission. These medications have a wide spectrum of psychiatric application, including depression, obsessive-compulsive disorder, panic disorder, and bulimia. In treating depression, the onset of action is generally within 3 to 8 weeks. Transient symptom worsening may be noted early in the course of treatment for patients with anxiety. There is some sense that SSRls are not as efficacious in treating melancholic depression as TCAs and MAOIs.
Dosing Regimens. The usual treatment doses of the SSRIs are listed in Table 9-8. It is important to begin with small doses and gradually increase the medication to the levels indicated over several weeks to minimize side effects.
Adverse Effects. Sexual dysfunction, generally defined as decreased sexual interest and inhibited orgasm, is often the most troublesome side effect associated with the use of these medICations. The incidence of this adverse effect is high, generally estimated at 40 to 50 percent. It is thought to be mediated through both central and spinal serotonin effects as well as effects on dopamine pathways.
Many methods have evolved to address SSRI mediated sexual dysfunction. Using agents with a shorter half-life and withholding the pills for 1 to 2 days before anticipated sexual activity are initial management strategies. Counteractive medications may also be used. For example, one strategy is to increase dopamine concentrations by adding bupropion (Wellbutrin), amantadine (Symmetrel), methylphenidate (Ritalin), or pramipexole (Mirapex) to the regimen. Another option is to increase norepinephrine activity through the use of yohimbine (Yocon). Inhibition of serotonin via cyproheptadine (Periactin) or buspirone (Buspar) is another approach that has been used. Ginkgo biloba and ginseng have some demonstrated efficacy, but their mechanisms of action are unknown. It may be necessary to use a different antidepressant altogether. Good alternatives to consider are bupropion (Wellbutrin), nefazodone (Serzone), and mirtazapine (Remeron). It is also Possible that one SSRI will not induce the same sexual dysfunction as another, and switching SSRIs may be a successful strategy.
Common Side Effects. Early observations suggested that weight loss was associated with the Use of SSRIs through serotonin-mediated effects On the brainstem and hypothalamus. However, long-term weight gain is observed in 1 to 50 percent of patients. The mechanism of weight gain is not well understood, but it may be mediated through a serotonin receptor subtype, 5-HT2C. Most often, the effect is a loss of a sense of satiety as opposed to a reduction in metabolism. It is important to counsel patients at the time of beginning a trial of an SSRI about possible weight gain and to monitor their food consumption and exercise. Other side effects.
Discontinuation Syndrome. A discontinuation syndrome is sometimes observed when a patient stops using an SSRI. The discontinuation syndrome is characterized by flulike symptoms including fatigue, dizziness, chills, sweating, lightheadedness, anxiety, and incoordination. Abrupt discontinuation of the medication is most likely to provoke this problem, but even tapering the medication will sometimes trigger the syndrome. The reported frequency of the syndrome varies widely, with rates of 5 to 80 percent quoted in the literature. Short half-life agents (sertraline, paroxetine, fluvoxamine, and venlafaxine) are more prone to this problem than fluoxetine. Symptoms are usually not severe, though, and generally remit within 3 weeks. Tapering the dose over 3 to 4 weeks before stopping a short-acting agent will decrease the likelihood of provoking the discontinuation syndrome. The cause of this adverse effect is unclear, but some posit that the symptoms represent hyposerotonergic tone in the central nervous system (CNS) or remodulation of other neurotransmitter systems in the setting of hyposerotonergic tone.
Drug-Drug Interactions. Much has been written about the potential drug-drug interactions of the SSRIs. These agents can be significant enzyme inhibitors of the P 450 system of hepatic metabolism. A number of drug interactions with the potential for clinical significance exist. particular concern, however, is the combination of SSRIs with other agents that may elevate serotonin levels because a lethal hyperserotonergic state can develop. Patients should be asked about concomitant use of alternative therapies that affect serotonin, such as St. John’s wort, before prescribing SSRIs.TCA stransmission, leaving the serotonin system affected. It is unique in its mechanism of action has also been shown to be effective in treatin attention deficit disorder and in helping people smoking cessation. The dosage range and side effects are Of note is that bupropion causes no sexual dysfunction or weight gain. It can cause seizures with overdose.
