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Dr Dolnak is assistant medical director of California Clinical Trials and a clinical instructor in psychiatry at the University of California, San Diego.

Address correspondence to Douglas R. Dolnak, DO, California Clinical Trials, 3625 Russin Rd, Suite 100, San Diego, CA 92123. E-mail: doug.dolnak{at}cctrials.com.

Patients who have comorbid depression and anxiety present primary care physicians a diagnostic as well as a treatment challenge. Identifying these patients is imperative as they have a higher suicide rate than those with depression alone. Patients with major depressive disorder and other psychiatric illness (ie, comorbid generalized anxiety disorder) have a doublefold increase of suicide attempts than patients without comorbid depression. Other medical illnesses may also be comorbid with depression and anxiety. The key to accurate diagnosis is the physician's high index of suspicion, the use of appropriate rating scales for assessment, including patients' self-rating scales, and the team approach. Such scales are also helpful in monitoring progress of treatment and in empowering patients to take an active role in their treatment, which may include pharmacologic or nonpharmacologic treatment options. Patient education in which depression and anxiety are described as biological disorders or medical illnesses averts patients' embarrassment and increases compliance. Referral for psychotherapy also increases compliance. Discussion includes summaries of studies documenting the efficacy, advantages, and disadvantages of medications that have been approved by the US Food and Drug Administration for depression and anxiety. A few medications used off label are mentioned briefly.

Because depression and anxiety disorders have a variety of overlapping symptoms,⁶ it is difficult to distinguish between the two disorders. A few of the symptoms co-overlap major depression and anxiety. Difficulty concentrating, gastrointestinal complaints (eg, nausea, constipation, diarrhea), and interpersonal sensitivity occur in patients with GAD, SAD, and major depressive disorder (MDD). Agitation, irritability, sleep disturbance, fatigue, and pain are symptoms present in patients with GAD and MDD. Patients with GAD usually have difficulty with sleep latency, and patients with MDD have some difficulty maintaining sleep, as well. Physical symptoms, nonspecific fatigue, tension headaches, and pain are related to disturbances in norepinephrine and serotonin stimulation of receptor function.

One study showed that GAD was diagnosed in approximately 60% of patients with MDD, and 35% of the population with GAD also had symptoms of panic disorder.¹ GAD is a pervasive disorder whereby patients have chronic daily anxiety and have difficulty controlling their anxiety. This difficulty affects both their functioning and their quality of life. It may also affect their compliance with other medications such as those for hypertension or diabetes mellitus. In contrast, patients with panic disorder have discrete symptom attacks that arise within minutes to seconds, escalate within 10 or 15 minutes, and then subside. Some patients with panic disorder also have clinically significant agoraphobia, which also affects their quality of life and functioning. Some patients have symptoms of agoraphobia that are so severe that they are unable to attend work or school.

Anxiety disorders as a group are the most common mental illness in the United States, affecting more than 40 million American adults (ages 18 and older). In a given year, about 18.1% of the population in this age group will have an anxiety disorder.⁷ Physicians may underestimate the significance of anxiety in patients with insomnia, anhedonia, or suicidal ideation. Yet, it is essential to establish that an anxiety disorder is comorbid with depression and consider treatment options.

	Lifetime History of Suicide Attempts

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Depression exacerbated by anxiety is associated with a much higher suicide rate than that in the general nondepressed population. In a study showing the lifetime history of suicide attempts in relation to the lifetime comorbid MDD, 34% of patients with MDD and PTSD had the highest lifetime history of suicide attempts.⁸ In contrast, 23% of the patients with PTSD without comorbid MDD had a lifetime history of suicide attempts. Patients with comorbid GAD and MDD had a 20% lifetime history of risk, compared with only 6% of patients with GAD alone. Physicians need to be aware of such comorbidities and their relation to suicide attempts and include a patient self-report questionnaire or questions related to suicidal ideation during examination. Office staff can help elicit information from patients to prompt physicians to ask appropriate and relevant questions during the examination.

