Neuroscience Alliance 614-893-0910 or BTCarroll1@cs.com - 614-937-9427 WHAT IS A DEPRESSIVE DISORDER? A depressive disorder is an illness that involves the body, mood, and thoughts. It affects the way a person eats and sleeps, the way one feels about oneself, and the way one thinks about things. A depressive disorder is not the same as a passing blue mood. It is not a sign of personal weakness or a condition that can be willed or wished away. People with a depressive illness cannot merely "pull themselves together" and get better. Without treatment, symptoms can last for weeks, months, or years. Appropriate treatment, however, can help most people who suffer from depression. TYPES OF DEPRESSION Depressive disorders come in different forms, just as is the case with other illnesses such as heart disease. This pamphlet briefly describes three of the most common types of depressive disorders. However, within these types there are variations in the number of symptoms, their severity, and persistence. Major depression is manifested by a combination of symptoms (see symptom list) that interfere with the ability to work, study, sleep, eat, and enjoy once pleasurable activities. Such a disabling episode of depression may occur only once but more commonly occurs several times in a lifetime. A less severe type of depression, dysthymia, involves long-term, chronic symptoms that do not disable, but keep one from functioning well or from feeling good. Many people with dysthymia also experience major depressive episodes at some time in their lives. Another type of depression is bipolar disorder, also called manic-depressive illness. Not nearly as prevalent as other forms of depressive disorders, bipolar disorder is characterized by cycling mood changes: severe highs (mania) and lows (depression). Sometimes the mood switches are dramatic and rapid, but most often they are gradual. When in the depressed cycle, an individual can have any or all of the symptoms of a depressive disorder. When in the manic cycle, the individual may be overactive, overtalkative, and have a great deal of energy. Mania often affects thinking, judgment, and social behavior in ways that cause serious problems and embarrassment. For example, the individual in a manic phase may feel elated, full of grand schemes that might range from unwise business decisions to romantic sprees. Mania, left untreated, may worsen to a psychotic state. SYMPTOMS OF DEPRESSION AND MANIA Not everyone who is depressed or manic experiences every symptom. Some people experience a few symptoms, some many. Severity of symptoms varies with individuals and also varies over time. Depression Persistent sad, anxious, or "empty" mood Feelings of hopelessness, pessimism Feelings of guilt, worthlessness, helplessness Loss of interest or pleasure in hobbies and activities that were once enjoyed, including sex Decreased energy, fatigue, being "slowed down" Difficulty concentrating, remembering, making decisions Insomnia, early-morning awakening, or oversleeping Appetite and/or weight loss or overeating and weight gain Thoughts of death or suicide; suicide attempts Restlessness, irritability Persistent physical symptoms that do not respond to treatment, such as headaches, digestive disorders, and chronic pain Mania Abnormal or excessive elation Unusual irritability Decreased need for sleep Grandiose notions Increased talking Racing thoughts Increased sexual desire Markedly increased energy Poor judgment Inappropriate social behavior CAUSES OF DEPRESSION Some types of depression run in families, suggesting that a biological vulnerability can be inherited. This seems to be the case with bipolar disorder. Studies of families in which members of each generation develop bipolar disorder found that those with the illness have a somewhat different genetic makeup than those who do not get ill. However, the reverse is not true: Not everybody with the genetic makeup that causes vulnerability to bipolar disorder will have the illness. Apparently additional factors, possibly stresses at home, work, or school, are involved in its onset. In some families, major depression also seems to occur generation after generation. However, it can also occur in people who have no family history of depression. Whether inherited or not, major depressive disorder is often associated with changes in brain structures or brain function. People who have low self-esteem, who consistently view themselves and the world with pessimism or who are readily overwhelmed by stress, are prone to depression. Whether this represents a psychological predisposition or an early form of the illness is not clear. In recent years, researchers have shown that physical changes in the body can be accompanied by mental changes as well. Medical illnesses such as stroke, a heart attack, cancer, Parkinson's disease, and hormonal disorders can cause depressive illness, making the sick person apathetic and unwilling to care for his or her physical needs, thus prolonging the recovery period. Also, a serious loss, difficult relationship, financial problem, or any stressful (unwelcome or even desired) change in life patterns can trigger a depressive episode. Very often, a combination of genetic, psychological, and environmental factors is involved in the onset of a depressive disorder. Later episodes of illness typically are precipitated by only mild stresses, or none at all. Depression in Women Women experience depression about twice as often as men.1 Many hormonal factors may contribute to the increased rate of depression in women—particularly such factors as menstrual cycle changes, pregnancy, miscarriage, postpartum period, pre-menopause, and menopause. Many women also face additional stresses such as responsibilities both at work and home, single parenthood, and caring for children and for aging parents. A recent NIMH study showed that in the case of severe premenstrual syndrome (PMS), women with a preexisting vulnerability to PMS experienced relief from mood and physical symptoms when their sex hormones were suppressed. Shortly after the hormones were re-introduced, they again developed symptoms of PMS. Women without a history of PMS reported no effects of the hormonal manipulation.6,7 Many women are also particularly vulnerable after the birth of a baby. The hormonal and physical changes, as well as the added responsibility of a new life, can be factors that lead to postpartum depression in some women. While transient "blues" are common in new mothers, a full-blown depressive episode is not a normal occurrence and requires active intervention. Treatment by a sympathetic physician and the family's emotional support for the new mother are prime considerations in aiding her to recover her physical and mental well-being and her ability to care for and enjoy the infant. Depression in Men Although men are less likely to suffer from depression than women, 3 to 4 million men in the United States are affected by the illness. Men are less likely to admit to depression, and doctors are less likely to suspect it. The rate of suicide in men is four times that of women, though more women attempt it. In fact, after age 70, the rate of men's suicide rises, reaching a peak after age 85. Depression can also affect the physical health in men differently from women. A new study shows that, although depression is associated with an increased risk of coronary heart disease in both men and women, only men suffer a high death rate.2 Men's depression is often masked by alcohol or drugs, or by the socially acceptable habit of working excessively long hours. Depression typically shows up in men not as feeling hopeless and helpless, but as being irritable, angry, and discouraged; hence, depression may be difficult to recognize as such in men. Even if a man realizes that he is depressed, he may be less willing than a woman to seek help. Encouragement and support from concerned family members can make a difference. In the workplace, employee assistance professionals or worksite mental health programs can be of assistance in helping men understand and accept depression as a real illness that needs treatment. Depression in the Elderly Some people have the mistaken idea that it is normal for the elderly to feel depressed. On the contrary, most older people feel satisfied with their lives. Sometimes, though, when depression develops, it may be dismissed as a normal part of aging. Depression in the elderly, undiagnosed and untreated, causes needless suffering for the family and for the individual who could otherwise live a fruitful life. When he or she does go to the doctor, the symptoms described are usually physical, for the older person is often reluctant to discuss feelings of hopelessness, sadness, loss of interest in normally pleasurable activities, or extremely prolonged grief after a loss. Recognizing how depressive symptoms in older people are often missed, many health care professionals are learning to identify and treat the underlying depression. They recognize that some symptoms may be side effects of medication the older person is taking for a physical problem, or they may be caused by a co-occurring illness. If a diagnosis of depression is made, treatment with medication and/or psychotherapy will help the depressed person return to a happier, more fulfilling life. Recent research suggests that brief psychotherapy (talk therapies that help a person in day-to-day relationships or in learning to counter the distorted negative thinking that commonly accompanies depression) is effective in reducing symptoms in short-term depression in older persons who are medically ill. Psychotherapy is also useful in older patients who cannot or will not take medication. Efficacy studies show that late-life depression can be treated with psychotherapy.4 Improved recognition and treatment of depression in late life will make those years more enjoyable and fulfilling for the depressed elderly person, the family, and caretakers. Depression in Children Only in the past two decades has depression in children been taken very seriously. The depressed child may pretend to be sick, refuse to go to school, cling to a parent, or worry that the parent may die. Older children may sulk, get into trouble at school, be negative, grouchy, and feel misunderstood. Because normal behaviors vary from one childhood stage to another, it can be difficult to tell whether a child is just going through a temporary "phase" or is suffering from depression. Sometimes the parents become worried about how the child's behavior has changed, or a teacher mentions that "your child doesn't seem to be himself." In such a case, if a visit to the child's pediatrician rules out physical symptoms, the doctor will probably suggest that the child be evaluated, preferably by a psychiatrist who specializes in the treatment of children. If treatment is needed, the doctor may suggest that another therapist, usually a social worker or a psychologist, provide therapy while the psychiatrist will oversee medication if it is needed. Parents should not be afraid to ask questions: What are the therapist's qualifications? What kind of therapy will the child have? Will the family as a whole participate in therapy? Will my child's therapy include an antidepressant? If so, what might the side effects be? The National Institute of Mental Health (NIMH) has identified the use of medications for depression in children as an important area for research. The NIMH-supported Research Units on Pediatric Psychopharmacology (RUPPs) form a network of seven research sites where clinical studies on the effects of medications for mental disorders can be conducted in children and adolescents. Among the medications being studied are antidepressants, some of which have been found to be effective in treating children with depression, if properly monitored by the child's physician.8 DIAGNOSTIC EVALUATION AND TREATMENT The first step to getting appropriate treatment for depression is a physical examination by a physician. Certain medications as well as some medical conditions such as a viral infection can cause the same symptoms as depression, and the physician should rule out these possibilities through examination, interview, and lab tests. If a physical cause for the depression is ruled out, a psychological evaluation should be done, by the physician or by referral to a psychiatrist or psychologist. A good diagnostic evaluation will include a complete history of symptoms, i.e., when they started, how long they have lasted, how severe they are, whether the patient had them before and, if so, whether the symptoms were treated and what treatment was given. The doctor should ask about alcohol and drug use, and if the patient has thoughts about death or suicide. Further, a history should include questions about whether other family members have had a depressive illness and, if treated, what treatments they may have received and which were effective. Last, a diagnostic evaluation should include a mental status examination to determine if