Antidepressant Use in Pregnancy and The Postpartum Period
Generally, antidepressants are well tolerated in pregnancy, and careful assessment of the risk of significant untreated psychiatric illness (e.g., poor maternal nutrition, suicide) must be weighed against the potential risk of teratogenicity. As a guiding principle, the use of medication in pregnancy should be correlated with the severity of mental illness. It is not unreasonable to maximize nonpharmacologic approaches in women with mild to moderate depression with a single episode of depression beginning in the first trimester. Likewise, women who are taking medication for their first episode of depression, with only mild or moderate symptoms, can be considered for tapering their medication when they become pregnant or if they wish to try to conceive. Medication is indicated, however, if the symptoms of depression are moderate to severe of if they persist into the second trimester.
Despite the desire of most women and their health care providers to avoid medication in the first trimester, if a woman has a history of recurrent moderate to severe depression with multiple failed attempts at antidepressant discontinuation, maintaining antidepressant treatment during conception attempts and pregnancy is preferable. The research to date would indicate that bupropion, maprotiline, fluoxetine, sertraline, paroxetine, or desipramine are probably safe to use. Only bupropion and maprotiline, however, are rated as Pregnancy Category B (no evidence of risk to fetus). In a study of 228 pregnant women treated with fluoxetine during the first trimester of pregnancy, investigators found no increase in teratogenicity, but did report perinatal neurobehavioral effects.71 Other investigators, however, found no effect on the neurobehavioral development of preschool children exposed in utero to either TCAs or fluoxetine.
It is especially important to monitor the affective state of women with a history of depression after delivery because up to 25 percent of these patients will develop a postpartum depression. Given the inherent stresses of new parenthood, increased vigilance for this possibility is required. There are no differences in the treatment of women in the postpaitum period from the treatment of women at other times, unless the woman is breast-feeding. For these mothers, antidepressants that have no adverse effects on breast-fed infants may be considered for use. These include amitriptyline, clomipramine, imipramine, desipramine, nortriptyline, bupropion, and sertraline.
There clearly has been an increased interest in alternative medicine over the past several years, and some of these therapies have been effective in the treatment of depression. Some of the best data support the “prescription” of exercise to depressed patients. The antidepressant effect of exercise is observed with all types of regular exercise and is independent of gender or age. Some data suggest that the antidepressant effect of exercise may be on a par with psychotherapy.
Another popular complementary therapy is St. John’s wort (Hypericum perforatum). The usual dose of hypericum is 300 mg tid. Experience in this country is still limited, however, and there is a general clinical sense that hypericum is useful primarily in depressions of mild intensity. St. John’s wort should not be used by patients taking SSRIs because both agents increase serotonin levels, placing patients at risk for serotonin syndrome.
A variety of other therapies have been put forth as effective in treating depression. Examples are aromatherapy, dance and movement therapy,homeopathy, hypnotherapy, massage therapy, acupuncture, music therapy, and relaxation therapy. Of these, however, supportive data are available only for acupuncture, massage, and relaxation. There are no controlled research trials regarding the relative efficacy ofthese other forms of therapy.
Recent information suggests a link between the amount and type of dietary fat and psychiatric illness. There has long been puzzlement over why depression occurs at such different rates in different societies, and diet may be one reason. Dietary fat may be important in mental health because of its role in supporting normal brain function. The cell membrane at neuron synapses is composed almost entirely of essential fatty acids. Speculation has centered on omega-3 polyunsaturated fatty acids in particular. These fatty acids are found in especially high concentrations in fish oils, and rates of major depression are markedly different depending on how much fish is consumed. In Japan, for example, people consume over 140 lb of fish per person per year, and the rate of depression in Japan is just 0.12 percent! In Germany, people eat a little over 20 lb of fish per person per year and have a depression rate of 5 percent. These low rates of depression are in stark contrast to those in the United States.
Anxiety disorders are the most common of all psychiatric conditions, and they are disproportionately common in women. Although up to 25 percent of Americans may have a diagnosable anxiety disorder during their lifetime, over 30 percent of women will at some time in their life develop an anxiety disorder. In addition to being more common, anxiety disorders can be just a disabling as depression, and the acute sense of subjective discomfort is often worse with anxiety symptoms. In some studies, up to 7 percent of people with one common anxiety disorder, panic disorder, will eventually commit suicide.