	Psychopathology

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Genetic research has elucidated the etiology of depression and anxiety. It includes genetic variability to certain genes, trauma to the brain, and disruption of the hypothalamic-pituitary-adrenal axis.⁹ Environmental factors, social support, and psychiatric intervention play a role in treatment and in monitoring progression in patients for whom depression and anxiety are refractory to treatment.¹⁰

The amygdala, a small structure deep in the brain, is one of the pathways associated with anxiety. It coordinates the body's fear response when an individual is confronted with danger (real or perceived). The cerebral cortex is the second pathway and the slower route involved in the fear response. It relays information to the cerebral cortex. Stress signals the amygdala to activate the cascade of events that are perceived as the fear response. This response readies the body for action before the brain comprehends what is wrong. Neuronal processes in the amygdala extend while neurons in the hippocampus shrink with stress.^11,12 Chronic stress causes degeneration of the hippocampus. Imaging studies have shown decreased volume of the hippocampus in major depression, as well.^13,14

The cerebral cortex processes a longer impulse later in the body's response to fear. The slower route through the cerebral cortex relays information for cognitive processing by the brain (Figure 1], thus allowing the assessment of the object and the situation. The fear response via the amygdala—the "fight or flight" mechanism—occurs automatically before the brain comprehends the danger or what is wrong. It is a physiologic cascade of events. The heart accelerates its output to the muscles, essentially shuting down the digestive tract. Stress hormones and glucose flood the blood stream to provide energy for the fight or flight response.

View larger version (61K): [in this window] [in a new window]   Figure 1. Depression and anxiety disorders alter the chemical balance in the brain as well as the anatomy of the brain. When an individual is stressed, neuronal processes in the amygdala extend while neurons in the hippocampus shrink. With chronic stress, the hippocampus degenerates and its volume is decreased.

In another example of the structures that are involved in the fight or flight response, muscles become tense and irritable bowel may result. When glucose is increased, patients may become hypervigilant. Hypervigilance is one of the symptoms seen in patients who have comorbid GAD and panic disorder. Chronic stress, which is associated with immunodepression, is a delayed response to a fearful object that is also seen in patients with depressive disorders. Chronic illnesses such as cancer, diabetes, and heart disease are associated with comorbid depression. Comorbid depression may also occur after stroke and myocardial infarction.

Although a link exists between depression and anxiety disorders so they appear similar, they have different internal mood states. Depression generates emotions of helplessness, hopelessness, worthlessness, despair, and anger that diminish patients' energy so that they have difficulty accomplishing the activities of daily living, being involved in social activities, going to work, or caring for family or friends. These patients usually have a decrease not only in symptoms that relate to physical energy, but also in attention and concentration. They feel overwhelmed by day-to-day activities because of depression.

In contrast, patients with an anxiety disorder have intense fear and panic; they worry excessively about family, friends, or finances. They have difficulty controlling anxiety; anxiety is controlling their lives. They also have difficulty in attending, concentrating, and focusing, as well as difficulties in falling asleep and in sleep latency. People who have clinically significant panic attacks or panic disorder characteristically have the panic attacks throughout the day without being under stress. Even during sleep, many patients have panic attacks that awaken them.

In one of the animal models that has been used in studying anxiety and depression, a rat presses a lever to avoid a shock and is "happy" and does not appear to be stressed. The level of dopamine, which is associated with the euthymic or content state, is increased. The levels of epinephrine and cortisol are unchanged. When pressing the lever no longer avoids the shock, the rat goes into a frenzy and exhibits the fight or flight mechanisms with an increased epinephrine level and a rising cortisol level. As chronic stress ensues, the rat has considerably higher levels of cortisol, which also can affect the immune system.

	Neurotransmitter System

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Norepinephrine and serotonin have been associated as a cause of exhaustion in depression and anxiety. Research looking at the role of the glutaminergic system, cytokines, and neuropeptides is under way. Prolonged exposure to stress depletes the stimulation of dopamine. The levels of dopamine are integral to the pleasure pathway (ie, mood state, euthymia, and feeling of contentment), which involves many structures in the brain.

With chronic stress, the locus coeruleus secretes less norepinephrine and attentiveness is diminished. Stress also produces reduced secretion of norepinephrine from the raphe nucleus, which communicates with the locus coeruleus and the cerebral cortex.