speech or thought patterns or memory have been affected, as sometimes happens in the case of a depressive or manic-depressive illness. Treatment choice will depend on the outcome of the evaluation. There are a variety of antidepressant medications and psychotherapies that can be used to treat depressive disorders. Some people with milder forms may do well with psychotherapy alone. People with moderate to severe depression most often benefit from antidepressants. Most do best with combined treatment: medication to gain relatively quick symptom relief and psychotherapy to learn more effective ways to deal with life's problems, including depression. Depending on the patient's diagnosis and severity of symptoms, the therapist may prescribe medication and/or one of the several forms of psychotherapy that have proven effective for depression. Electroconvulsive therapy (ECT) is useful, particularly for individuals whose depression is severe or life threatening or who cannot take antidepressant medication.3 ECT often is effective in cases where antidepressant medications do not provide sufficient relief of symptoms. In recent years, ECT has been much improved. A muscle relaxant is given before treatment, which is done under brief anesthesia. Electrodes are placed at precise locations on the head to deliver electrical impulses. The stimulation causes a brief (about 30 seconds) seizure within the brain. The person receiving ECT does not consciously experience the electrical stimulus. For full therapeutic benefit, at least several sessions of ECT, typically given at the rate of three per week, are required. Medications There are several types of antidepressant medications used to treat depressive disorders. These include newer medications—chiefly the selective serotonin reuptake inhibitors (SSRIs)—the tricyclics, and the monoamine oxidase inhibitors (MAOIs). The SSRIs—and other newer medications that affect neurotransmitters such as dopamine or norepinephrine—generally have fewer side effects than tricyclics. Sometimes the doctor will try a variety of antidepressants before finding the most effective medication or combination of medications. Sometimes the dosage must be increased to be effective. Although some improvements may be seen in the first few weeks, antidepressant medications must be taken regularly for 3 to 4 weeks (in some cases, as many as 8 weeks) before the full therapeutic effect occurs. Patients often are tempted to stop medication too soon. They may feel better and think they no longer need the medication. Or they may think the medication isn't helping at all. It is important to keep taking medication until it has a chance to work, though side effects (see section on Side Effects on page 13) may appear before antidepressant activity does. Once the individual is feeling better, it is important to continue the medication for at least 4 to 9 months to prevent a recurrence of the depression. Some medications must be stopped gradually to give the body time to adjust. Never stop taking an antidepressant without consulting the doctor for instructions on how to safely discontinue the medication. For individuals with bipolar disorder or chronic major depression, medication may have to be maintained indefinitely. Antidepressant drugs are not habit-forming. However, as is the case with any type of medication prescribed for more than a few days, antidepressants have to be carefully monitored to see if the correct dosage is being given. The doctor will check the dosage and its effectiveness regularly. For the small number of people for whom MAO inhibitors are the best treatment, it is necessary to avoid certain foods that contain high levels of tyramine, such as many cheeses, wines, and pickles, as well as medications such as decongestants. The interaction of tyramine with MAOIs can bring on a hypertensive crisis, a sharp increase in blood pressure that can lead to a stroke. The doctor should furnish a complete list of prohibited foods that the patient should carry at all times. Other forms of antidepressants require no food restrictions. Medications of any kind—prescribed, over-the counter, or borrowed—should never be mixed without consulting the doctor. Other health professionals who may prescribe a drug—such as a dentist or other medical specialist—should be told of the medications the patient is taking. Some drugs, although safe when taken alone can, if taken with others, cause severe and dangerous side effects. Some drugs, like alcohol or street drugs, may reduce the effectiveness of antidepressants and should be avoided. This includes wine, beer, and hard liquor. Some people who have not had a problem with alcohol use may be permitted by their doctor to use a modest amount of alcohol while taking one of the newer antidepressants. Antianxiety drugs or sedatives are not antidepressants. They are sometimes prescribed along with antidepressants; however, they are not effective when taken alone for a depressive disorder. Stimulants, such as amphetamines, are not effective antidepressants, but they are used occasionally under close supervision in medically ill depressed patients. Questions about any antidepressant prescribed, or problems that may be related to the medication, should be discussed with the doctor. Lithium has for many years been the treatment of choice for bipolar disorder, as it can be effective in smoothing out the mood swings common to this disorder. Its use must be carefully monitored, as the range between an effective dose and a toxic one is small. If a person has preexisting thyroid, kidney, or heart disorders or epilepsy, lithium may not be recommended. Fortunately, other medications have been found to be of benefit in controlling mood swings. Among these are two mood-stabilizing anticonvulsants, carbamazepine (Tegretol®) and valproate (Depakote®). Both of these medications have gained wide acceptance in clinical practice, and valproate has been approved by the Food and Drug Administration for first-line treatment of acute mania. Other anticonvulsants that are being used now include lamotrigine (Lamictal®) and gabapentin (Neurontin®): their role in the treatment hierarchy of bipolar disorder remains under study. Most people who have bipolar disorder take more than one medication including, along with lithium and/or an anticonvulsant, a medication for accompanying agitation, anxiety, depression, or insomnia. Finding the best possible combination of these medications is of utmost importance to the patient and requires close monitoring by the physician. Side Effects Antidepressants may cause mild and, usually, temporary side effects (sometimes referred to as adverse effects) in some people. Typically these are annoying, but not serious. However, any unusual reactions or side effects or those that interfere with functioning should be reported to the doctor immediately. The most common side effects of tricyclic antidepressants, and ways to deal with them, are: Dry mouth—it is helpful to drink sips of water; chew sugarless gum; clean teeth daily. Constipation—bran cereals, prunes, fruit, and vegetables should be in the diet. Bladder problems—emptying the bladder may be troublesome, and the urine stream may not be as strong as usual; the doctor should be notified if there is marked difficulty or pain. Sexual problems—sexual functioning may change; if worrisome, it should be discussed with the doctor. Blurred vision—this will pass soon and will not usually necessitate new glasses. Dizziness—rising from the bed or chair slowly is helpful. Drowsiness as a daytime problem—this usually passes soon. A person feeling drowsy or sedated should not drive or operate heavy equipment. The more sedating antidepressants are generally taken at bedtime to help sleep and minimize daytime drowsiness. The newer antidepressants have different types of side effects: Headache—this will usually go away. Nausea—this is also temporary, but even when it occurs, it is transient after each dose. Nervousness and insomnia (trouble falling asleep or waking often during the night)—these may occur during the first few weeks; dosage reductions or time will usually resolve them. Agitation (feeling jittery)—if this happens for the first time after the drug is taken and is more than transient, the doctor should be notified. Sexual problems—the doctor should be consulted if the problem is persistent or worrisome. Herbal Therapy In the past few years, much interest has risen in the use of herbs in the treatment of both depression and anxiety. St. John's wort (Hypericum perforatum), an herb used extensively in the treatment of mild to moderate depression in Europe, has recently aroused interest in the United States. St. John's wort, an attractive bushy, low-growing plant covered with yellow flowers in summer, has been used for centuries in many folk and herbal remedies. Today in Germany, Hypericum is used in the treatment of depression more than any other antidepressant. However, the scientific studies that have been conducted on its use have been short-term and have used several different doses. Because of the widespread interest in St. John's wort, the National Institutes of Health (NIH) conducted a 3-year study, sponsored by three NIH components—the National Institute of Mental Health, the National Center for Complementary and Alternative Medicine, and the Office of Dietary Supplements. The study was designed to include 336 patients with major depression of moderate severity, randomly assigned to an 8-week trial with one-third of patients receiving a uniform dose of St. John's wort, another third sertraline, a selective serotonin reuptake inhibitor (SSRI) commonly prescribed for depression, and the final third a placebo (a pill that looks exactly like the SSRI and the St. John's wort, but has no active ingredients). The study participants who responded positively were followed for an additional 18 weeks. At the end of the first phase of the study, participants were measured on two scales, one for depression and one for overall functioning. There was no significant difference in rate of response for depression, but the scale for overall functioning was better for the antidepressant than for either St. John's wort or placebo. While this study did not support the use of St. John's wort in the treatment of major depression, ongoing NIH-supported research is examining a possible role for St. John's wort in the treatment of milder forms of depression. The Food and Drug Administration issued a Public Health Advisory on February 10, 2000. It stated that St. John's wort appears to affect an important metabolic pathway that is used by many drugs prescribed to treat conditions such as AIDS, heart disease, depression, seizures, certain cancers, and rejection of transplants. Therefore, health care providers should alert their patients about these potential drug interactions. Some other herbal supplements frequently used that have not been evaluated in large-scale clinical trials are ephedra, gingko biloba, echinacea, and ginseng. Any herbal supplement should be taken only after consultation with the doctor or other health care provider. PSYCHOTHERAPIES Many forms of psychotherapy, including some short-term (10-20 week) therapies, can help depressed individuals. "Talking" therapies help patients gain insight into and resolve their problems through verbal exchange with the therapist, sometimes combined with "homework" assignments between sessions. "Behavioral" therapists help patients learn how to obtain more satisfaction and rewards through their own actions and how to unlearn the behavioral patterns that contribute to or result from their depression. Two of the short-term psychotherapies that research has shown helpful for some forms of depression are interpersonal and cognitive/behavioral therapies. Interpersonal therapists focus on the patient's disturbed personal relationships that both cause and exacerbate (or increase) the depression. Cognitive/behavioral therapists help patients change the negative styles of thinking and behaving often associated with depression. Psychodynamic therapies, which are sometimes used to treat depressed persons, focus on resolving the patient's conflicted feelings. These therapies are often reserved until the depressive symptoms are significantly improved. In general, severe depressive illnesses, particularly those that are recurrent, will require medication (or ECT under special conditions) along with, or preceding, psychotherapy for the best outcome. HOW TO HELP YOURSELF IF YOU ARE DEPRESSED Depressive disorders make one feel exhausted, worthless, helpless, and hopeless. Such negative thoughts and feelings make some people feel like giving up. It is important to realize that these negative views are part of the depression and typically do not accurately reflect the actual circumstances. Negative thinking fades as treatment begins to take effect. In the meantime: Set realistic goals in light of the depression and assume a reasonable amount of responsibility. Break large tasks into small