Medical Conditions That Can Mimic Anxiety
Because of the number of somatic symptoms that are a part of anxiety syndromes, non-psychiatrists are often the first medical professionals consulted by patients suffering from these symptoms. Medical conditions that can mimic anxiety include a number of cardiac conditions, ischemic heart disease, and arrhythmias. Conversely, up to 20 percent of people referred to a cardiologist for the first time will actually have an anxiety disorder, especially panic disorder. Pulmonary conditions can likewise simulate anxiety. Chronic obstructive pulmonary disease, pulmonary embolism, and asthma can all cause the sense of dyspnea that is a frequent feature of anxiety. Gastrointestinal symptoms such as abdominal discomfort, cramping, and diarrhea can all be easily confused with anxiety. Other medical conditions such as hyperthyroidism, hypoglycemia, menopause, premenstrual syndrome, pheochromocytoma, transient ischemic attacks, vitamin deficiencies, and various drugs including caffeine, alcohol, bronchodilators, amphetamines, corticosteroids, and illicit drugs may produce symptoms identical to those occurring in anxiety disorders.
Coexisting Psychiatric Disorders
As difficult as it can be to separate medical conditions and anxiety disorders, and indeed the two often coexist, the same is true of psychiatric disorders. The anxiety disorders themselves are not always easy to discern from each other (e.g., panic disorder and social phobia) and often coexist with other subtypes of psychiatric disorders. Anxiety can be a comorbid or complicating feature of psychotic, substance abuse, somatoform, sexual, personality, and especially mood disorders. Depression also commonly coexists with anxiety. The presence of significant anxiety symptoms not only complicates the treatment of depression, but it also signifies a more chronic and treatment-resistant course. Independent identification of anxiety symptoms is important because separate and effective treatments are available.
Coexisting Substance Abuse
It is not uncommon for patients to resort to the use of alcohol or illicit substances to self-medicate anxiety symptoms. Alcohol is particularly treacherous because it can effectively ameliorate anxiety symptoms acutely, but it can aggravate them through complicating depression and inhibiting normal sleep. Withdrawal symptoms, when present, can provoke anxiety and lead to more alcohol consumption to reduce the discomfort associated with them. Unfortunately, some of the medications used to treat anxiety can themselves be problematic in that they can be abused. Barbiturates and benzodiazepines are the worst offenders in this regard.
To diagnose anxiety disorders, a high index of suspicion must be maintained by the clinician along with an open approach, using open-ended questions, careful listening, and observation. Given the increasing time constraints faced by clinicians, this task may appear daunting. Nevertheless, it is important to be successful in discerning and diagnosing these conditions, so that unnecessary, fruitless, and expensive workups for somatic symptoms of anxiety can be avoided. Effective treatment cannot begin until an accurate diagnosis is made.
Types of Anxiety Disorders
Of all the anxiety disorders, panic disorder is the best known. The definition of panic disorder consists of the recurrence of unexpected panic attacks, discrete periods of intense anxiety or fear, accompanied by at least four of the symptoms. In addition, there must be a period of at least 1 month after at least one attack where there is persistent concern about having additional attacks, worry about the implications of the attack or its consequences, or a significant change in behavior related to the attacks. Furthermore, it must be determined that the panic attacks are not due to the effects of a substance, a medical condition, or another mental disorder. Panic disorder mayor may not be complicated by agoraphobia. Agoraphobia is anxiety or fear about being in places or situations from which escape might be difficult or in which help may not be available in the event of having a panic attack.
The overall lifetime incidence of panic disorder is 3.5 percent in the United States; among women, the incidence is about 5 percent. One year prevalence rates are 1 to 2 percent. About one-third to one-half of patients with panic disorder also have agoraphobia. Age of onset is generally between adolescence and the midthirties, although it can begin in childhood and, rarely, after age 45. The usual course is chronic, but symptom intensity can wax and wane with time. With treatment, about one-third of patients can achieve remission of their symptoms for long periods of time, one-third achieve some improvement in their symptoms, and the remaining third have chronic symptoms that sometimes get worse. Although a genetic factor is involved in the development of panic disorder, at least half of the patients do not have an affected first degree relative.
There are no significant differences between men and women in panic symptoms noted at the onset of the disorder, in symptom severity, or in remission rates (about 40 percent). The clinical course of the disorder, however, appears different. Women are more likely to have panic disorder with agoraphobia (85 versus 75 percent). In contrast, men are more likely to have uncomplicated panic disorder (25 versus 15 percent). In addition, of those who achieve remission, 25 percent of women and 15 percent of men reexperienced symptoms within 6 months. Also, recurrence of panic symptoms remains higher among women (82 versus 51 percent).
