Mary Kay Smith, Marijo B. Tamburrino, Rollin W. Nagel1 and Denis J. Lynch,
Departments of Family Medicine and Psychiatry
College of Medicine and Life Sciences
University of Toledo

Corresponding author: Marijo Tamburrino, M.D.
Department of Psychiatry
College of Medicine
University of Toledo
3129 Glendale Ave.. Mail Stop 1193
Toledo, Ohio 43614

Telephone number: (419) 383-5669
Fax number: (419) 383-2810
e-mail: marijo.tamburrino@utoledo.edu

This study was funded in part by an unrestricted educational grant from Eli Lilly and Company to the corresponding author.

1 Now at Ohio State University, Center for Education and Scholarship

Abstract

Background: The current study was intended to assess the frequency of comorbid anxiety disorders in primary care patients with major depressive disorder (MDD).
Methods: Subjects 18 years or older who were recruited from three family medicine practices completed a demographic questionnaire and the Primary Care Evaluation of Mental Disorder (PRIME-MD) Patient Questionnaire. Subjects responding positively to one of the depression screening questions were administered the PRIME-MD Clinical Evaluation Guide to assess for depression and anxiety diagnoses. Diagnosis was based on the Diagnostic and Statistical Manual of the American Psychiatric Association (DSM-IV).
Results: Of 1704 subjects completing the assessment, 28% (N=475) screened positively for depression. For the entire sample, an estimated rate of 4.6% would receive a diagnosis of MDD. Of the subjects with a diagnosis of MDD, 66% (N=47) also received an anxiety diagnosis.
Limitations: Diagnostic information could not be obtained from 177 subjects who screened positively for depression.
Conclusions: This study supported earlier work that identified a high rate of comorbid depression and anxiety disorders in primary care patients. Primary care practitioners are treating potentially severe comorbid patients at rates higher than previously thought and may benefit from effective treatment algorithms for this patient population.
Key words: depression, anxiety, comorbidity, primary care

Comorbidity Of Anxiety In Depressed Primary Care Patients

The comorbidity of anxiety disorders in patients with major depressive disorder (MDD) has been the topic of continued interest. Early epidemiological studies (Kessler et al., 1999) noted the frequent occurrence of anxiety disorders in depressed patients. Later studies documented the clinical relevance of this comorbidity.
Rush et al (2005) analyzed findings from the STAR*D trials (Fava et al., 2003) and found that depressed subjects who had comorbid anxiety had greater depressive severity, poorer mental and physical functioning, and more general medical comorbidity. Kessler et al (2008) also reported greater severity of symptoms in depressed subjects with comorbid anxiety. Higher rates of suicide have also been reported in comorbid patients compared to those with depression alone (Aina & Susman, 2006). Further study of the incidence and management of anxious depressed patients is clearly indicated (Mittal, Fortney, Pyne, & Wetherell, 2011).
Occurrence of comorbid anxiety in depressed patients has been studied in both psychiatric and primary care settings. Gaynes et al (2007) studied primary care and psychiatric outpatients with depression and found anxiety comobidity rates of around 50% in both groups. Other studies conducted in psychiatry clinics have found comorbidity rates ranging from 49% to 57 % (Yerevanian, Koek, & Ramdev, 2001; Zimmerman, McDermut, & Mattia, 2000). An earlier study by Gaynes and his colleagues (1999) found a comorbidity rate of about 50% in a primary care sample. However both Stein et al (1995) and Rush et al (2005) reported significantly higher rates of comorbidity in primary care samples. The reason for this variation is not clear, but further research is needed to clarify the comorbidity rate in primary care patients.
There have also been mixed findings regarding treatment implications of comorbid anxiety in depressed patients. Kashdan and Roberts (2011) described a group intervention for depressed patients with and without anxiety. They reported that the anxiety disorder did not have a detrimental effect on the treatment of depression in the group intervention. Others, however, have suggested that depressed patients with anxiety are more challenging to treat (Kessler, Chiu, Demler, Merikangas, & Walters, 2005; Mittal et al., 2011). Psychopharmacological treatment has been specifically discussed in this regard, and it has been reported that depressive symptoms are slower to resolve in patients with comorbid anxiety compared to those with depression alone (Mittal et al., 2011).
In response to the suggestions of both Fava and colleagues (2004) and Mittal and colleagues (2011), the purpose of this study was to determine the prevalence of comorbid anxiety in depressed patients. A large sample of community patients was assessed to clarify the prevalence of comorbid anxiety disorders in depressed outpatients from family medicine settings.