ones, set some priorities, and do what you can as you can. Try to be with other people and to confide in someone; it is usually better than being alone and secretive. Participate in activities that may make you feel better. Mild exercise, going to a movie, a ballgame, or participating in religious, social, or other activities may help. Expect your mood to improve gradually, not immediately. Feeling better takes time. It is advisable to postpone important decisions until the depression has lifted. Before deciding to make a significant transition—change jobs, get married or divorced—discuss it with others who know you well and have a more objective view of your situation. People rarely "snap out of" a depression. But they can feel a little better day-by-day. Remember, positive thinking will replace the negative thinking that is part of the depression and will disappear as your depression responds to treatment. Let your family and friends help you. How Family and Friends Can Help the Depressed Person The most important thing anyone can do for the depressed person is to help him or her get an appropriate diagnosis and treatment. This may involve encouraging the individual to stay with treatment until symptoms begin to abate (several weeks), or to seek different treatment if no improvement occurs. On occasion, it may require making an appointment and accompanying the depressed person to the doctor. It may also mean monitoring whether the depressed person is taking medication. The depressed person should be encouraged to obey the doctor's orders about the use of alcoholic products while on medication. The second most important thing is to offer emotional support. This involves understanding, patience, affection, and encouragement. Engage the depressed person in conversation and listen carefully. Do not disparage feelings expressed, but point out realities and offer hope. Do not ignore remarks about suicide. Report them to the depressed person's therapist. Invite the depressed person for walks, outings, to the movies, and other activities. Be gently insistent if your invitation is refused. Encourage participation in some activities that once gave pleasure, such as hobbies, sports, religious or cultural activities, but do not push the depressed person to undertake too much too soon. The depressed person needs diversion and company, but too many demands can increase feelings of failure. Do not accuse the depressed person of faking illness or of laziness, or expect him or her "to snap out of it." Eventually, with treatment, most people do get better. Keep that in mind, and keep reassuring the depressed person that, with time and help, he or she will feel better. WHERE TO GET HELP If unsure where to go for help, check the Yellow Pages under "mental health," "health," "social services," "suicide prevention," "crisis intervention services," "hotlines," "hospitals," or "physicians" for phone numbers and addresses. In times of crisis, the emergency room doctor at a hospital may be able to provide temporary help for an emotional problem, and will be able to tell you where and how to get further help. Listed below are the types of people and places that will make a referral to, or provide, diagnostic and treatment services. Family doctors Mental health specialists, such as psychiatrists, psychologists, social workers, or mental health counselors Health maintenance organizations Community mental health centers Hospital psychiatry departments and outpatient clinics University- or medical school-affiliated programs State hospital outpatient clinics Family service, social agencies, or clergy Private clinics and facilities Employee assistance programs Local medical and/or psychiatric societies FURTHER INFORMATION Please visit the following link for more information about organizations that focus on depression. REFERENCES 1 Blehar MD, Oren DA. Gender differences in depression. Medscape Women's Health, 1997;2:3. Revised from: Women's increased vulnerability to mood disorders: Integrating psychobiology and epidemiology. Depression, 1995;3:3-12. 2 Ferketick AK, Schwartzbaum JA, Frid DJ, Moeschberger ML. Depression as an antecedent to heart disease among women and men in the NHANES I study. National Health and Nutrition Examination Survey. Archives of Internal Medicine, 2000; 160(9): 1261-8. 3 Frank E, Karp JF, Rush AJ (1993). Efficacy of treatments for major depression. Psychopharmacology Bulletin, 1993; 29:457-75. 4 Lebowitz BD, Pearson JL, Schneider LS, Reynolds CF, Alexopoulos GS, Bruce MI, Conwell Y, Katz IR, Meyers BS, Morrison MF, Mossey J, Niederehe G, Parmelee P. Diagnosis and treatment of depression in late life: consensus statement update. Journal of the American Medical Association, 1997; 278:1186-90. 5 Robins LN, Regier DA (Eds). Psychiatric Disorders in America, The Epidemiologic Catchment Area Study, 1990; New York: The Free Press. 6 Rubinow DR, Schmidt PJ, Roca CA. Estrogen-serotonin interactions: Implications for affective regulation. Biological Psychiatry, 1998; 44(9):839-50. 7 Schmidt PJ, Neiman LK, Danaceau MA, Adams LF, Rubinow DR. Differential behavioral effects of gonadal steroids in women with and in those without premenstrual syndrome. Journal of the American Medical Association, 1998; 338:209-16. 8 Vitiello B, Jensen P. Medication development and testing in children and adolescents. Archives of General Psychiatry, 1997; 54:871-6. -------------------------------------------------------------------------------- This brochure is a new version of the 1994 edition of Plain Talk About Depression and was written by Margaret Strock, Information Resources and Inquiries Branch, Office of Communications, National Institute of Mental Health (NIMH). Expert assistance was provided by Raymond DePaulo, MD, Johns Hopkins School of Medicine; Ellen Frank, MD, University of Pittsburgh School of Medicine; Jerrold F. Rosenbaum, MD, Massachusetts General Hospital; Matthew V. Rudorfer, MD, and Clarissa K. Wittenberg, NIMH staff members. Lisa D. Alberts, NIMH staff member, provided editorial assistance. What are anxiety disorders? Anxiety disorders range from feelings of uneasiness to immobilizing bouts of terror. This fact sheet briefly describes the different types of anxiety disorders. This fact sheet is not exhaustive, nor does it include the full range of symptoms and treatments. Keep in mind that new research can yield rapid and dramatic changes in our understanding of and approaches to mental disorders. If you believe you or a loved one has an anxiety disorder, seek competent, professional advice or another form of support. Generalized Anxiety Disorder: Most people experience anxiety at some point in their lives and some nervousness in anticipation of a real situation. However if a person cannot shake unwarranted worries, or if the feelings are jarring to the point of avoiding everyday activities, he or she most likely has an anxiety disorder. Symptoms: Chronic, exaggerated worry, tension, and irritability that appear to have no cause or are more intense than the situation warrants. Physical signs, such as restlessness, trouble falling or staying asleep, headaches, trembling, twitching, muscle tension, or sweating, often accompany these psychological symptoms. Formal diagnosis: When someone spends at least six months worried excessively about everyday problems. However, incapacitating or troublesome symptoms warranting treatment may exist for shorter periods of time. Treatment: Anxiety is among the most common, most treatable mental disorders. Effective treatments include cognitive behavioral therapy, relaxation techniques, and biofeedback to control muscle tension. Medication, most commonly anti-anxiety drugs, such as benzodiazepine and its derivatives, also may be required in some cases. Some commonly prescribed anti-anxiety medications are diazepam, alprazolam, and lorazepam. The non-benzodiazepine anti-anxiety medication buspirone can be helpful for some individuals. Panic Disorder: People with panic disorder experience white-knuckled, heart-pounding terror that strikes suddenly and without warning. Since they cannot predict when a panic attack will seize them, many people live in persistent worry that another one could overcome them at any moment. Symptoms: Pounding heart, chest pains, lightheadedness or dizziness, nausea, shortness of breath, shaking or trembling, choking, fear of dying, sweating, feelings of unreality, numbness or tingling, hot flashes or chills, and a feeling of going out of control or going crazy. Formal Diagnosis: Either four attacks within four weeks or one or more attacks followed by at least a month of persistent fear of having another attack. A minimum of four of the symptoms listed above developed during at least one of the attacks. Most panic attacks last only a few minutes, but they occasionally go on for ten minutes, and, in rare cases, have been known to last for as long as an hour. They can occur at any time, even during sleep. Treatment: Cognitive behavioral therapy and medications such as high-potency anti-anxiety drugs like alprazolam. Several classes of antidepressants (such as paroxetine, one of the newer selective serotonin reuptake inhibitors) and the older tricyclics and monoamine oxidase inhibitors (MAO inhibitors) are considered "gold standards" for treating panic disorder. Sometimes a combination of therapy and medication is the most effective approach to helping people manage their symptoms. Proper treatment helps 70 to 90 percent of people with panic disorder, usually within six to eight weeks. Phobias: Most of us steer clear of certain, hazardous things. Phobias however, are irrational fears that lead people to altogether avoid specific things or situations that trigger intense anxiety. Phobias occur in several forms, for example, agoraphobia is the fear of being in any situation that might trigger a panic attack and from which escape might be difficult. Social phobia is a fear of being extremely embarrassed in front of other people. The most common social phobia is fear of public speaking. Symptoms: Many of the physical symptoms that accompany panic attacks - such as sweating, racing heart, and trembling - also occur with phobias. Formal Diagnosis: The person experiences extreme anxiety with exposure to the object or situation; recognizes that his or her fear is excessive or unreasonable; and finds that normal routines, social activities, or relationships are significantly impaired as a result of these fears. Treatment: Cognitive behavioral therapy has the best track record for helping people overcome most phobic disorders. The goals of this therapy are to desensitize a person to feared situations or to teach a person how to recognize, relax, and cope with anxious thoughts and feelings. Medications, such as anti-anxiety agents or antidepressants, can also help relieve symptoms. Sometimes therapy and medication are combined to treat phobias. Post-traumatic Stress Disorder: Researchers now know that anyone, even children, can develop PTSD if they have experienced, witnessed, or participated in a traumatic occurrence-especially if the event was life threatening. PTSD can result from terrifying experiences such as rape, kidnapping, natural disasters, or war or serious accidents such as airplane crashes. The psychological damage such incidents cause can interfere with a person's ability to hold a job or to develop intimate relationships with others. Symptoms: The symptoms of PTSD can range from constantly reliving the event to a general emotional numbing. Persistent anxiety, exaggerated startle reactions, difficulty concentrating, nightmares, and insomnia are common. People with PTSD typically avoid situations that remind them of the traumatic event, because they provoke intense distress or even panic attacks. Formal Diagnosis: Although the symptoms of PTSD may be an appropriate initial response to a traumatic event, they are considered part of a disorder when they persist beyond three months. Treatment: Psychotherapy can help people who have PTSD regain a sense of control over their lives. They also may need cognitive behavior therapy to change painful and intrusive patterns of behavior and thought and to learn relaxation techniques. Support from family and friends can help speed recovery and healing. Medications, such as antidepressants and anti-anxiety agents to reduce anxiety, can ease the symptoms of depression and sleep problems. Treatment for PTSD often includes both psychotherapy and medication. For more information, as well as referrals to specialists and self-help groups in your State, contact: Anxiety Disorders Association of America 8730 Georgia Avenue - Suite 600 Silver Spring, MD 20910 Telephone: 240-485-1001 Fax: 240-485-1035 www.adaa.org Mental Help Net CenterSite, LLC 570 Metro Place Dublin, OH 43017 http://mentalhelp.net/poc/center_index.php?id=1 National Mental Health Association 2001 Beauregard Street, 12th Floor Alexandria, VA 22311 Telephone: 800-969-6642 Fax: 703-684-5968 (TDD): 800-433-5959 www.nmha.org/infoctr/factsheets/index.cfm The National Institute of Mental Health's toll-free information line is 1-888-ANXIETY; their web address is www.nimh.nih.gov/anxiety/anxietymenu.cfm. Treatment Refractory Anxiety Disorders Advances in the Treatment of Anxiety Disorders Anxiety disorders are the most common psychiatric disorders. Approximately 1 in 4 individuals in the United States reports a lifetime history of at least 1 anxiety disorder. According to the Epidemiologic Catchment Area (ECA) data, in a 6-month period, 6% of men and 13% of women in the United States have an anxiety disorder.