According to DSM-IV, the core definition of social phobia is a marked and persistent fear of social or performance situations in which embarrassment may occur. Exposure to the feared social situation almost invariably provokes anxiety that can mimic a panic attack. One potentially distinguishing feature of the anxiety of social phobia is the presence of blushing during the episode. Other associated features include the recognition by the patient that the fear is excessive or unreasonable, the avoidance of feared social or performance situations, and the impaired occupational or social functioning that results.
The most common symptom is fear of public speaking. Other performance fears such as eating, drinking, or writing in public or using a public restroom are less common. Social phobia is estimated to occur in 3 to 13 percent of individuals (lifetime prevalence). AS with panic disorder, women appear to be more frequently affected than men. Symptom onset typically occurs in adolescence. There appears to be an increased incidence of social phobia in first-degree relatives of those with the disorder. Stressful or humiliating childhood experiences can predispose to the development of this disorder. At other times the onset can be more insidious. The duration of the disorder is generally thought to be lifelong.
Postiraumatic Stress Disorder
The diagnosis of posttraumatic stress disorder, according to the DSM-IV. Although this diagnosis is often considered in the context of exposure to such situations as war or large-scale natural disasters, it can also apply to physical or sexual abuse, which is more common for women and children. Because abuse is often surrounded by shame and secrecy, the possibility of this diagnosis as an explanation for anxiety symptoms may be easily overlooked. When considering the prevalence of posttraumatic stress disorder, it is useful to divide the population into an “at-large” group and an “at-risk” group. In the general population (the at-large group), posttraumatic stress disorder affects between 1 and 14 percent of all people. However, in groups of people who have been exposed to a severe traumatic event (the at-risk group), the potential prevalence rate rises to 58 percent.
Consistent with both of the major epidemiologic psychiatric studies, the ECA survey and the National Comorbidity Study, Breslau et al. found that the lifetime prevalence rate of posttraumatic stress disorder in women is about double that observed in men. Interestingly, these prevalence rates are consistent in the face of approximately equal numbers of traumatic events in the lives of men and women. The widest difference in prevalence rates occurred in childhood age groups; girls experiencing traumatic events developed posttraumatic stress disorder significantly more frequently than boys, but after the age of 15, the prevalence rates became similar. It is not clear, however, why this discrepancy in prevalence rates in childhood exists.
Generalized Anxiety Disorder
The chief feature of generalized anxiety disorder, according to the DSM-IV, is excessive worry or anxiety more days than not about a number of events or activities, and the person so affected finds it difficult to control the worry. A number of accompanying symptoms (e.g., restlessness, easy fatigue, insomnia, and irritability) are also necessary to make the diagnosis. The 1-year prevalence rate is about 3 percent and the lifetime rate is 5 percent. Women are affected more frequently than men by a ratio of about 3:2. Generalized anxiety disorder frequently coexists with other anxiety and depressive disorders, such as panic disorder and dysthymia. The usual course of the disorder is chronic with waxing and waning symptoms.
The diagnosis of this anxiety disorder depends on the presence of obsessions and compulsions, Obsessions are recurring and persistent ideas, thoughts, images, or impulses that are experienced by the patient as intrusive and that cause marked anxiety or distress. The most common obsessions are about contamination, repeated doubts, a need to have things in a particular order, aggressive or horrific impulses, and sexual images. Compulsions are repetitive behaviors that are intended to reduce anxiety or distress. The most common compulsions are washing and cleaning, counting, checking, requesting or demanding assurances, repeating actions, and ordering. Patients with this disorder recognize that the obsessions or compulsions are either excessive or unreasonable. They also experience these symptoms with significant distress. Although there is no gender difference in prevalence or incidence rates, women tend to be afflicted later in life, with the onset most frequently in their twenties. Stress predictably worsens symptoms, although the overall course is generally waxing and waning. Once thought to be rare, obsessive-compulsive disorder is actually relatively common, affecting 2 to 3 percent of the population over their lifetimes; the I-year prevalence rate is estimated to be 1 to 2 percent. Patients do not often volunteer the presence of these symptoms, and a high degree of suspicion must be maintained, coupled with direct questions during the interview to elicit an accurate history.