Methods

Subjects: Patients waiting to see their physicians in three different outpatient family medicine practices were approached in the waiting rooms and invited to participate. The practices were located in urban, suburban and rural areas respectively. The majority of the patients in the urban practice were on Medicaid while the other two practices had less than 10% Medicaid patients. Private insurance was the prevalent payor for the patients in the rural and suburban practices. Individuals were excluded from the study if they were younger than 18 years or if they were unable to understand and/or respond to study instruments.
Procedure: Patients were asked to complete a demographic information sheet and the Primary Care Evaluation of Mental Disorder (PRIME-MD). Patient Questionnaire (PQ) (Spitzer et al., 1994). Subjects who screened positively for depression on this instrument were contacted within two weeks by telephone and were administered the depression module of the PRIME-MD Clinical Evaluation Guide (CEG) and the Hamilton Rating Scale for Depression (Hamilton, 1960).
If they screened positively for anxiety on the PQ they were administered the anxiety module of the CEG as well.
Measures: The PRIME-MD (Spitzer et al., 1994) was devised as a screening and diagnostic instrument for mental health problems in primary care settings. It assesses five areas: mood, anxiety, alcohol use, eating disorders and somatoform disorders. Validity studies of the screening instrument (PQ) have found that high scores on depression and anxiety are associated with functional impairment, disability days and healthcare use (Kroenke, Spitzer, Williams, & Lowe, 2009). If patients responded positively to screening items in one or more of the areas, they were administered the CEG. For each area assessed, a diagnosis based on the Diagnostic and Statistical Manual of the American Psychiatric Association (DSM-IV) (1994) can be assigned. In this study, patients who screened positively for depression on the PQ were contacted by trained research assistants, and were administered the CEG for positive PQ components.
To be considered a positive screen for depression on this PQ, subjects must respond positively to at least one of the two items (“depressed mood” or “loss of interest in activities”) in the last two weeks. At least one of the three anxiety items (“nerves” or “feeling anxious”, “worrying about a lot of different things”, or “anxiety attack”) must be endorsed for a positive anxiety screen.
Data analysis: Percentages of subjects who screened positively for depression on the PQ and the number receiving a depression diagnosis on the CEG were calculated. The percentage of subjects with a diagnosis of MDD who also had an anxiety diagnosis was calculated.
Institutional review: The study was approved by the institutional review boards of the authors’ academic institution and the clinical institution responsible for the medical care of the subjects. Informed written consent was obtained from all subjects.

Results

A total of 1704 subjects completed the assessment packet (PRIME-MD PQ and demographic information sheet). The average age was 42.7 years, 72.6 % (n=1237) were female, and 73.3 % (n=1249) were working either full-time or part- time. Less than 10% of those approached declined participation. Since we do not have information for these patients, we cannot say how they compared to the study participants.
On the PRIME-MD PQ, 475 (28%) subjects screened positively for depression. Of those screening positively for depression, 87% (n=413) also screened positive for anxiety. One hundred and seventy-seven (37%) of those screening positive for depression could not be reached by telephone to complete the PRIME-MD CEG.

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The rates of depression diagnoses for those screening positively on the PRIME-MD PQ who were administered the CEG (n=298) were: MDD 23.5% (n=70), dysthymia 10.4% (n=31) minor depressive disorder (mDD) 14.4% (n=43). Given the high sensitivity of the PRIME-MD (U. S. Preventive Services Task Force, 2002; Whooley, Avins, Miranda, & Browner, 1997) estimated rates for the entire sample (not including those who could not be reached by telephone, n=1527) can be made and would be as follows: MDD = 4.6%, dysthymia = 2%, mDD= 2.8%. Of the subjects who were diagnosed with MDD, 66.7% (n=47) also had an anxiety diagnosis. For dysthymia and mDD, the rates of comorbid anxiety diagnosis were 34.5% (n=11) and 20.8% (n=9) respectively. These results are presented in Table 1.

Table 1. Estimated frequency of PRIME-MD depression diagnoses and comorbid anxiety diagnoses (N=1527)

Subjects who screened positively for anxiety, as well as depression, were significantly more likely to receive a depression diagnosis when administered the PRIME-MD CEG (X=14.47, p< .002) than those who screened positive only for depression. The likelihood of receiving a depression diagnosis was even greater (X=68.75, p<. 001) in subjects receiving an anxiety diagnosis (compared to those who simply screened positive for anxiety). About 62 % of this group received a diagnosis of MDD (compared to 13% in the group without an anxiety diagnosis).