[1] Comorbidity is also a significant problem, with approximately 75% of individuals with an anxiety disorder meeting criteria for at least 1 comorbid psychiatric condition. The lifetime prevalence of panic disorder ranges from 1.5% to 3.5%, social phobia from 2.4% to 13.3%, and generalized anxiety disorder (GAD) from 4.1% to 6.6%.[2-4] Despite these high prevalence rates, fewer than 30% of individuals who suffer from anxiety disorders seek treatment. Moreover, anxiety disorders are not culture-bound; they are prevalent worldwide, and their individual, societal, and economic impact is considerable. Currently, patients with anxiety disorders seldom receive appropriate treatment in primary care, most often due to underrecognition, misdiagnosis, and the complications of comorbidity. Panic Disorder Panic disorder is a commonly occurring, chronic, often unremitting anxiety disorder that can be associated with extreme impairment and disability. The core symptoms of panic disorder are recurrent and often unexpected; panic attacks are often coupled with anticipatory anxiety and phobic avoidance, which together impair the patient's professional, social, and familial functioning. Research into the optimal treatment of this disorder has been undertaken in the past 2 decades, and numerous randomized, controlled trials have been published. Selective serotonin reuptake inhibitors (SSRIs) have emerged as the most favorable treatment due to their safe and tolerable side-effect profile. High-potency benzodiazepines, monoamine oxidase inhibitors (MAOIs), tricyclic antidepressants (TCAs), and cognitive-behavioral therapy (CBT) are efficacious in the acute and long-term treatment of panic disorder.[5,6] In recent years, however, there has been a "certain neglect" of pharmacologic advances for panic disorder, perhaps due to a perceived, or misperceived, notion that the current pharmacologic agents are effective. Long-term efficacy data suggest that acute treatment benefits often fail to endure over time, and relapse rates are high. Starcevic stated that there is "significant room for improvement" in the management of panic disorder. Both pharmacologic and cognitive-behavioral treatments suggest clinical efficacy in panic disorder,[5,6] yet the relative advantages and disadvantages of each are debated between the two camps. "Perceived" advantages of pharmacologic interventions vs CBT: • "Faster" therapeutic onset (especially with benzodiazepines); • More reliable prevention/elimination of panic attacks and decreased anxiety; • More likely prevention and/or treatment of psychiatric complications and secondary psychopathology such as major depressive disorder; • Easier to comply with treatment protocol; • More widely available, easier to administer, and lower cost. "Perceived" disadvantages of pharmacologic interventions vs CBT: • Less effective in decreasing agoraphobic avoidance; • Associated with side effects, which are at times intolerable; • Failure to promote active coping, and encouragement of excessive reliance on medications; • May be associated with dependence (psychological and/or physiological); • Less able to affect vulnerability to relapse, and associated with increased relapse upon treatment cessation. Pharmacologic Improvement Strategies. To date, there has been equivocal evidence of increased treatment efficacy, long-term outcome, treatment compliance, and faster response with add-on medications. There is, however, good evidence that dependence-related problems have decreased, particularly since treatment no longer relies on short-acting benzodiazepines for longer-term treatment.[8,9] Antidepressants (TCAs, SSRIs) and benzodiazepines were the first effective treatments for panic disorder and remain valuable tools in the management of panic and other anxiety disorders. There are publications supporting the efficacy of all SSRIs in the treatment of panic disorder,[10] and the US Food and Drug Administration (FDA) has approved paroxetine and sertraline for panic treatment. Meta-analyses suggest that both high-potency benzodiazepines and antidepressants are effective in reducing panic attacks, achieving a panic-free state, and improving anxiety, agoraphobic avoidance, and overall functional impairment.[11-13] Antidepressants may hold a distinct advantage over benzodiazepines in their ability to reduce depressive symptoms. Drawbacks exist for each drug class. Benzodiazepines are associated with sedation, interdose anxiety, and rebound symptoms upon discontinuation; TCAs provoke undesirable anticholinergic effects, which may be particularly troublesome for panic patients; and SSRIs have a slow therapeutic onset and may cause sexual side effects or hyperstimulation. Maximizing the strengths and minimizing the weaknesses of these agents can result in a successful combination treatment. New pharmacologic approaches for panic have been examined in pursuit of enhanced efficacy, response, and tolerability. Results thus far have provided neither consistent nor convincing evidence that the new medications are more effective; however, some agents may have an earlier onset of efficacy (eg, escitalopram, mirtazapine) and better tolerability (eg, escitalopram, nefazodone, mirtazapine).[17-22] Pharmacologic Improvement Strategies CBT has demonstrated efficacy as a treatment for panic disorder.[32] Pharmacologic agents have also been successfully combined with CBT and may offer distinct treatment advantages. Evidence suggests that pharmacotherapies may be most effective against unexpected panic attacks, and therefore more so in the treatment of panic disorder without agoraphobia. Furthermore, cognitive-behavioral tools and exposure-based practice may enhance pharmacotherapeutic outcomes in the long-term and facilitate relapse prevention efforts. In one study, Barlow and colleagues[33] conducted a methodologically rigorous randomized, double-blind, placebo-controlled study examining the efficacies of CBT, imipramine, or their combination in the acute (3-month) and maintenance (6-month) treatment of 312 patients with panic disorder. Both imipramine and CBT were significantly superior to placebo in the acute treatment phase, as measured by improvement on the Panic Disorder Severity Scale (PDSS); however, this advantage did not hold up on the Clinical Global Impressions Scale (CGI). After 6 months of maintenance treatment, imipramine and CBT were more effective than placebo on both primary outcome measures. The acute response rate for the combined treatment was 60.3% for the PDSS and 64.1% for the CGI. CBT plus imipramine did not differ significantly from the other treatment groups. The 6-month response rates for CBT plus imipramine were greater than CBT alone and imipramine alone on the PDSS, and greater than imipramine alone on the CGI. Of note, CBT plus imipramine did not confer a unique advantage over CBT plus placebo. At 6-month follow-up, patients receiving CBT plus imipramine were more likely to relapse than those receiving CBT plus placebo or CBT alone. Though the implications of this finding are somewhat unclear, the authors concluded that the combination of CBT plus imipramine may confer limited advantage in the acute management of panic disorder and more substantial advantage by the end of maintenance therapy. Each treatment worked well immediately following treatment and during maintenance, and CBT appeared particularly robust at follow-up. Treatment - Refractory Panic Disorder TRPD can be defined as those patient who do not respond to: 1) SSRI (1), SNRI (1) or TCA (1) trial(s) of an adequate dose or duration 2) CBT of an adequate duration 3) High -potentcy BZD 4) Have substance abuse, or are not candidates for CBT One option for these patient is to consider second line agents such as anticonvulsants or antipsychotics. Novel agents may offer distinct advantages, but until their efficacy profiles are better established, their status should still be considered experimental. Treatments combining pharmacologic and/or cognitive-behavioral techniques may be useful in increasing long-term outcome and decreasing risk of relapse upon treatment cessation. Recent Advances in Generalized Anxiety Disorder Sigfried Kasper, MD,[36] from the University of Vienna, Austria, described GAD as a "poorly understood disorder," and highlighted the recent upsurge in attention to its diagnosis and treatment. The diagnostic criteria of GAD have continuously evolved over the past 2 decades, making consistent research efforts difficult. Despite these changes, clinicians and researchers generally agree that the principal targets of intervention in GAD are persistent and uncontrollable worry, psychological anxiety, and somatic symptoms (eg, physical tension, difficulty concentrating). The symptoms of GAD are excessive and endure for most of the day nearly every day for a minimum of 6 months. Prevalence rates of GAD range from 1.5% to 3% for current GAD, 3% to 5% for GAD in the past 12 months, and 4% to 8% for lifetime GAD.[37] Many more individuals experience subsyndromal forms of GAD. GAD is highly comorbid; lifetime and current comorbidity estimates are 89.9% and 65%, respectively.[38-40] Studies suggest that approximately 38.6% patients with GAD also meet criteria for major depressive disorder,[40] the latter of which often drives professional help-seeking. According to Dr. Kasper, GAD patients frequently attend treatment, though treatment is often inadequate. Effective treatment of GAD should strive to attain a strong therapeutic alliance, reduce acute symptoms, resolve persistent and chronic anxiety, and prevent relapse. Optimal treatments may incorporate pharmacotherapy and psychotherapy for long-term symptom management. Treatment options for GAD are many and include empathic listening, applied relaxation, CBT, benzodiazepines, serotonin-1A (5-HT1a) partial agonists, antidepressants (ie, SSRIs, SNRIs), and newer compounds such as pregabalin. Historically, GAD was treated with benzodiazepines, which offer a good low-cost anxiolytic effect in the short-term. Several randomized, controlled trials of benzodiazepines have demonstrated acute clinical efficacy in reducing GAD symptom severity. The long-term efficacy of benzodiazepines is less robust.[41-43] The primary anxiolytic effect of the benzodiazepines addresses the somatic symptoms of GAD but leaves the cognitive features of GAD such as worry and psychological distress somewhat unresolved. Furthermore, benzodiazepines do not appear to be efficacious in reducing the depressive symptoms common in GAD. Because of the risk for physical dependence, rebound anxiety upon discontinuation, and side effects, benzodiazepines are now a secondary treatment option or an acute adjunct to long-term treatment with other agents. In general, 5-HT1a partial agonists have proven substandard in the treatment of GAD, with the exception of the azapirone buspirone. Early trials of buspirone suggested it was an efficacious alternative to benzodiazepines for treating anxiety, with some specificity for the psychological symptoms of GAD.[44-46] However, recent studies are more equivocal about buspirone's efficacy in GAD[47,48] and the symptoms of its common comorbid conditions.[41] More recently, antidepressants have secured a primary role in the pharmacopoeia of GAD. Data suggest that TCAs are equally as effective, if not more effective, as benzodiazepines in treating GAD, and imiprimane consistently produces higher improvement rates than placebo.[41] The anticholinergic effect of TCAs may exacerbate anxiety in patients who are already disposed to somatic symptoms. Rickels and colleagues[49] conducted a randomized, double-blind, 8-week comparative trial of imipramine (mean maximum daily dose, 143 mg), trazodone (255 mg), and diazepam (26 mg) in 230 patients with GAD. Patients with comorbid panic disorder or depression were excluded. All active treatments were more effective than placebo at reducing GAD symptoms. The greatest number of patients responded to imipramine (73%), followed by trazodone (69%), diazepam (66%), and placebo (47%). Patients treated with diazepam showed the most improvement in anxiety ratings during the initial weeks of treatment, with enhanced efficacy for somatic symptoms. However, imipramine achieved better anxiolytic efficacy in the latter weeks of treatment. Trazodone was comparable with diazepam. Imipramine was most effective for psychic symptoms of tension, apprehension, and worry, and all 3 treatments reduced somatic symptoms. Overall, patients treated with antidepressants reported a higher rate of adverse effects than diazepam-treated patients, but discontinuation rates did not differ by treatment group. There is a growing body of literature demonstrating the efficacy of SSRIs in placebo-controlled studies of GAD.[50-53] While the majority of these reports have studied paroxetine,[52] which is now approved by the FDA for the treatment of GAD, positive findings with fluvoxamine and sertraline are also published.[41-43] A pooled analysis of 3 positive, double-blind, placebo-controlled studies in 856 patients with GAD found that escitalopram has effective anxiolytic properties in this population.[53] The SNRIs such as venlafaxine have also demonstrated efficacy in reducing GAD symptoms; venlafaxine is the first agent indicated for the long-term treatment of GAD. Several placebo-controlled studies have indicated that venlafaxine-XR is effective in reducing the somatic and psychic symptoms of anxiety specific to GAD both in acute[54-56] and long-term treatment.[57-59] For example, Davidson and colleagues[55] found that venlafaxine-XR was associated with a greater reduction in Hamilton Anxiety Rating Scale scores than both buspirone and placebo. Taken as a whole, these studies suggest a rapid onset of action, greater tolerability than TCAs, and relapse prevention efficacy for at least 6 months with venlafaxine-XR administration. Psychotherapeutic tools that help patients develop coping and cognitive-restructuring strategies to manage their symptoms of anxiety are also efficacious in the integrated treatment of GAD. The most extensively studied psychotherapy for GAD is CBT, which targets the intolerance of uncertainty and the perceived uncontrollability or danger associated with worry. CBT has demonstrated efficacy as a short-term and long-term treatment option in GAD and is associated with low relapse rates.[42] In an interesting study, Fisher and Durham[64] conducted a reanalysis of 6 randomized, controlled trials of psychological therapy with GAD. Individual CBT and applied relaxation, focusing on excessive worry and physiological arousal, performed well, with overall recovery rates of 50% to 60% at 6-month follow-up. In general, GAD patients are responsive to treatment; however, they are also sensitive to medication side effects. Combined pharmacotherapy (eg, benzodiazepines plus SSRIs) or pharmacotherapy plus CBT may be appropriate for treatment-resistant patients. Treatment - Refractory Generalized Anxiety Disorder TRGAD can be defined as those patient who do not respond to: 5) SSRI (1), SNRI (1), Buspar (1) or TCA (1) trial(s) of an adequate dose or duration 6) CBT of an adequate duration 7) High or Low -potency BZD 8) Have substance abuse, or are not candidates for CBT Novel therapeutic options include the pregabalin (FDA approved for neuralgia,) which has shown early onset of action and short-term and long-term efficacy in GAD patients.[60-62] In a controlled trial, Pollack and colleagues[62] found that pregabalin was more effective than placebo at 300, 450, and 600 mg, and more effective than alprazolam at 300 and 600 mg/day. A 10-week, randomized, open-label trial of tiagabine,[63] a GABA reuptake inhibitor, and paroxetine found that both agents significantly reduced anxiety and depressive symptoms and improved sleep quality and overall functioning. Both tiagabine and paroxetine were well tolerated. Social Anxiety Disorder SAD has been the subject of increased research scrutiny in recent years. SAD is an early onset, chronic, frequently disabling disorder with lifetime reported prevalence rates around 13%.[2] SAD is characterized by a persistent fear of negative evaluation or scrutiny by others in social situations, resulting in excessive fear of humiliation or embarrassment, decrease in adaptive functioning, and clinical distress.[65] Patients with SAD are at high risk for comorbid disorders including other anxiety disorders, depression, and substance abuse problems. Both pharmacologic and cognitive-behavioral approaches to SAD are effective and offer complementary strengths. The efficacy of irreversible MAOIs in the treatment of SAD is well established with several randomized, placebo-controlled trials.[67,68] For example, in a study of 65 severe and chronic SAD patients, Gelernter and colleagues[69] found that phenelzine, cognitive-behavioral group therapy (CBGT), and alprazolam were superior to placebo (self-instructed exposure) in reducing SAD symptoms. Phenelzine conferred some advantage over alprazolam on measures of work and social disability. At week 12, 69% of the phenelzine group had responded compared with 38% of the alprazolam group, 24% of the CBGT group, and 20% of the placebo group. At the 2-month follow-up, following medication discontinuation, only the phenelzine and CBGT treatment groups maintained their treatment gains. These results are somewhat difficult to interpret since the study included one of the principal components of CBT, exposure, as a control group. In a 12-week treatment study, Heimberg and colleagues[70] examined phenelzine and CBGT vs a pill-placebo and psychotherapy control (educational supportive group therapy) in SAD patients. At end point, both phenelzine therapy and CBGT were associated with a significant positive response. Although phenelzine therapy was superior to CBGT on some measures, both treatment conditions were superior to the pill-placebo and psychotherapy control conditions. Responders to the acute trial entered a 6-month maintenance phase, and patients who continued to respond through the maintenance phase entered a 6-month treatment-free phase. In general, phenelzine patients entered the maintenance phase with greater improvements than did CBGT patients, and groups did not differ on relapse rates. Of note, phenelzine patients showed a trend toward greater relapse during the treatment-free follow-up. In a separate study, Liebowitz and colleagues[67] found that 64% of generalized SAD patients responded to phenelzine compared with 30% and 23% of patients treated with atenolol and placebo, respectively. Despite phenelzine's efficacy in SAD, the dietary restrictions and risk of hypertensive crisis have reduced its acceptability as the favored first-line treatment for chronic SAD. The reversible MAOIs, such as moclobemide and brofaromine, have lower risk potential and fewer side effects than traditional MAOIs. Controlled trials of moclobemide have yielded inconsistent findings over the past several years.[71-75] For example, in a double-blind, placebo-controlled comparison of phenelzine and moclobemide, both active treatments demonstrated clinical efficacy beyond placebo, and phenelzine was associated with significantly more adverse side effects than moclobemide. Relapse rates for both agents were quite high after discontinuation.[72] Large, multicenter, placebo-controlled studies of moclobemide have found minimal[73] to no efficacy.[71] Partial responders may benefit from SSRI augmentation with CBT,[90,95] buspirone,[110] benzodiazepines, gabapentin,[74] or venlafaxine.[113] Treatment - Refractory Social Anxiety Disorder TRSAD can be defined as those patients who do not respond to: 9) SSRI (1), SNRI (1), Buspar (1) or MAOI (1) trial(s) of an adequate dose or duration 10) CGBT or Social Skills Training of an adequate duration 11) Have active alcohol or substance abuse, or are not candidates for CGBT or Social Skills Training Decreasing Side Effects to Increase Adherence Robert Golden, MD,[126] Chair of the Department of Psychiatry, UNC School of Medicine, discussed the impact of drug-related side effects on patient compliance. SSRIs are safe and effective and have become the most widely prescribed antidepressants worldwide; however, several issues limit SSRI treatment outcomes. SSRIs have a favorable side effect profile when compared with earlier antidepressant agents, but even "minor" side effects can significantly affect treatment outcome by interfering with patient compliance. Approximately 33% of patients stop taking their prescribed medication within the first month; nonadherence increases to 56% after 4 months of treatment.[127] Adherence may be increased with increased patient and family education, careful and sensitive inquiry and monitoring over the cause of treatment-related side effects, and selection of medications based on expected side effects (including an understanding of pharmacodynamic and pharmacokinetic profile). Nausea is one of the most common and early-occurring SSRI side effects. Nausea is reported in 20% to 25% of patients on SSRIs.[128] Over time, gastrointestinal (GI) side effects typically wane; however, this time-lag carries a burden in terms of treatment outcome. For example, GI effects are associated with medication noncompliance, which is associated with delaying the time to attain a full therapeutic dose, or resulting in the failure to reach that desired dose due to early treatment discontinuation. SSRIs are initially absorbed in the upper small intestine. The drug stimulates serotonin receptors in the submucosal plexus, which is associated with orchestrated peristalsis. When the SSRI is present, serotonin floods the receptors and causes overstimulated contractions. Recent delivery advances (eg, a controlled-release formulation of paroxetine) can diminish these effects. Specifically, the active SSRI is an enteric-coated formula that is absorbed in a more distal region of the small intestine, thus avoiding the stimulation of gastrointestinal 5-HT receptors that mediate nausea. Recent studies have demonstrated that Paxil-CR is associated with fewer dropout rates due to side effects than the original formulation of Paxil.[129] Sexual side effects are also associated with decreased compliance in SSRI maintenance treatment. Approximately 15% to 50% of individuals will report some sexual side effect with SSRI therapy. According to Dr. Golden, several strategies may be employed to decrease these undesired effects. • Consider using an antidepressant that is not associated with sexual side effects. • Switch to a different antidepressant if symptoms emerge • Add adjunctive medications to counteract side effects (eg, sildenafil for erectile dysfunction, bupropion for decreased libido or ejaculatory problems). • Adjust dose and dosing schedule. • Allow drug holiday in anticipation of sexual activity (if clinically warranted; some reports suggest an increase of relapse even with shorter drug holidays). According to Dr. Golden, future research should focus on making advances where it matters; specifically, using medical knowledge to decrease side effects that may sabotage patient treatment compliance. References 1. Leon AC, Portera L, Weissman MM. The social costs of anxiety disorders. Br J Psychiatry Suppl. 1995;(27):19-22 2. Kessler RC, McGonagle KA, Zhao S, et al. Lifetime and 12-month prevalence of DSM-III-R psychiatric disorders in the United States. Results from the National Comorbidity Survey. Arch Gen Psychiatry. 1994;51:8-19 3. Wittchen HU, Hoyer J. Generalized anxiety disorder: nature and course. J Clin Psychiatry. 2001;62(suppl 11):15-19; discussion 20-21. 4. Lepine JP. The epidemiology of anxiety disorders: Prevalence and societal costs. J Clin Psychiatry. 2002;63(suppl 14):4-8 5. Sheehan DV. The management of panic disorder. J Clin Psychiatry. 2002;63(suppl 14):17-21 6. Sheehan DV. Current concepts in the treatment of panic disorder. J Clin Psychiatry. 1999;60(suppl 18):16-21 7. Starcevic V. Recent advances in the treatment of panic disorder. Program and abstracts of the International Congress of Biological Psychiatry; February 9-13, 2004; Sydney, Australia. Symposium 120. 8. Sheehan DV. Why sustained-relates medications? Practical considerations in the management of patients with anxiety. Psychiatr Ann. 1993;23(10 suppl):3-6. 9. Otto MW, Hong JJ, Safren SA. Benzodiazepine discontinuation difficulties in panic disorder: conceptual model and outcome for cognitive-behavior therapy. Curr Pharm Des. 2002;8:75-80 10. Otto MW, Tuby KS, Gould RA, McLean RY, Pollack MH. An effect-size analysis of the relative efficacy and tolerability of serotonin selective reuptake inhibitors for panic disorder. Am J Psychiatry. 2001;158:1989-1992 11. den Boer JA. Pharmacotherapy of panic disorder: differential efficacy from a clinical viewpoint. J Clin Psychiatry. 1998;59(suppl 8):30-36 12. Rickels K, Schweizer E. Panic disorder: long-term pharmacotherapy and discontinuation. J Clin Psychopharmacol. 1998;18(suppl 2):12-18. 13. van Balkom AJ, Bakker A, Spinhoven P, Blaauw BM, Smeenk S, Ruesink B. A meta-analysis of the treatment of panic disorder with or without agoraphobia: a comparison of psychopharmacological, cognitive-behavioral, and combination treatments. J Nerv Ment Dis. 1997;185:510-516 14. Woods SW, Nagy LM, Koleszar AS, Krystal JH, Heninger GR, Charney DS. Controlled trial of alprazolam supplementation during imipramine treatment of panic disorder.J Clin Psychopharmacol. 1992;12:32-38 15. Goddard AW, Brouette T, Almai A, Jetty P, Woods SW, Charney D. Early coadministration of clonazepam with sertraline for panic disorder. Arch Gen Psychiatry. 2001;58:681-686 16. Pollack MH, Allgulander C, Bandelow B, et al. WCA recommendations for the long-term treatment of panic disorder. CNS Spectr. 2003;8(8 suppl 1):17-30. 17. Carli V, Sarchiapone M, Camardese G, Romano L, DeRisio S. Mirtazapine in the treatment of panic disorder. Arch Gen Psychiatry. 2002;59:661-662 18. Stahl SM, Gergel I, Li D. Escitalopram in the treatment of panic disorder: a randomized, double-blind, placebo-controlled trial. J Clin Psychiatry. 2003;64:1322-1327 19. Bystritsky A, Rosen R, Suri R, Vapnik T. Pilot open-label study of nefazodone in panic disorder. Depress Anxiety. 1999;10:137-139 20. Papp LA, Coplan JD, Martinez JM, de Jesus M, Gorman JM. Efficacy of open-label nefazodone treatment in patients with panic disorder. J Clin Psychopharmacol. 2000;20:544-546 21. Sarchiapone M, Amore M, De Risio S, et al. Mirtazapine in the treatment of panic disorder: an open-label trial. Int Clin Psychopharmacol. 2003;18:35-38 22. Schatzberg AF. New indications for antidepressants. J Clin Psychiatry. 2000;61(suppl 11):9-17 23. Sheehan D, Iyengar M, Burnham D, Beebe KL. Efficacy and tolerability of controlled-release paroxetine HCL in panic disorder. Program and abstracts of the International Congress of Biological Psychiatry; February 9-13, 2004; Sydney, Australia. 24. Versiani M, Cassano G, Perugi G, et al. Reboxetine, a selective norepinephrine reuptake inhibitor, is an effective and well-tolerated treatment for panic disorder. J Clin Psychiatry. 2002;63:31-37. 25. Pollack MH, Worthington JJ 3rd, Otto MW, et al. Venlafaxine for panic disorder: results from a double-blind, placebo-controlled study. Psychopharmacol Bull. 1996;32:667-670 26. Papp LA, Sinha SS, Martinez JM, Coplan JD, Amchin J, Gorman JM. Low-dose venlafaxine treatment in panic disorder. Psychopharmacol Bull. 1998;34:207-209. 27. Bradwejn J, Emilien G, Ahokas A, Whitaker T. Treatment of panic disorder with venlafaxine XR. Program and abstracts of the International Congress of Biological Psychiatry; February 9-13, 2004; Sydney, Australia. 28. Pollack M, Emilien G, Tzanis E, Witaker T. Venlafaxine XR and paroxetine in the short-term treatment of panic disorder. Program and abstracts of the International Congress of Biological Psychiatry; February 9-13, 2004; Sydney, Australia. 29. Pande AC, Pollack MH, Crockatt J, et al. Placebo-controlled study of gabapentin treatment of panic disorder. J Clin Psychopharmacol. 2000;20:467-471 30. Zwanzger P, Baghai T, Boerner RJ, Moller HJ, Rupprecht R. Anxiolytic effects of vigabatrin in panic disorder. J Clin Psychopharmacol. 2001;21:539-540. 31. Zwanzger P, Baghai T, Schule C, et al. Tiagabine improves panic and agoraphobia in panic disorder patients [letter]. J Clin Psychiatry. 2001;62:656-657. Social Anxiety DisorderSocial Anxiety Disorder SAD has been the subject of increased research scrutiny in recent years. SAD is an early onset, chronic, frequently disabling disorder with lifetime reported prevalence rates around 13%.[2] SAD is characterized by a persistent fear of negative evaluation or scrutiny by others in social situations, resulting in excessive fear of humiliation or embarrassment, decrease in adaptive functioning, and clinical distress.[65] Patients with SAD are at high risk for comorbid disorders including other anxiety disorders, depression, and substance abuse problems. Both pharmacologic and cognitive-behavioral approaches to SAD are effective and offer complementary strengths. The efficacy of irreversible MAOIs in the treatment of SAD is well established with several randomized, placebo-controlled trials.[67,68] For example, in a study of 65 severe and chronic SAD patients, Gelernter and colleagues[69] found that phenelzine, cognitive-behavioral group therapy (CBGT), and alprazolam were superior to placebo (self-instructed exposure) in reducing SAD symptoms. Phenelzine conferred some advantage over alprazolam on measures of work and social disability. At week 12, 69% of the phenelzine group had responded compared with 38% of the alprazolam group, 24% of the CBGT group, and 20% of the placebo group. At the 2-month follow-up, following medication discontinuation, only the phenelzine and CBGT treatment groups maintained their treatment gains. These results are somewhat difficult to interpret since the study included one of the principal components of CBT, exposure, as a control group. In a 12-week treatment study, Heimberg and colleagues[70] examined phenelzine and CBGT vs a pill-placebo and psychotherapy control (educational supportive group therapy) in SAD patients. At end point, both phenelzine therapy and CBGT were associated with a significant positive response. Although phenelzine therapy was superior to CBGT on some measures, both treatment conditions were superior to the pill-placebo and psychotherapy control conditions. Responders to the acute trial entered a 6-month maintenance phase, and patients who continued to respond through the maintenance phase entered a 6-month treatment-free phase. In general, phenelzine patients entered the maintenance phase with greater improvements than did CBGT patients, and groups did not differ on relapse rates. Of note, phenelzine patients showed a trend toward greater relapse during the treatment-free follow-up. In a separate study, Liebowitz and colleagues[67] found that 64% of generalized SAD patients responded to phenelzine compared with 30% and 23% of patients treated with atenolol and placebo, respectively. Despite phenelzine's efficacy in SAD, the dietary restrictions and risk of hypertensive crisis have reduced its acceptability as the favored first-line treatment for chronic SAD. The reversible MAOIs, such as moclobemide and brofaromine, have lower risk potential and fewer side effects than traditional MAOIs. Controlled trials of moclobemide have yielded inconsistent findings over the past several years.[71-75] For example, in a double-blind, placebo-controlled comparison of phenelzine and moclobemide, both active treatments demonstrated clinical efficacy beyond placebo, and phenelzine was associated with significantly more adverse side effects than moclobemide. Relapse rates for both agents were quite high after discontinuation.[72] Large, multicenter, placebo-controlled studies of moclobemide have found minimal[73] to no efficacy.[71] Partial responders may benefit from SSRI augmentation with CBT,[90,95] buspirone,[110] benzodiazepines, gabapentin,[74] or venlafaxine.[113] Treatment - Refractory Social Anxiety Disorder TRSAD can be defined as those patients who do not respond to: 9) SSRI (1), SNRI (1), Buspar (1) or MAOI (1) trial(s) of an adequate dose or duration 10) CGBT or Social Skills Training of an adequate duration 11) Have active alcohol or substance abuse, or are not candidates for CGBT or Social Skills Training Decreasing Side Effects to Increase Adherence Robert Golden, MD,[126] Chair of the Department of Psychiatry, UNC School of Medicine, discussed the impact of drug-related side effects on patient compliance. SSRIs are safe and effective and have become the most widely prescribed antidepressants worldwide; however, several issues limit SSRI treatment outcomes. SSRIs have a favorable side effect profile when compared with earlier antidepressant agents, but even "minor" side effects can significantly affect treatment outcome by interfering with patient compliance. Approximately 33% of patients stop taking their prescribed medication within the first month; nonadherence increases to 56% after 4 months of treatment.[127] Adherence may be increased with increased patient and family education, careful and sensitive inquiry and monitoring over the cause of treatment-related side effects, and selection of medications based on expected side effects (including an understanding of pharmacodynamic and pharmacokinetic profile). Nausea is one of the most common and early-occurring SSRI side effects. Nausea is reported in 20% to 25% of patients on SSRIs.[128] Over time, gastrointestinal (GI) side effects typically wane; however, this time-lag carries a burden in terms of treatment outcome. For example, GI effects are associated with medication noncompliance, which is associated with delaying the time to attain a full therapeutic dose, or resulting in the failure to reach that desired dose due to early treatment discontinuation. SSRIs are initially absorbed in the upper small intestine. The drug stimulates serotonin receptors in the submucosal plexus, which is associated with orchestrated peristalsis. When the SSRI is present, serotonin floods the receptors and causes overstimulated contractions. Recent delivery advances (eg, a controlled-release formulation of paroxetine) can diminish these effects. Specifically, the active SSRI is an enteric-coated formula that is absorbed in a more distal region of the small intestine, thus avoiding the stimulation of gastrointestinal 5-HT receptors that mediate nausea. Recent studies have demonstrated that Paxil-CR is associated with fewer dropout rates due to side effects than the original formulation of Paxil.[129] Sexual side effects are also associated with decreased compliance in SSRI maintenance treatment. Approximately 15% to 50% of individuals will report some sexual side effect with SSRI therapy. According to Dr. Golden, several strategies may be employed to decrease these undesired effects. • Consider using an antidepressant that is not associated with sexual side effects. • Switch to a different antidepressant if symptoms emerge • Add adjunctive medications to counteract side effects (eg, sildenafil for erectile dysfunction, bupropion for decreased libido or ejaculatory problems). • Adjust dose and dosing schedule. • Allow drug holiday in anticipation of sexual activity (if clinically warranted; some reports suggest an increase of relapse even with shorter drug holidays). According to Dr. Golden, future research should focus on making advances where it matters; specifically, using medical knowledge to decrease side effects that may sabotage patient treatment compliance. Treatment Refractory Anxiety Disorders Advances in the Treatment of Anxiety Disorders Anxiety disorders are the most common psychiatric disorders. Approximately 1 in 4 individuals in the United States reports a lifetime history of at least 1 anxiety disorder. According to the Epidemiologic Catchment Area (ECA) data, in a 6-month period, 6% of men and 13% of women in the United States have an anxiety disorder.[1] Comorbidity is also a significant problem, with approximately 75% of individuals with an anxiety disorder meeting criteria for at least 1 comorbid psychiatric condition. The lifetime prevalence of panic disorder ranges from 1.5% to 3.5%, social phobia from 2.4% to 13.3%, and generalized anxiety disorder (GAD) from 4.1% to 6.6%.[2-4] Despite these high prevalence rates, fewer than 30% of individuals who suffer from anxiety disorders seek treatment. Moreover, anxiety disorders are not culture-bound; they are prevalent worldwide, and their individual, societal, and economic impact is considerable. Currently, patients with anxiety disorders seldom receive appropriate treatment in primary care, most often due to underrecognition, misdiagnosis, and the complications of comorbidity. Panic Disorder Panic disorder is a commonly occurring, chronic, often unremitting anxiety disorder that can be associated with extreme impairment and disability. The core symptoms of panic disorder are recurrent and often unexpected; panic attacks are often coupled with anticipatory anxiety and phobic avoidance, which together impair the patient's professional, social, and familial functioning. Research into the optimal treatment of this disorder has been undertaken in the past 2 decades, and numerous randomized, controlled trials have been published. Selective serotonin reuptake inhibitors (SSRIs) have emerged as the most favorable treatment due to their safe and tolerable side-effect profile. High-potency benzodiazepines, monoamine oxidase inhibitors (MAOIs), tricyclic antidepressants (TCAs), and cognitive-behavioral therapy (CBT) are efficacious in the acute and long-term treatment of panic disorder.