Hippocampal shrinkage is also a response to stress. The hippocampus has been found to be 12% smaller in depressed individuals,¹¹ an impairment that can lead to memory problems.¹²

Researchers are beginning to look at the immune system and its interaction with depression, anxiety, and the cytokine system. Cortisol affects the immune system, and it is known that stress affects stimulation of cortisol. The immune system is modulated through the locus coeruleus and the raphe nucleus via the stimulation of the release of norepinephrine and serotonin.

	Depression: A Systemic Illness

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Depression is a systemic illness. Serotonin and norepinephrine pathways are mediated through the brain. Peripheral spinal projections modulate neurotransmitter activity, creating the somatic symptoms that we have come to label as "stress related" (pain, vague abdominal discomfort, etc). Therefore, patients with depression and anxiety have a biological basis via these two descending pathways—serotonin and norepinephrine. Headaches and gastrointestinal complaints are associated with the serotonin pathway; vague pains in the joints, limbs, back, and the abdomen are associated with the norepinephrine pathway. Disturbance in these pathways is associated with the emotional and physical symptoms that physicians see in patients with depression and anxiety. Many patients have vague somatic complaints such as headaches, back pain, or leg pain for which no clear organic etiology can be found. Such patients warrant a physician's high index of suspicion for comorbid depression as well as anxiety.

Numerous physical symptoms may be associated with depression and anxiety as shown in a 3-year study by Kroenke and Mangelsdorff¹⁵ identifying organic causes for physical complaints in an ambulatory care clinic. Organic causes were found in some patients, but no organic cause could be found in most patients. The authors found that the cause of these complaints were psychological disturbances such as anxiety and depression. The percentage of patients in whom no organic cause could be identified for chest pain was approximately four times higher than the percentage of patients in whom an organic cause was found. About 8% of patients with fatigue had no organic cause; no organic cause was found in 10% of patients with dizziness and approximately 6% of those with headaches.

	Physical and Social Functioning

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A study by Wells et al¹⁶ describes physical and social functioning of patients with depression, as compared with patients with and without chronic medical conditions. They found that depression greatly affected functioning and quality of life. Treatment with selective serotonin reuptake inhibitors (SSRIs) or other neuropharmacologic treatment modalities improves the symptoms as well as psychosocial functioning of patients with depression.¹⁷

Comorbid depression can exacerbate poor physical and social functioning and have an impact on quality of life in patients with comorbid medical illnesses such as diabetes, arthritis, and hypertension.

Katon et al¹⁸ examined the lifetime mental disorders of distressed high utilizers of general medical care (N=119). They found that such patients frequently come to physicians' offices for a variety of complaints (Figure 2). Their findings indicate that physicians need a high index of suspicion for MDD or anxiety disorders. In another study, at least 75% of patients with major depression were found to be high utilizers of general medical care.¹⁹

View larger version (47K): [in this window] [in a new window]   Figure 2. Possible markers for depression in medically ill patients. (Source: Katon W, Sullivan MD. Depression and chronic medical illness. J Clin Psychiatry. 1990;51[Suppl]3–11.)

Possible markers of depression in patients with somatic illnesses are physical complaints that are disproportionate to other findings. The mechanism of action for these physical complaints are disturbances in the serotonin and norepinephrine descending pathways. Thus, a real cause exists for these symptoms. Patients with significant MDD and GAD have excessive functional disability and frequent utilization of medical care resources.¹⁹

Depression and anxiety may affect patients' compliance with regimens they have to follow for comorbid somatic illnesses such as controlling blood sugar levels in diabetes, managing blood pressure medication, or managing multiple medications. Physicians need to be aware of such regimens as well as alert to patients' self-medication with drugs and alcohol, as depression is a clinically significant comorbidity with alcohol abuse.

Few cases of anxiety and depression were recognized by physicians at the initial examination of patients with chest pain who were seen in a primary care setting.²¹ In a given year, approximately 2.4 million Americans have panic disorder.²² Many patients with symptoms of panic disorder may visit 10 or more physicians and repeatedly visit emergency departments before their panic disorder is correctly diagnosed.²³

Again, the key to accurate diagnosis is a high index of suspicion. Research has shown genetic predisposition to anxiety disorders^24,25 and depression.^26,27 Therefore, the patient's past history, genetic history, and family history of depression and anxiety disorders such as panic disorder are valuable clues to diagnosis.