Antidepressants As if to underscore the neurochemical and pathophysiologic overlap between anxiety and depressive disorders, antidepressant agents are also the mainstay of pharmacologic treatment of anxiety. The main classes of antidepressants (i.e., MAOIs, TCAs, and SSRIs) all have proven efficacy in the treatment of anxiety. Nearly all of the newer antidepressants (e.g., Effexor, Serzone, and Remeron) also have antianxiety properties. Wellbutrin is the single exception to this rule.
Selective Serotonin Reuptake Inhibitors. The SSRIs have demonstrated efficacy in treating most anxiety disorders, including panic disorder (with or without agoraphobia), posttraumatic stress disorder, social phobia, obsessive-compulsive disorder, and generalized anxiety disorder. One caveat in using SSRIs in patients with anxiety disorders is that smaller starting doses are generally better tolerated than the usual starting doses. Suggested initial doses are: fluoxetine (Prozac), 5 to 10 mg/d; sertraline (Zoloft), 25 to 50 mg/d; paroxetine (Paxil), 10 mg/d; fluvoxamine (Luvox), 25 mg/d; and citalopram (Celexa), 10 to 20 mg/d. An irony in treating anxiety disorders, however, is that it is not uncommon to eventually use higher doses than antidepressant doses to control anxiety symptoms.
Tricyclic Antidepressants. The TCAs were the mainstay of therapy for anxiety disorders for many years until the advent of SSRIs. More research is available about the use of imipramine (TofraniD in panic disorder than any other antidepressant, and it was long considered to be the gold standard for treating panic. These agents have largely been supplanted by the SSRIs because of the better safety and side-effect profiles of SSRIs. When used, TCAs are also initiated at low doses. In the case of imipramine, a starting dose of 10 mg/d is appropriate. This class of antidepressants is effective especially in patients with panic disorder but also useful in those with generalized anxiety disorder and posttraumatic stress disorder.
Monoamine Oxidase Inhibitors. The MAOIs also have a role in the treatment in anxiety disorders. In fact, they are still without peer in the treatment of social phobia, although SSRIs have some efficacy in this disorder as well. Unlike other antidepressants, however, these agents are rarely associated with any initial exacerbation of anxiety when beginning treatment. In addition to social phobia, they are useful in treating panic disorder and posttraumatic stress disorder. While the concern about hypertensive crisis is justified, these agents are probably underused in treating anxiety just as they are underused in depression.
Other Agents. The atypical antidepressants Effexor and Serzone both have shown effectiveness as well. As is the case with the SSRIs, lower starting doses are likely to be better tolerated by the anxious patient. With Effexor, begin with 18.75 mg bid, and with Serzone, the starting dose is 50 mg bid. Remeron has shown some efficacy with anxiety, but experience is limited to date.
Benzodiazepines. Benzodiazepines have an important but limited role in the treatment of anxiety disorders. The use of the benzodiazepines is associated with both tolerance and withdrawal symptoms. Because of these problems, benzodiazepines should not be considered first-line agents in the treatment of anxiety disorders. Their use is best reserved for acute situations, especially panic attacks. In clinical practice, SSRIs are used to provide prophylaxis against chronic anxiety; the benzodiazepines are used in an adjunctive role. Chronic use of benzodiazepines is discouraged, especially in the elderly and in patients with any significant history of substance abuse.
Virtually all of the benzodiazepines are equally effective in treating anxiety disorders when used in equipotent doses . The higher-potency agents, alprazolam (Xanax) and clonazepam (Klonopin), are used more frequently for the treatment of panic disorder, although diazepam (Valium), too, has a long history of proven effectiveness. For the most part, selection of these agents depends on the best match of pharmacokinetic properties to the clinical situation. In treating an acute panic attack, for example, use of an agent with a rapid onset of action (e.g., lorazepam, clorazepate) would be preferable to an agent with a slower onset.
Benzodiazepines can adversely affect gait and balance in the elderly, resulting in a higher incidence of falls. Another concern is the depression that can be caused or aggravated by chronic and especially high-dose use of benzodiazepines. However, benzodiazepines can be especially useful, in moderate doses, in the early phases of treating an anxiety disorder, as the clinician and patient wait for the onset of action of the antidepressant.