[5,6] In recent years, however, there has been a "certain neglect" of pharmacologic advances for panic disorder, perhaps due to a perceived, or misperceived, notion that the current pharmacologic agents are effective. Long-term efficacy data suggest that acute treatment benefits often fail to endure over time, and relapse rates are high. Starcevic stated that there is "significant room for improvement" in the management of panic disorder. Both pharmacologic and cognitive-behavioral treatments suggest clinical efficacy in panic disorder,[5,6] yet the relative advantages and disadvantages of each are debated between the two camps. "Perceived" advantages of pharmacologic interventions vs CBT: · "Faster" therapeutic onset (especially with benzodiazepines); · More reliable prevention/elimination of panic attacks and decreased anxiety; · More likely prevention and/or treatment of psychiatric complications and secondary psychopathology such as major depressive disorder; · Easier to comply with treatment protocol; and · More widely available, easier to administer, and lower cost. "Perceived" disadvantages of pharmacologic interventions vs CBT: · Less effective in decreasing agoraphobic avoidance; · Associated with side effects, which are at times intolerable; · Failure to promote active coping, and encouragement of excessive reliance on medications; · May be associated with dependence (psychological and/or physiological); and · Less able to affect vulnerability to relapse, and associated with increased relapse upon treatment cessation. Pharmacologic Improvement Strategies To date, there has been equivocal evidence of increased treatment efficacy, long-term outcome, treatment compliance, and faster response with add-on medications. There is, however, good evidence that dependence-related problems have decreased, particularly since treatment no longer relies on short-acting benzodiazepines for longer-term treatment.[8,9] Antidepressants (TCAs, SSRIs) and benzodiazepines were the first effective treatments for panic disorder and remain valuable tools in the management of panic and other anxiety disorders. There are publications supporting the efficacy of all SSRIs in the treatment of panic disorder,[10] and the US Food and Drug Administration (FDA) has approved paroxetine and sertraline for panic treatment. Meta-analyses suggest that both high-potency benzodiazepines and antidepressants are effective in reducing panic attacks, achieving a panic-free state, and improving anxiety, agoraphobic avoidance, and overall functional impairment.[11-13] Antidepressants may hold a distinct advantage over benzodiazepines in their ability to reduce depressive symptoms. Drawbacks exist for each drug class. Benzodiazepines are associated with sedation, interdose anxiety, and rebound symptoms upon discontinuation; TCAs provoke undesirable anticholinergic effects, which may be particularly troublesome for panic patients; and SSRIs have a slow therapeutic onset and may cause sexual side effects or hyperstimulation. Maximizing the strengths and minimizing the weaknesses of these agents can result in a successful combination treatment. New pharmacologic approaches for panic have been examined in pursuit of enhanced efficacy, response, and tolerability. Results thus far have provided neither consistent nor convincing evidence that the new medications are more effective; however, some agents may have an earlier onset of efficacy (eg, escitalopram, mirtazapine) and better tolerability (eg, escitalopram, nefazodone, mirtazapine).[17-22] Pharmacologic Improvement Strategies CBT has demonstrated efficacy as a treatment for panic disorder.[32] Pharmacologic agents have also been successfully combined with CBT and may offer distinct treatment advantages. Evidence suggests that pharmacotherapies may be most effective against unexpected panic attacks, and therefore more so in the treatment of panic disorder without agoraphobia. Furthermore, cognitive-behavioral tools and exposure-based practice may enhance pharmacotherapeutic outcomes in the long-term and facilitate relapse prevention efforts. In one study, Barlow and colleagues[33] conducted a methodologically rigorous randomized, double-blind, placebo-controlled study examining the efficacies of CBT, imipramine, or their combination in the acute (3-month) and maintenance (6-month) treatment of 312 patients with panic disorder. Both imipramine and CBT were significantly superior to placebo in the acute treatment phase, as measured by improvement on the Panic Disorder Severity Scale (PDSS); however, this advantage did not hold up on the Clinical Global Impressions Scale (CGI). After 6 months of maintenance treatment, imipramine and CBT were more effective than placebo on both primary outcome measures. The acute response rate for the combined treatment was 60.3% for the PDSS and 64.1% for the CGI. CBT plus imipramine did not differ significantly from the other treatment groups. The 6-month response rates for CBT plus imipramine were greater than CBT alone and imipramine alone on the PDSS, and greater than imipramine alone on the CGI. Of note, CBT plus imipramine did not confer a unique advantage over CBT plus placebo. At 6-month follow-up, patients receiving CBT plus imipramine were more likely to relapse than those receiving CBT plus placebo or CBT alone. Though the implications of this finding are somewhat unclear, the authors concluded that the combination of CBT plus imipramine may confer limited advantage in the acute management of panic disorder and more substantial advantage by the end of maintenance therapy. Each treatment worked well immediately following treatment and during maintenance, and CBT appeared particularly robust at follow-up. Treatment - Refractory Panic Disorder TRPD can be defined as those patient who do not respond to: 1) SSRI (1), SNRI (1) or TCA (1) trial(s) of an adequate dose or duration 2) CBT of an adequate duration 3) High -potentcy BZD 4) Have substance abuse, or are not candidates for CBT One option for these patient is to consider second line agents such as anticonvulsants or antipsychotics. Novel agents may offer distinct advantages, but until their efficacy profiles are better established, their status should still be considered experimental. Treatments combining pharmacologic and/or cognitive-behavioral techniques may be useful in increasing long-term outcome and decreasing risk of relapse upon treatment cessation. Recent Advances in Generalized Anxiety Disorder Sigfried Kasper, MD,[36] from the University of Vienna, Austria, described GAD as a "poorly understood disorder," and highlighted the recent upsurge in attention to its diagnosis and treatment. The diagnostic criteria of GAD have continuously evolved over the past 2 decades, making consistent research efforts difficult. Despite these changes, clinicians and researchers generally agree that the principal targets of intervention in GAD are persistent and uncontrollable worry, psychological anxiety, and somatic symptoms (eg, physical tension, difficulty concentrating). The symptoms of GAD are excessive and endure for most of the day nearly every day for a minimum of 6 months. Prevalence rates of GAD range from 1.5% to 3% for current GAD, 3% to 5% for GAD in the past 12 months, and 4% to 8% for lifetime GAD.[37] Many more individuals experience subsyndromal forms of GAD. GAD is highly comorbid; lifetime and current comorbidity estimates are 89.9% and 65%, respectively.[38-40] Studies suggest that approximately 38.6% patients with GAD also meet criteria for major depressive disorder,[40] the latter of which often drives professional help-seeking. According to Dr. Kasper, GAD patients frequently attend treatment, though treatment is often inadequate. Effective treatment of GAD should strive to attain a strong therapeutic alliance, reduce acute symptoms, resolve persistent and chronic anxiety, and prevent relapse. Optimal treatments may incorporate pharmacotherapy and psychotherapy for long-term symptom management. Treatment options for GAD are many and include empathic listening, applied relaxation, CBT, benzodiazepines, serotonin-1A (5-HT1a) partial agonists, antidepressants (ie, SSRIs, SNRIs), and newer compounds such as pregabalin. Historically, GAD was treated with benzodiazepines, which offer a good low-cost anxiolytic effect in the short-term. Several randomized, controlled trials of benzodiazepines have demonstrated acute clinical efficacy in reducing GAD symptom severity. The long-term efficacy of benzodiazepines is less robust.[41-43] The primary anxiolytic effect of the benzodiazepines addresses the somatic symptoms of GAD but leaves the cognitive features of GAD such as worry and psychological distress somewhat unresolved. Furthermore, benzodiazepines do not appear to be efficacious in reducing the depressive symptoms common in GAD. Because of the risk for physical dependence, rebound anxiety upon discontinuation, and side effects, benzodiazepines are now a secondary treatment option or an acute adjunct to long-term treatment with other agents. In general, 5-HT1a partial agonists have proven substandard in the treatment of GAD, with the exception of the azapirone buspirone. Early trials of buspirone suggested it was an efficacious alternative to benzodiazepines for treating anxiety, with some specificity for the psychological symptoms of GAD.[44-46] However, recent studies are more equivocal about buspirone's efficacy in GAD[47,48] and the symptoms of its common comorbid conditions.[41] More recently, antidepressants have secured a primary role in the pharmacopoeia of GAD. Data suggest that TCAs are equally as effective, if not more effective, as benzodiazepines in treating GAD, and imiprimane consistently produces higher improvement rates than placebo.[41] The anticholinergic effect of TCAs may exacerbate anxiety in patients who are already disposed to somatic symptoms. Rickels and colleagues[49] conducted a randomized, double-blind, 8-week comparative trial of imipramine (mean maximum daily dose, 143 mg), trazodone (255 mg), and diazepam (26 mg) in 230 patients with GAD. Patients with comorbid panic disorder or depression were excluded. All active treatments were more effective than placebo at reducing GAD symptoms. The greatest number of patients responded to imipramine (73%), followed by trazodone (69%), diazepam (66%), and placebo (47%). Patients treated with diazepam showed the most improvement in anxiety ratings during the initial weeks of treatment, with enhanced efficacy for somatic symptoms. However, imipramine achieved better anxiolytic efficacy in the latter weeks of treatment. Trazodone was comparable with diazepam. Imipramine was most effective for psychic symptoms of tension, apprehension, and worry, and all 3 treatments reduced somatic symptoms. Overall, patients treated with antidepressants reported a higher rate of adverse effects than diazepam-treated patients, but discontinuation rates did not differ by treatment group. There is a growing body of literature demonstrating the efficacy of SSRIs in placebo-controlled studies of GAD.[50-53] While the majority of these reports have studied paroxetine,[52] which is now approved by the FDA for the treatment of GAD, positive findings with fluvoxamine and sertraline are also published.[41-43] A pooled analysis of 3 positive, double-blind, placebo-controlled studies in 856 patients with GAD found that escitalopram has effective anxiolytic properties in this population.[53] The SNRIs such as venlafaxine have also demonstrated efficacy in reducing GAD symptoms; venlafaxine is the first agent indicated for the long-term treatment of GAD. Several placebo-controlled studies have indicated that venlafaxine-XR is effective in reducing the somatic and psychic symptoms of anxiety specific to GAD both in acute[54-56] and long-term treatment.[57-59] For example, Davidson and colleagues[55] found that venlafaxine-XR was associated with a greater reduction in Hamilton Anxiety Rating Scale scores than both buspirone and placebo. Taken as a whole, these studies suggest a rapid onset of action, greater tolerability than TCAs, and relapse prevention efficacy for at least 6 months with venlafaxine-XR administration. Psychotherapeutic tools that help patients develop coping and cognitive-restructuring strategies to manage their symptoms of anxiety are also efficacious in the integrated treatment of GAD. The most extensively studied psychotherapy for GAD is CBT, which targets the intolerance of uncertainty and the perceived uncontrollability or danger associated with worry. CBT has demonstrated efficacy as a short-term and long-term treatment option in GAD and is associated with low relapse rates.[42] In an interesting study, Fisher and Durham[64] conducted a reanalysis of 6 randomized, controlled trials of psychological therapy with GAD. Individual CBT and applied relaxation, focusing on excessive worry and physiological arousal, performed well, with overall recovery rates of 50% to 60% at 6-month follow-up. In general, GAD patients are responsive to treatment; however, they are also sensitive to medication side effects. Combined pharmacotherapy (eg, benzodiazepines plus SSRIs) or pharmacotherapy plus CBT may be appropriate for treatment-resistant patients. Treatment - Refractory Generalized Anxiety Disorder TRGAD can be defined as those patient who do not respond to: 5) SSRI (1), SNRI (1), Buspar (1) or TCA (1) trial(s) of an adequate dose or duration 6) CBT of an adequate duration 7) High or Low -potentcy BZD 8) Have substance abuse, or are not candidates for CBT Novel therapeutic options include the pregabalin (FDA approved for neuralgia,) which has shown early onset of action and short-term and long-term efficacy in GAD patients.[60-62] In a controlled trial, Pollack and colleagues[62] found that pregabalin was more effective than placebo at 300, 450, and 600 mg, and more effective than alprazolam at 300 and 600 mg/day. A 10-week, randomized, open-label trial of tiagabine,[63] a GABA reuptake inhibitor, and paroxetine found that both agents significantly reduced anxiety and depressive symptoms and improved sleep quality and overall functioning. Both tiagabine and paroxetine were well tolerated. Social Anxiety Disorder SAD has been the subject of increased research scrutiny in recent years. SAD is an early onset, chronic, frequently disabling disorder with lifetime reported prevalence rates around 13%.[2] SAD is characterized by a persistent fear of negative evaluation or scrutiny by others in social situations, resulting in excessive fear of humiliation or embarrassment, decrease in adaptive functioning, and clinical distress.[65] Patients with SAD are at high risk for comorbid disorders including other anxiety disorders, depression, and substance abuse problems. Both pharmacologic and cognitive-behavioral approaches to SAD are effective and offer complementary strengths. The efficacy of irreversible MAOIs in the treatment of SAD is well established with several randomized, placebo-controlled trials.[67,68] For example, in a study of 65 severe and chronic SAD patients, Gelernter and colleagues[69] found that phenelzine, cognitive-behavioral group therapy (CBGT), and alprazolam were superior to placebo (self-instructed exposure) in reducing SAD symptoms. Phenelzine conferred some advantage over alprazolam on measures of work and social disability. At week 12, 69% of the phenelzine group had responded compared with 38% of the alprazolam group, 24% of the CBGT group, and 20% of the placebo group. At the 2-month follow-up, following medication discontinuation, only the phenelzine and CBGT treatment groups maintained their treatment gains. These results are somewhat difficult to interpret since the study included one of the principal components of CBT, exposure, as a control group. In a 12-week treatment study, Heimberg and colleagues[70] examined phenelzine and CBGT vs a pill-placebo and psychotherapy control (educational supportive group therapy) in SAD patients. At end point, both phenelzine therapy and CBGT were associated with a significant positive response. Although phenelzine therapy was superior to CBGT on some measures, both treatment conditions were superior to the pill-placebo and psychotherapy control conditions. Responders to the acute trial entered a 6-month maintenance phase, and patients who continued to respond through the maintenance phase entered a 6-month treatment-free phase. In general, phenelzine patients entered the maintenance phase with greater improvements than did CBGT patients, and groups did not differ on relapse rates. Of note, phenelzine patients showed a trend toward greater relapse during the treatment-free follow-up. In a separate study, Liebowitz and colleagues[67] found that 64% of generalized SAD patients responded to phenelzine compared with 30% and 23% of patients treated with atenolol and placebo, respectively. Despite phenelzine's efficacy in SAD, the dietary restrictions and risk of hypertensive crisis have reduced its acceptability as the favored first-line treatment for chronic SAD. The reversible MAOIs, such as moclobemide and brofaromine, have lower risk potential and fewer side effects than traditional MAOIs. Controlled trials of moclobemide have yielded inconsistent findings over the past several years.[71-75] For example, in a double-blind, placebo-controlled comparison of phenelzine and moclobemide, both active treatments demonstrated clinical efficacy beyond placebo, and phenelzine was associated with significantly more adverse side effects than moclobemide. Relapse rates for both agents were quite high after discontinuation.[72] Large, multicenter, placebo-controlled studies of moclobemide have found minimal[73] to no efficacy.[71] Partial responders may benefit from SSRI augmentation with CBT,[90,95] buspirone,[110] benzodiazepines, gabapentin,[74] or venlafaxine.[113] Treatment - Refractory Social Anxiety Disorder TRSAD can be defined as those patient who do not respond to: 9) SSRI (1), SNRI (1), Buspar (1) or MAOI (1) trial(s) of an adequate dose or duration 10) CGBT or Social Skills Training of an adequate duration 11) Have active alcohol or substance abuse, or are not candidates for CGBT or Social Skills Training Decreasing Side Effects to Increase Adherence Robert Golden, MD,[126] Chair of the Department of Psychiatry, UNC School of Medicine, discussed the impact of drug-related side effects on patient compliance. SSRIs are safe and effective and have become the most widely prescribed antidepressants worldwide; however, several issues limit SSRI treatment outcomes. SSRIs have a favorable side effect profile when compared with earlier antidepressant agents, but even "minor" side effects can significantly affect treatment outcome by interfering with patient compliance. Approximately 33% of patients stop taking their prescribed medication within the first month; nonadherence increases to 56% after 4 months of treatment.[127] Adherence may be increased with increased patient and family education, careful and sensitive inquiry and monitoring over the cause of treatment-related side effects, and selection of medications based on expected side effects (including an understanding of pharmacodynamic and pharmacokinetic profile). Nausea is one of the most common and early-occurring SSRI side effects. Nausea is reported in 20% to 25% of patients on SSRIs.[128] Over time, gastrointestinal (GI) side effects typically wane; however, this time-lag carries a burden in terms of treatment outcome. For example, GI effects are associated with medication noncompliance, which is associated with delaying the time to attain a full therapeutic dose, or resulting in the failure to reach that desired dose due to early treatment discontinuation. SSRIs are initially absorbed in the upper small intestine. The drug stimulates serotonin receptors in the submucosal plexus, which is associated with orchestrated peristalsis. When the SSRI is present, serotonin floods the receptors and causes overstimulated contractions. Recent delivery advances (eg, a controlled-release formulation of paroxetine) can diminish these effects. Specifically, the active SSRI is an enteric-coated formula that is absorbed in a more distal region of the small intestine, thus avoiding the stimulation of gastrointestinal 5-HT receptors that mediate nausea. Recent studies have demonstrated that Paxil-CR is associated with fewer dropout rates due to side effects than the original formulation of Paxil.[129] Sexual side effects are also associated with decreased compliance in SSRI maintenance treatment. Approximately 15% to 50% of individuals will report some sexual side effect with SSRI therapy. According to Dr. Golden, several strategies may be employed to decrease these undesired effects. · Consider using an antidepressant that is not associated with sexual side effects. · Switch to a different antidepressant if symptoms emerge. · Add adjunctive medications to counteract side effects (eg, sildenafil for erectile dysfunction, bupropion for decreased libido or ejaculatory problems). · Adjust dose and dosing schedule. · Allow drug holiday in anticipation of sexual activity (if clinically warranted; some reports suggest an increase of relapse even with shorter drug holidays). According to Dr. Golden, future research should focus on making advances where it matters; specifically, using medical knowledge to decrease side effects that may sabotage patient treatment compliance. References 1. Leon AC, Portera L, Weissman MM. The social costs of anxiety disorders. Br J Psychiatry Suppl. 1995;(27):19-22 2. Kessler RC, McGonagle KA, Zhao S, et al. Lifetime and 12-month prevalence of DSM-III-R psychiatric disorders in the United States. Results from the National Comorbidity Survey. Arch Gen Psychiatry. 1994;51:8-19 3. Wittchen HU, Hoyer J. Generalized anxiety disorder: nature and course. J Clin Psychiatry. 2001;62(suppl 11):15-19; discussion 20-21. 4. Lepine JP. The epidemiology of anxiety disorders: Prevalence and societal costs. J Clin Psychiatry. 2002;63(suppl 14):4-8 5. Sheehan DV. The management of panic disorder. J Clin Psychiatry. 2002;63(suppl 14):17-21 6. Sheehan DV. Current concepts in the treatment of panic disorder. J Clin Psychiatry. 1999;60(suppl 18):16-21 7. Starcevic V. Recent advances in the treatment of panic disorder. Program and abstracts of the International Congress of Biological Psychiatry; February 9-13, 2004; Sydney, Australia. Symposium 120. 8. Sheehan DV. Why sustained-relates medications? Practical considerations in the management of patients with anxiety. Psychiatr Ann. 1993;23(10 suppl):3-6. 9. Otto MW, Hong JJ, Safren SA. Benzodiazepine discontinuation difficulties in panic disorder: conceptual model and outcome for cognitive-behavior therapy. Curr Pharm Des. 2002;8:75-80 10. Otto MW, Tuby KS, Gould RA, McLean RY, Pollack MH. An effect-size analysis of the relative efficacy and tolerability of serotonin selective reuptake inhibitors for panic disorder. Am J Psychiatry. 2001;158:1989-1992 11. den Boer JA. Pharmacotherapy of panic disorder: differential efficacy from a clinical viewpoint. J Clin Psychiatry. 1998;59(suppl 8):30-36 12. Rickels K, Schweizer E. Panic disorder: long-term pharmacotherapy and discontinuation. J Clin Psychopharmacol. 1998;18(suppl 2):12-18. 13. van Balkom AJ, Bakker A, Spinhoven P, Blaauw BM, Smeenk S, Ruesink B. A meta-analysis of the treatment of panic disorder with or without agoraphobia: a comparison of psychopharmacological, cognitive-behavioral, and combination treatments. J Nerv Ment Dis. 1997;185:510-516 14. Woods SW, Nagy LM, Koleszar AS, Krystal JH, Heninger GR, Charney DS. Controlled trial of alprazolam supplementation during imipramine treatment of panic disorder.J Clin Psychopharmacol. 1992;12:32-38 15. Goddard AW, Brouette T, Almai A, Jetty P, Woods SW, Charney D. Early coadministration of clonazepam with sertraline for panic disorder. Arch Gen Psychiatry. 2001;58:681-686 16. Pollack MH, Allgulander C, Bandelow B, et al. WCA recommendations for the long-term treatment of panic disorder. CNS Spectr. 2003;8(8 suppl 1):17-30. 17. Carli V, Sarchiapone M, Camardese G, Romano L, DeRisio S. Mirtazapine in the treatment of panic disorder. Arch Gen Psychiatry. 2002;59:661-662 18. Stahl SM, Gergel I, Li D. Escitalopram in the treatment of panic disorder: a randomized, double-blind, placebo-controlled trial. J Clin Psychiatry. 2003;64:1322-1327 19. Bystritsky A, Rosen R, Suri R, Vapnik T. Pilot open-label study of nefazodone in panic disorder. Depress Anxiety. 1999;10:137-139 20. Papp LA, Coplan JD, Martinez JM, de Jesus M, Gorman JM. Efficacy of open-label nefazodone treatment in patients with panic disorder. J Clin Psychopharmacol. 2000;20:544-546 21. Sarchiapone M, Amore M, De Risio S, et al. Mirtazapine in the treatment of panic disorder: an open-label trial. Int Clin Psychopharmacol. 2003;18:35-38 22. Schatzberg AF. New indications for antidepressants. J Clin Psychiatry. 2000;61(suppl 11):9-17 23. Sheehan D, Iyengar M, Burnham D, Beebe KL. Efficacy and tolerability of controlled-release paroxetine HCL in panic disorder. Program and abstracts of the International Congress of Biological Psychiatry; February 9-13, 2004; Sydney, Australia. 24. Versiani M, Cassano G, Perugi G, et al. Reboxetine, a selective norepinephrine reuptake inhibitor, is an effective and well-tolerated treatment for panic disorder. J Clin Psychiatry. 2002;63:31-37. 25. Pollack MH, Worthington JJ 3rd, Otto MW, et al. Venlafaxine for panic disorder: results from a double-blind, placebo-controlled study. Psychopharmacol Bull. 1996;32:667-670 26. Papp LA, Sinha SS, Martinez JM, Coplan JD, Amchin J, Gorman JM. Low-dose venlafaxine treatment in panic disorder. Psychopharmacol Bull. 1998;34:207-209. 27. Bradwejn J, Emilien G, Ahokas A, Whitaker T. Treatment of panic disorder with venlafaxine XR. Program and abstracts of the International Congress of Biological Psychiatry; February 9-13, 2004; Sydney, Australia. 28. Pollack M, Emilien G, Tzanis E, Witaker T. Venlafaxine XR and paroxetine in the short-term treatment of panic disorder. Program and abstracts of the International Congress of Biological Psychiatry; February 9-13, 2004; Sydney, Australia. 29. Pande AC, Pollack MH, Crockatt J, et al. Placebo-controlled study of gabapentin treatment of panic disorder. J Clin Psychopharmacol. 2000;20:467-471 30. Zwanzger P, Baghai T, Boerner RJ, Moller HJ, Rupprecht R. Anxiolytic effects of vigabatrin in panic disorder. J Clin Psychopharmacol. 2001;21:539-540. 31. Zwanzger P, Baghai T, Schule C, et al. Tiagabine improves panic and agoraphobia in panic disorder patients [letter]. J Clin Psychiatry. 2001;62:656-657. CME Credits Serotonin Syndrome Alzheimer's / Namenda Refractory Psychosis Types of NMS Catatonia The Brain Trust/Speakers Fibromyalgia & Pain Targeting Non Compliance Compliance Issues