Anatomy, Physiology, and Pathophysiology Overview

From time to time, most people experience the normal emotions of anxiety, depression, excitement, and grief. Many times such emotions are simply situational. They arise because of a specific event and subside with time. Treatment, if any, is often limited to psychotherapy, and possibly short-term drug therapy. However, longer-term pharmacotherapy in conjunction with psychotherapy is usually recommended when a person’s emotions or behaviors compromise his or her quality of life, ability to carry out normal activities of daily living, social functioning (interactions and relationships with others), or occupational functioning (e.g., employment, school) over a prolonged period (at least several months).

Anxiety is a normal reaction to stress; however, results of epidemiologic studies show that 5% to 8% of adults suffer from generalized anxiety disorder, 2.7% from panic disorder, 6.8% to 12% from posttraumatic stress disorder, and 3.8% from agoraphobia (the fear of being in unfamiliar situations or places). Obsessive-compulsive disorder is twice as common as schizophrenia or panic disorder in the general population. Anxiety may occur as a result of medical illnesses (e.g., cardiovascular or pulmonary disease, hypothyroidism, hyperthyroidism, pheochromocytoma, Cushing syndrome, and hypoglycemia).

Affective disorders, also called mood disorders, are characterized by changes in mood and range from mania (exaggerated emotions) to depression (fewer emotions or emotional range). Some patients may exhibit both mania and depression, experiencing periodic swings in emotions between these two extremes. This is referred to as bipolar disorder. Hypomania is a form of mania that is less severe and less potentially dangerous (to patient and others).

Bipolar disorder occurs in an estimated 2% of the population. Depression is currently reported to have prevalence rates ranging from 8% to 12%. Major depressive disorders are expected to become the second leading cause of disability by the year 2020. Common depressive symptoms include feelings of worthlessness, loss of interest in normally pleasurable activities, reduced energy level, reduced motivation and ability to meet routine responsibilities, drastic increase or decrease in appetite, insomnia or hypersomnia, and recurrent thoughts of death or suicide. In addition to being associated with reductions in quality of life and occupational and social functioning, depression is also accompanied by the occurrence of major sleep disturbances in up to 80% of patients. Despite recent advances in pharmacotherapy for depression, it remains undertreated in many cases.

Pharmacology Overview

Psychotropic drugs are among the most commonly prescribed drugs in the United States. Because of the inherent variability in the description of symptoms and the diagnoses, the effects of these drugs are less easily quantified than many other types of medications. For example, it is usually not known how long a given psychotropic drug works in the body (duration of action). Thus, the effectiveness of psychotropic drug therapy is often measured by verbal reports from patients regarding the level of improvement (if any) in their social and occupational functioning. Drug selection is often a trial-and-error process, which can be long and frustrating for both prescribers and patients.

Anxiety Disorders

Drug Profiles

Mood-Stabilizing Drugs

Drug Profile

Antidepressant Drugs

Research indicates that early and aggressive antidepressant treatment increases the chances for full remission. The first 6 to 8 weeks of therapy constitute the acute phase. The primary goals during this time are to obtain a response to drug therapy and to improve the patient’s symptoms. It is currently recommended that antidepressant drug therapy be maintained at the effective dose for an additional 8 to 14 months after remission of depressive symptoms. In choosing an antidepressant, the patient’s previous psychotropic drug response history (if any) needs to be considered. Family history of depression with known drug responses are also helpful. Therapeutic response is measured primarily by subjective patient feedback. In addition, a few measurement tools are available that attempt to quantify the patient’s response to drug therapy, such as the Hamilton Rating Scale for Depression and the Symptom Checklist-90 anxiety factor scale.

Anxiety and depression commonly occur together and reinforce each other. Similarly, there is much crossover in terms of symptom control between antidepressant and anxiolytic drugs. A nonresponse to antidepressant drug therapy is defined as failure to respond to at least 6 weeks of therapy with adequate drug dosages. Twenty percent to 30% of patients who do not respond to the usual dosage of an antidepressant will respond to higher dosages. Therefore, dosage optimization, which involves careful upward titration of dose for several weeks, is recommended before concluding that a given drug is ineffective. Often times a switch to a different pharmacologic class of antidepressant is necessary. Forty percent to 60% of patients will respond to the second drug class tried. Anxiolytic and antipsychotic drugs may also be used, either alone or as adjunct therapy. Evidence suggests that psychotherapy given with antidepressant medication is more effective than medication alone.

The most severe cases of refractory depression may warrant an attempt at treatment with electroconvulsive therapy. Electroconvulsive therapy treatment is generally carried out in a postanesthesia care unit setting under brief general anesthesia. Seizure activity is induced in the anesthetized patient via externally applied electric shocks to the brain.

Treatment failure in cases of depression may be due to a misdiagnosis or failure to treat comorbid mental illness (e.g., anxiety disorder, substance abuse) and/or comorbid nonpsychiatric illness (e.g., hypothyroidism). It may also be due to nonadherence to drug therapy. Careful choice of drug therapy to minimize adverse effects may improve patient compliance with treatment and therapeutic outcome. Another reason for treatment failure may be the discouragement associated with depression itself. This alone may cause patients to give up prematurely on their drug therapy, especially because antidepressants often take several weeks to reach their full effect. Effective psychotherapy and support groups can help encourage patients to be consistent with prescribed psychotropic drug therapy.

In 2005, the U.S. Food and Drug Administration (FDA) issued special black box warnings regarding the use of all classes of antidepressants in both adult and pediatric patient populations. Data from the FDA indicated a higher risk for suicide in patients receiving these medications (up to 4% of patients taking the drugs showed suicidal thoughts or behaviors compared with 2% receiving a placebo). As a result, current recommendations for all patients receiving antidepressants include regular monitoring for signs of worsening depressive symptoms, especially when the medication is started or the dosage is changed. Patients need immediate evaluation if they report, or others observe, signs of worsening depression or other emotional instability. Most patients do not experience severe adverse effects from these medications, and many patients obtain significant relief.

Tricyclic Antidepressants

Tricyclic antidepressants (TCAs) were the original first-generation antidepressants. Their use has largely been replaced with the SSRIs and serotonin-norepinephrine reuptake inhibitors (SNRIs). The TCAs are considered second-line drug therapy in patients for whom the SSRIs are ineffective or as adjunct therapy with newer drugs. The TCAs are so named because of their characteristic three-ring chemical structure.