Discussion

The results of our study add further support to previous findings that primary care patients with MDD are likely to also have an anxiety disorder. In our study, this comorbidity occurred in about 67% of the patients which was consistent with that found by Stein et al (1995) (68.2%), and Rush et al (2005) (62%) but higher than that reported by Gaynes et al (2007) (50.3%). Our sample and that of Stein et al (1995) tended to have older subjects and a higher proportion of males than that reported by Gaynes et al (2007). It is possible that these differences might have contributed to the varied results.
Unlike those previous two studies, ours used the PRIME-MD, which was developed specifically for use in primary care settings. Regardless, our study had similar overall rates of MDD (about 4.6%) as the other researchers (Gaynes et al., 2007; Stein et al., 1995), although the number screened as positive was somewhat higher (28% for the PRIME-MD, as compared to 16% by Stein who used the Beck Depression Inventory, and 15.3% by Gaynes who used the Center for Epidemiological Studies Depression Scale (CES-D.)
We found that patients screening positive for both depression and anxiety were significantly more likely to receive a depression diagnosis, particularly MDD. This finding may have particular clinical utility. Used by itself, the depression PQ module of the PRIME-MD led to a relatively high false positive rate (74%). In clinical situations where greater specificity is desired, combined use of both the depression and anxiety modules may be effective. Further research of this question would be helpful.
Wittchen and colleagues (1999) had suggested that comorbidity of anxiety with depression would be more common in mental health clinics, since these are patients with more severe conditions who would be more likely to seek specialized care. However, our results suggest otherwise. Studies done in psychiatry clinics found comorbidity rates ranging from 49 to 57 % (Yerevanian et al., 2001; Zimmerman et al., 2000). These rates are lower than we found and also lower than the rate reported by Stein et al (1995). It may be, then, that the severity and complexity of psychiatric conditions seen in primary care is greater than previously thought.
The fact that we were not able to reach 177 (37%) subjects who screened positive for depression represents a limitation of this study. It is not clear if or how these subjects may differ from the other subjects. It is not known how their inclusion might have affected the results.
Clinical management of patients with comorbid anxiety and depression is more challenging than treatment for those with only one of these disorders (Fava et al., 2008). Suicide rates are higher in comorbid patients (Aina & Susman, 2006), and the choice of appropriate medications is more complex (Mittal et al., 2011; Schoevers, Van, Koppelmans, Kool, & Dekker, 2008). Psychiatric consultation may be indicated for treatment-resistant individuals to facilitate symptom remission. Like Gaynes et al (2007), our results suggest that primary care practitioners are seeing a high number of depressed patients with comorbid anxiety disorders. Future research that leads to the development of effective treatment algorithms for this patient population should be helpful to the busy primary care physician managing depressive and anxiety symptoms.

References

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Copyright Priory Lodge Education Limited 2013 onwards.

First Publsihed May 2013.

Kava is the best studied herb for treating anxiety. Researchers searching for the active part of the plant have discovered that Kava contains chemicals known as kavalactones. In various research studies, kavalactones have demonstrated sedative (calming and relaxing), anxiolytic (anti-anxiety), analgesic (pain reducing), local anesthetic (numbing), and anticonvulsant (reduces muscle spasms) properties. These properties combine to make Kava ideal for use in treating anxiety.

Scientists are not certain about how Kava combats the body’s anxiety response. Other anti-anxiety medications work by increasing the activity of a neurotransmitter (a chemical that conveys messages in the brain and nervous system) known as GABA (gamma-aminobutyric acid). GABA is thought to produce an upbeat mood, positive self-image, sense of calm/contentment, and sound sleep. People who experience anxiety often have low levels of GABA in their brains. Some studies have shown that kavalactones decrease anxiety by stimulating the activity of GABA; however, others studies have not found this result.

Common Side Effects of Kava

• Balance problems (dizziness)
• Drowsiness
• Headache
• Mild stomach upset
• Morning fatigue
• Mouth numbness
• Skin rash
• Slow muscle reflexes
• Visual problems (problems focusing)

Another theory about Kava’s mechanism of action suggest that kavalactones may cause a calcium ion channel blockade. Calcium ion channels are little tunnels across the membranes of nerve cells. Such channels are like border crossings; they exist to allow calcium to enter the nerve cells. A blockade of nerve cell ion channels has the effect of closing a gate across the channel, preventing calcium from entering the nerves. It is thought that partial blockade of calcium ion channels may cause a calming effect because nerve cells require calcium ions in order to fire, and blocking calcium from entering affected nerves thus may keep them from firing and causing symptoms of anxiety. Though this is an interesting theory, current research does not support this line of thinking.