It is appropriate to refer to the disorder as biological depression, the medical illness of depression, or medical illness of anxiety. Offering patients explanations using such terms based on recent clinical information may help them understand what they are experiencing and be more accepting of such a diagnosis.

	Assessment Tools

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Successful treatment requires a team approach and the use of appropriate rating scales for assessment (Figure 3). Self-rating scales are available for physicians to give patients to fill out in the waiting room. They include the Beck Depression Inventory, the Inventory to Diagnose Depression, and the Self-rating Anxiety Scale. The physician's staff can be trained to use the Hamilton Rating Scale for Anxiety (HAM-A) or the Hamilton Scale for Rating Depression (HAM-D), which elicit the symptoms of GAD and MDD, respectively. These scales can also be of value in the treatment of patients. They help to empower patients to take an active role in their treatment and monitor the progress of treatment in reducing symptoms.

View larger version (45K): [in this window] [in a new window]   Figure 3. Tools for assessment for proper diagnosis.

The Montgomery Asberg Depression Rating Scale (MADRS) and the HAM-D can be administered in the physician's office. The HAM-D looks at the core symptoms of depression (ie, mood, interests, sleep, concentration, attention, suicidal thoughts, cognition, and functioning), whereas the MADRS assesses mood, interest, and other subjective mood states of depression.

The HAM-A can also be used in the physician's office. It assesses the symptoms of anxiety (eg, anxious mood, tension, sleep), as well as myriad physical symptoms related to anxiety (eg, central nervous system, gastrointestinal, neurologic complaints ranging from tension headaches to dry mouth, indigestion, paresthesias, changes in menstrual symptoms). The HAM-A rating scale is the gold standard in clinical trials evaluating medications for anxiety treatment.

	Treatment

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Community resources are valuable in the treatment of patients with depression and anxiety. The National Alliance for the Mentally Ill (NAMI) has local chapters in all areas of the United States and offers community and family support for patients as well as community clinics and crisis centers that are especially helpful in the treatment of patients who have a lack of resources.

Evidence-Based Pharmacologic Treatment
Pharmacotherapy is effective in the office treatment of patients with depression and anxiety disorders (Figure 4). The US Food and Drug Administration (FDA) has approved SSRIs, serotonergic and norepinephrine receptor inhibitors, and tricyclic antidepressants (TCAs) for use in MDD. For panic disorder and GAD, SSRIs and selective norepinephrine reuptake inhibitors (SNRIs) are effective. Benzodiazepines are used in the treatment of patients with anxiety disorders. For short-term treatment of patients with anxiety disorders or panic disorder, these two medications usually are used in combination with an SSRI. For long-term use, however, the use of benzodiazepines is avoided and SSRIs are used.

View larger version (71K): [in this window] [in a new window]   Figure 4. Advantages and disadvantages of medications used in the treatment of patients with depression and anxiety. (Sources: Gorman JM. Treatment of generalized anxiety disorder. J Clin Psychiatry. 2002;63[Suppl 8]:17–23; Treating generalized anxiety disorder. J Clin Psychiatry. 2003;64[Suppl]:24–29; Van Meter SA, Doraiswamy PM. Anxiety disorders. In: Rakel RE, Bope ET, eds. Conn's Current Therapy. Philadelphia, Pa: WB Saunders Co; 2001:1137–1142.)

A disadvantage of the SSRIs is their slow onset of action, usually taking 2 weeks to as long as 6 weeks to become effective. Other disadvantages are their cost and sexually adverse side effects. The usual protocol for dosing is to "start low and go slow" with SSRIs in patients with comorbid anxiety. A slower titration might minimize initial side effects and avoid an initial exacerbation of anxiety and side effects. For severely anxious patients who have severe comorbid GAD or panic disorder, it might be more appropriate to use low-dose benzodiazepines short term during the first 4 to 6 weeks of treatment as an adjunct to the SSRIs. Research in patients with panic disorder and MDD has provided evidence that such adjunctive treatment is effective.^32-33

Some ß-blockers and anticonvulsants have been used off label. Some low-dose antipsychotics have been used off label in patients who have augmentation of depression as well as in patients with anxiety and insomnia.

One study³⁴ involved patients who at baseline had severe depression as rated by the MADRS with a score of 30 or higher. They were randomly assigned to one of two treatment arms: escitalopram oxalate at 10 mg/d (a starting dose according to labeling) or sertraline hydrochloride at a flexible dose (50 mg/d to 200 mg/d). Although in practice the dose of escitalopram may be increased to 20 mg/d, the patients assigned to the escitalopram arm received the 10 mg/d dose throughout the study. Each treatment group comprised approximately 100 patients. By week 4, 45% of the patients in the sertraline arm were receiving 150 mg or greater per day. Thus, titration was necessary to improve the symptoms of depression in this group. After week 4, more than 50% of patients in the sertraline arm were receiving 150 mg or greater per day. By week 8, both treatment groups had a statistically significant difference in MADRS scores from baseline. Although symptoms of depression improved in both treatment arms, the difference between the two groups was not statistically significant.

A study by Bielski et al³⁵ in patients with MDD who were treated with escitalopram oxalate rapidly titrated to 20 mg/d or venlafaxine hydrochloride extended release (XR) rapidly titrated to 225 mg/d showed a response to remission. Remission of depression was rigorously defined as a MADRS score of less than or equal to 10 at endpoint and a HAM-D score of less than or equal to 7. The group receiving the escitalopram (N=97) had a mean baseline MADRS score of 30.7 and a mean change at endpoint of –15.9 (41.2% remission rate). The group receiving the venlafaxine XR (N=98) had a mean baseline MADRS score of 30.0 and a mean MADRS score of –13.6 at endpoint (36.7% remission rate).

Stocchi et al³⁶ evaluated the maintained efficacy of paroxetine hydrochloride and the prevention of relapse after discontinuation of paroxetine therapy in patients with GAD. Remission rates were defined as a HAM-A score of less than or equal to 7. The first phase of this study was an 8-week single-blind trial during which patients (n=559 responders) received paroxetine hydrochloride at doses ranging from 20 mg/d to 50 mg/d. Patients who responded at week 8 were randomly assigned to receive paroxetine (N=278) or placebo (N=288) for the next 24 weeks. The patients receiving paroxetine continued on their flexible dosage through week 32 and showed continued improvement; 73% had remission of GAD symptoms. Among the group that had discontinued paroxetine therapy at week 8 and then were randomly assigned to receive placebo, 39.9% had a relapse.

Goldstein et al³⁷ conducted an 8-week multicenter, double-blind placebo-controlled clinical trial to evaluate the efficacy and tolerability of duloxetine hydrochloride, a serotonin and norepinephrine reuptake inhibitor, in the treatment of patients with MDD. Patients were randomly assigned to receive placebo (N=70), fluoxetine hydrochloride, 20 mg/d (N=33), or duloxetine hydrochloride (N=70) titrated from 40 mg in two divided doses a day up to 120 mg/d in two divided doses. The 17-item HAM-D scale was the primary measure of efficacy. The duloxetine-treated group had a 9-point change and the fluoxetine-treated group had an 8-point change in the HAM-D score. The change on the HAM-D scale was statistically significant for duloxetine versus placebo (P=.009) at week 8.

Tricyclic antidepressants are still used as second-line therapy to alleviate anxiety symptoms. They have well-documented significant benefit in depression. Another benefit of the TCAs is their cost, which is considerably lower than the cost of SSRIs. The disadvantages of TCAs are their numerous anticholinergic side effects, especially drug-drug interactions in patients who are taking other medications for comorbid medical illness. Symptoms of anxiety may initially worsen. The use of TCAs is associated with the potential for overdose and cardiovascular risk.²⁸

Buspirone hydrochloride, indicated for GAD, alleviates the symptoms of this anxiety disorder but has a fairly slow onset of action, usually taking more than 2 weeks to reach efficacy. It requires twice-daily dosing versus the once-daily dosing of the SSRIs and other medications used in depression and anxiety. This disadvantage may affect compliance. Buspirone has only moderate efficacy compared with the stronger efficacy of the SSRIs, and proof of long-term efficacy in GAD is lacking. Finally, buspirone lacks antidepressant effect compared with other medications such as the SSRIs. Lacking such effect is thus a disadvantage in patients who have depression as well as anxiety.

Davidson et al³⁸ compared the efficacy of venlafaxine XR and buspirone in outpatients who had GAD but no concomitant MDD. They used the patient-rated Hospital Anxiety and Depression (HAD) Scale and its anxiety subscale, the primary measure of efficacy at week 8. The group receiving venlafaxine hydrochloride XR at 75 mg/d (n=86) and the group receiving venlafaxine hydrochloride XR at 150 mg/d (n=85) showed significant improvement compared with the group receiving placebo (n=97) and the group receiving buspirone hydrochloride at 30 mg/d (n=92) on the HAD anxiety subscale (P<.05). No significant change was seen between the HAD anxiety subscale scores of the group receiving buspirone and those scores of the group receiving placebo.

Benzodiazepines offer advantage in the short-term treatment of patients with anxiety, GAD, or panic disorder. A treatment regimen combining a benzodiazepine with another medication may warrant consideration, especially in patients who have severe anxiety or severe panic. They are effective shortly after administration, having a quick therapeutic onset, and they are well tolerated. A rapid dose adjustment is feasible, and they can be used as needed for situational anxiety, acute anxiety, or acute panic. Disadvantages of the benzodiazepines are sedation, cognitive and psychomotor impairment, interaction with alcohol causing increasing sedation, drowsiness, impairment while driving, and physiologic dependence. Additionally, benzodiazepines have the potential for abuse, and they are not effective in the treatment of patients with comorbid depression.

In their study, Soumerai et al³⁹ determined that the long-term use of benzodiazepines in a group of 2400 Medicaid patients did not result in dose escalation. Eighty percent of these patients had used benzodiazepines for more than 2.5 years. The analysis of escalation to high dosage was defined in this study as at least 20 diazepam milligram equivalents (DMEs) per day for the elderly and at least 40 DMEs a day for younger patients. Among all groups of continuing recipients (n=1980), the median daily dosage remained constant at 10 DMEs per day during the 2 years of continuous use. The incidence of escalation to a high dosage was 1.6%.

In a study with no placebo control, Rocca et al⁴⁰ compared the efficacy of paroxetine versus imipramine versus benzodiazepine in patients with GAD (N=81). At week 8, all three groups had improvement in the mean HAM-A rating scale. Greater improvement occurred in the paroxetine- and imipramine-treated groups than in the group treated with the benzodiazepine. Imipramine has not been approved by the FDA for GAD. Further, evidence-based treatment prevents relapse and aids in management of medical comorbidities.

Nonpharmacologic Treatment Options
Physicians should also consider the use of nonpharmacologic treatment modalities such as psychotherapy and cognitive behavioral therapy in combination with pharmacologic therapy. Electroconvulsive therapy can effect a quicker response and is an option for patients with major depression who have severe functional impairment. Referral is appropriate for patients who have major depression that is refractory to pharmacologic therapy, even therapy including multiple medications.

Another option is the vagal nerve stimulator that the FDA has approved for treatment of patients with severe depression refractory to other treatment modalities.

Patient education is a vital component of treatment much needed by patients with anxiety and depression. Physicians need to instruct these patients to avoid coffee and other caffeine-containing beverages and over-the-counter drug products as well as excessive alcohol use and nicotine. Exercise can relieve tension and improve sleep. Physician and staff support will allay patients' fears and worry. To avoid patients' embarrassment about the illness, physicians should remind their patients that depression and anxiety are medical illnesses and reinforce that medications are available that can relieve the symptoms of depression and anxiety, even to remission. Patient education affords the opportunity to raise patients' awareness and to elicit any issues or questions that they may have about treatment.

	Comment

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The goals of treatment of patients with anxiety, depression, and medical comorbidities are the reduction of symptoms, with progression to remission, restoration of functioning, and improvement in quality of life. Many pharmacologic agents are available to reach these goals.

Psychotherapy referral may increase patients' acceptance of treatment as well as increase their compliance with their treatment. It may also decrease the rate of relapse in patients with depression and increase the success rate of treatment. Thus, primary care physicians share the responsibility with other licensed health-care professionals in the treatment of patients with comorbid depression and generalized anxiety.

	Footnotes

 
Dr Dolnak has received research/grant support from Eli Lilly and Company and Forest Pharmaceuticals, Inc, and he is on the speakers bureau of Eli Lilly and Company and Forest Pharmaceuticals, Inc.

This continuing medical education publication is supported by an unrestricted educational grant from Forest Laboratories, Inc.

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