Buspirone. Buspirone (Buspar), a nonbenzodiazepine anxiolytic, is another agent with proven efficacy in the treatment of anxiety disorders, although its usefulness is limited to generalized anxiety disorder. Advantages of buspirone include the absence of tolerance and withdrawal symptoms. However, it has a long onset of action and full effects may take as long as 4 to 8 weeks to achieve. Buspirone has gained the reputation of not being particularly effective, but this inaccurate perception is likely related to its slow onset of effect as well as inadequate dosing. Doses of 30 to 60 mg/ d are necessary in most patients to achieve beneficial clinical effects. For patients who are being treated with benzodiazepines chronically, it is helpful to add buspirone and gradually decrease and taper the benzodiazepine dose in an effort to wean these agents. Buspirone occupies an especially useful niche in the treatment of generalized anxiety disorder in the elderly and in patients with a significant history of substance abuse.
Other Agents. Other pharmacologic agents that have been used adjunctively in the treatment of anxiety include f3-adrenergic blockers and anticonvulsants. The adrenergic blockers decrease autonomic arousal and can be useful for the somatic symptoms of panic and generalized anxiety disorder, but not as primary treatment. They can be especially helpful in social phobia of the performance anxiety subtype.8o Somewhat surprisingly, anticonvulsants can have efficacy in the adjunctive treatment of anxiety. Both val pro ate (Depakote) and gabapentin (Neurontin) are used for the treatment of panic disorder, and gabapentin has been successfully used in treating social phobia.
Treatment During Pregnancy And Postpartum Many benzodiazepines are known to cross the placenta; information is not available for all agents. These agents should be avoided in the first trimester because diazepam and clordiazepoxide have been reported to increase the risk of congenital malformation, and other agents may also increase risk. The use of benzodiazepines during the last weeks of pregnancy may cause neonatal CNS depression. Maternal administration just before or during labor may also cause neonatal flaccidity. In addition, chronic use of these medications during pregnancy may cause withdrawal symptoms in the infant after delivery.
In contrast, buspirone (Pregnancy Category B) is not known to have any adverse effects on pregnancy or labor and delivery. Information on antidepressant use in pregnancy can be found in the previous section of this chapter on depression in pregnancy.
A number of benzodiazepines are known to be excreted in breast milk, and it is expected that all of these agents would appear in breast milk. There is a possibility of pharmacologic effects in nursing infants (e.g., sedation, lethargy, poor feeding, weight loss). Neonates metabolize benzodiazepines more slowly than adults, and accumulation of drug is possible. Potential adverse effects to the infant are a concern especially if exposure is prolonged or in the case of high maternal doses. No problems in humans have been documented with buspirone use during lactation; it is not known, however, whether this agent is excreted in human milk.
As in depression, non pharmacologic treat. ments are also helpful. It is wise to use a com. prehensive treatment strategy in treating anxiety disorders, with pharmacologic interventions accounting for only one dimension of available treatments. Various types of psychotherapy and especially cognitive-behavioral therapy can be highly effective. Graded exposure to the anxiety producing circumstances is a core component of this type of therapy. Other components include the correction of cognitive misperceptions, breathing retraining, and muscle relaxation. Improvement in anxiety symptoms is reported to be better sustained when patients engage in cognitivebehavioral treatment, as compared to use of only pharmacologic treatment.
Using relaxation techniques, engaging in regular exercise, and avoiding stimulants such as caffeine, diet pills, and decongestants are also important. It is also necessary to address the potential complication of substance abuse in these patients. Finally, combined pharmacologic and psychotherapeutic interventions appear to hold the most promise in sustaining remission of symptoms.
Anxiety and depressive disorders are complex, important conditions with significant and often underestimated morbidity and mortality. The causes of these conditions are many and varied, and it is crucial to search for all of the components of the etiologies of depression and anxiety. A significant pitfall in clinical practice is to not allot sufficient time to explore the subtleties involved in eliciting an accurate and complete history. All too often, histories of abuse, substance abuse, and psychological conflict or family history are missed, to the detriment of effective treatment. It is not easy in this age of managed care and shrinking appointment times to give these conditions the time needed for both diagnosis and treatment, but it is nevertheless critical to do so. It is also crucial to be ever mindful that these conditions do not easily resolve with pharmacologic interventions alone. The construction of a comprehensive treatment plan is mandatory and needs to consider all forms of therapy that might be helpful. Most patients can be successfully managed by a primary care provider. It is incumbent on that provider to consider all of the etiologic and treatment factors pertinent to the individual patient.