Still another theory suggests that kavalactones act in a manner analogous to antidepressant medications. These medications work by increasing the total amount of specific neurotransmitters in the brain or by allowing existing neurotransmitters to stay at work longer before being broken down.

The truth is, there are well over 1000 different chemicals (!) in Kava, any number of which may have anti-anxiety drug effects, either in isolation or in combination with each other. Any search for the one chemical that makes Kava work may be futile.

Studies in humans with a range of anxiety levels have shown that Kava is a very effective treatment, with little demonstrated side effects (see box). Kava is effective in treating sub-clinical (mild) anxiety, clinical (severe) anxiety, anxiety associated with a disease (such as cancer), and anxiety that occurs before an event (such as before surgery).

Side effects tend to occur in less than 5% of the people who take Kava, and are considered mild or negligible (not significant). The most well-known side effect of Kava, “kava dermopathy”, occurs primarily in people who take large amounts of this herb every day for long periods of time (over three months). Kava dermopathy is a rash that starts in the face and works its way down the body. This rash usually does not appear in people who take Kava as a supplement, but is common in people in the tropical areas where Kava grows and who consume a large amount of this herb every day. The rash disappears when Kava is stopped.

Safety and Dosing

Kava is generally considered safe when taken as directed. The normal dose for Kava is 50-70 milligrams of a standardized kavalactones preparation, three times a day. Kava has only been studied for short-term use (1-24 weeks). Continuous long-term use is not recommended.

Kava has the potential to interfere with other drugs and should not be used with sedative-hypnotics (sleep aids or tranquilizing medicine), anxiolytics (anti-anxiety medicine), or MAO inhibitors (a type of antidepressants). Taking Kava with alcohol is also potentially dangerous and should be avoided. You should never drive or operate heavy machinery when taking Kava.

There is always a potential for an allergic reaction to any medication. If you experience any itching, swelling, difficulty breathing, increased heart rate or any other symptom that worries you, stop using Kava immediately.

Special Note: Kava was previously thought to cause liver failure in a few cases Europe. However, additional studies of Kava-induced liver toxicity failed to show any connection between taking this herb and subsequent liver damage. It is now assumed that the Kava taken by the Europeans who experienced liver failure was somehow adulterated (changed or tampered with), but this has not been proven. Consult a health practitioner before starting any herbal therapy, especially if you have a history of previous or current liver problems.

Anxiety is one of the most common psychiatric disorders. Whether it is the fear of an upcoming public speaking situation, or experiencing discomfort before going into a doctor’s office, most people have felt anxiety at some point in their lives. The symptoms of anxiety are well-known and include increased heart rate and shallow breathing, sweating, cold hands, trembling, nausea and/or “butterflies” in the stomach, and a host of other symptoms.

Anxiety is a normal part of life and generally does not need to be treated unless it interferes with a person’s normal daily routine or prevents that person from fully experiencing life. Problematic anxiety occurs when the anxious response is out of proportion to an actual threat (for example, disabling anxiety that prevents a person from attending a social function) or the perceived threat is not real.

Complementary and Alternative Therapies for Anxiety

Multiple strategies exist for treating anxiety with alternative therapies. Many of these strategies are herbs that have been used by different cultures for hundreds, if not thousands, of years. Scientists are just beginning to investigate whether these herbs work for anxiety in controlled studies.

The only well-studied herb that is presently supported for use in treating anxiety is Kava Kava. Other herbs, such as Valerian, Passionflower, Hops, and Chamomile all have a long history of safe use in the herbal community, but don’t have many high quality scientific studies to support their use. This does not mean that these herbs should not be used for anxiety, but that they should only be taken as recommended. Passionflower, Hops, Chamomile and other mildly calming herbs are especially safe when taken alone and not in combination with any other medications.

Complementary medicines for anxiety can be used for a range of anxiety states. Natural anti-anxiety medications can be used for anxiety and insomnia in response to a time-limited stressor (such as before a public speaking engagement, or a big event). Some CAM remedies can also be used just like prescription medications for severe clinical anxiety. More often, though, natural remedies are mild (such as hops and chamomile) and can be taken as a tea before a potentially stressful event or before going to sleep.

The following chart summarizes the common natural treatments for anxiety and the degree of scientific study to support their use: