Depression

Jenny, a 36 year-old married, white female with three children, presents to her primary nurse practitioner at her husband's request because she has been increasingly irritable, tired all the time and complaining of dizziness and frequent low back pain. The physical exam was unremarkable. Some routine blood work including a complete blood count, complete metabolic panel, and thyroid panel was unremarkable.

On follow up exam the nurse practitioner reviewed her labs and performed a Physician Depression Questionnaire (PDQ-9). The PDQ-9 score was 14 which equated with moderate depression. The patient denied any suicidal thoughts and no grief was detected on exam. The exam did not reveal any manic or psychotic symptoms. The physical and neurological exam was unremarkable. The patient revealed that she had felt like this before but, the feelings did not persist and never impacted the lives of her family or friends.

John, a 78-year-old man present to his primary care physician with the complaint of low back pain. John lives with his son and daughter-in-law and his son accompanies him to the appointment. The low back pain has been present for three weeks and there has been no trauma or injury that would indicate a cause of the back pain. John reports that the pain is mild, but he is very worried that this is cancer. He is convinced that he is going to die.

John's son is not as concerned about the low back pain, he reports that he has complained of on and off back pain his whole life. He is most concerned about is increased irritability and social withdrawal. John's past medical history is positive for hypertension, arthritis and mild dementia. He has never had a surgery.

He lives with his son because his son had noticed an increase in confusion after the death of his wife one year ago. He was not able to cook, clean or handle finances, but is still able to drive and shop. Over the past couple months, he has become more isolated in his room and has had increased irritability. His daughter-in-law is threatening him to put him in a nursing home. He has limited contact with his friends after moving in with his son because he lived 20 miles away and has no friends in his new neighborhood. His son discourages him to drive the 20 miles to visit his old friends.

The physical exam was unremarkable. His mini-mental state exam was 19/30 and his Cornell depression score was 9.

No test definitively diagnoses depression, but diagnostic testing is used to rule out other contributing or causative factors of a depressed mood. Common blood tests run in the depressed patient include:

• Complete blood count
• Thyroid panel
• Kidney function tests
• Liver function tests
• Electrolytes
• Vitamin B-12 level
• Drug screen - urine toxicology
• Alcohol level
• Antinuclear antibody (ANA).
• Erythrocyte sedimentation rate (ESR)
• Arterial blood gases
• Rapid plasma reagin (RPR)
• Human immunodeficiency virus blood test

Imaging studies are rarely performed in the management of depression. Some patients may be candidates for a computed tomography or magnetic resonance imaging for the brain to rule out intracranial pathology. Rarely electroencephalography (EEG) or lumbar puncture is performed.

After common causes of conditions that mimic depression are ruled out, the clinician should perform a test for depression. A few of the common screening tests to evaluate for depression include:

• Physician Depression Questionnaire 9 (PDQ-9) is a commonly used quick screening tool that asks nine questions to evaluate for the presence of depression.
• Beck Depression Inventory is a 21 question multiple choice tests that helps identify and measure the severity of depression.
• Hamilton Depression Inventory asks 17 questions to evaluate mood. A score above 11 is likely associated with depression. A higher score is associated with a more severe depression.
• Mood Disorder Questionnaire (MDQ) is a five minute questionnaire that helps screen for the presence of bipolar disease.
• Geriatric Depression Scale is used on geriatric patients. This test does not work well on those with dementia (a mini-mental status score below 15).
• Cornell Depression Scale was developed for older adults with dementia and interviews not only the patient but someone who knows the patient to further help determine the mental state of the patient. A score above 18 is highly suggestive of depression, a score between 10 and 17 indicates a probable depression and one below 6 likely indicates the absences of depression.

A quick screen for depression can be run by asking the patient two questions.

1. In the last two weeks have you felt down or depressed?
2. In the last two weeks have you had little interest or pleasure in doing things?

Depression is a diagnosis of exclusion. No diagnostic test is available to definitely diagnose the disease. When it is suspected, other conditions must be ruled out. This is done with a history, physical exam, selected blood tests and occasionally radiographic tests to rule out conditions that may mimic depression.

In order for the condition to be managed appropriately, it needs to be diagnosed. A new clinical guideline recommends screening adults for depression when there is a place to ensure a correct diagnosis, appropriate treatment and follow up (U.S. Preventive Services Task Force, 2009). A similar statement has been made for adolescents with depression. Those between the ages of 12-18 years-old should be screened for major depression if a system is in place to accurately diagnose, provide psychotherapy and follow up. For those between 7-11 years-old there is not enough evidence to evaluate if screening is appropriate (U.S. Preventive Services Task Force, 2009).

Depression often co-exists with other mental health conditions. Healthcare professionals need to be on the lookout for other conditions. Identifying other conditions is important because it can significantly impact treatment options. For example, certain antidepressant medications are indicated for both anxiety and depression. Other antidepressant medications, while treating the depression, will make the anxiety worse.

One of the most common co-existent conditions is anxiety disorders. Anxiety disorders may include: generalized anxiety disorders, social phobia, obsessive compulsive disorder, panic disorder and post-traumatic stress disorder.

Other mental health conditions that may co-exist with depression include: substance and alcohol abuse, personality disorders, bipolar disease, eating disorders, adjustment disorder and schizophrenia.

In addition to mental illness, depression often co-exists with many medical diseases. Depression may be the result of the medical diseases or depression may exacerbate the medical disease. Common medical illnesses that are seen in combination with depression include: heart disease, cancer, stroke, Parkinson's disease, dementia and diabetes.

When evaluating someone with depression, identifying these medical conditions is critical in relation to medication selection. For example, individuals with high blood pressure and heart disease may want to avoid certain antidepressants that increase blood pressure such as venlafaxine.

Depression adversely affects chronic disease. Those with depression typically have more severe underlying medical illness and more cost associated with their medical illness (Katon & Ciechanowski, 2002). When faced with a person with probable depression it is important to consider other diagnoses. Some of them include:

• Anxiety disorders and other mental health conditions as discussed above
• Dementia
• Cancer of the central nervous system, mood changes are often noted before other neurological signs and symptoms
• Substance abuse: alcoholism, cocaine use, marijuana use or opioid abuse
• Inflammatory conditions such as systemic lupus erythematosus
• Sleep problems such as obstructive sleep apnea or insomnia
• Infectious disease such as Lyme Disease, syphilis or HIV
• Chronic fatigue syndrome
• Endocrine diseases such as hypothyroidism/hyperthyroidism, Cushing disease, prolactinoma and hyperparathyroidism
• Anemia
• Female hormonal disorders such as menopause or premenstrual dysphoric disorder

Some medications can cause depression. Common medications to consider as causes of depression include: Beta blockers, calcium channel blockers, steroids, H2 blockers, sedatives, chemotherapy agents or hormones.

Talk therapy can be used to treat depression either alone or in combination with medications. The two most popular therapies are cognitive behavioral therapy (CBT) and interpersonal therapy (IPT). Cognitive behavioral therapy helps change thought patterns and behaviors to improve mood. It is believed that the way one thinks and behaves contributes to their depression. Interpersonal therapy helps people with relationships that may be contributing to their depression.

Talk therapy is more effective in certain groups of people. Talk therapy is recommended for those with mild to moderate depression. In severe depression, it is recommended to stabilize the patient on medications before implementing talk therapy. A combination of talk therapy and medications is ideal for adolescents with depression (March, Silva, Petrycki, Curry, Wells, Fairbank, Burns, Domino, McNulty, Vitiello & Severe, 2004).

Psychotherapy helps to address the causative factors and the maintaining factors in depression. It is most effective in moderate-to-severe depression after a medication has stabilized the disease.

Many medications are available for the treatment of depression. Medications used to manage depression work mainly by altering the chemicals in the brain, particularly serotonin, norepinephrine and dopamine. Medications take a period of time before they work, typically 4 to 6 weeks. There is some evidence that some antidepressants have a quicker onset of action.

Medications for depression are not as effective as medications for many other conditions. A recent analysis showed that 38% of those treated with antidepressants did not have a positive response in 6-12 weeks (Agency for Healthcare Research and Quality, 2007).

It is critical that those with depression are diligent and follow up with their healthcare provider to assure that medication management is optimized. The initial drug at the initial dose is often not enough to provide an adequate response for depression. The dose often needs to be pushed or the medication needs to be changed or augmented.

Many different choices are available for the management of depression. The medication choice depends on multiple factors including physician preference, patient preference, adverse side effects and co-morbid conditions.

For years the treatment of choice for depression was tricyclic antidepressants (TCAs). Common TCAs include desipramine (Norpramin), amitriptyline (Elavil), nortriptyline (Pamelor), doxepin (Sinequan) and imipramine (Tofranil).

With the advent of newer antidepressants (selective serotonin reuptake inhibitors and others) the TCAs have fallen out of favor. TCAs have more side effects. Selective serotonin reuptake inhibitors (SSRIs) have many advantages over TCAs. Common side effects with TCAs include urinary retention, drowsiness, blurred vision, dry mouth, constipation and sexual side effects. One major concern with TCAs is that they are more lethal in overdose when compared to newer antidepressants. TCAs in high dose increase the risk of cardiac arrhythmia. TCAs are also associated with a number of drug interactions

Monoamine oxidase inhibitors (MAOIs) are another older class of antidepressants. They are not used often today because of better tolerated agents. MAOIs have the potential for serious interactions with both food and other medications, including over the counter medications. MAOIs are typically only prescribed by a prescriber who is well versed in monitoring these medications.

Individuals who take MAOIs and consume foods that contain tyramine have a significant risk of having a hypertensive crisis. Food that are high in tyramine include yogurt, fava beans, aged cheese, soy sauce, avocados, meat tenderizer, raisins, pickled/cured fish or meat, sauerkraut and caviar. Alcohol should not be used in those on MAOI. All individuals who take these drugs need to be well versed in which foods they need to avoid and which medications that need to be avoided. Common side effects include sexual dysfunction, insomnia, orthostatic hypotension, anxiety and weight gain. Two common MAOIs are phenelzine (Nardil) and tranylcypromine (Parnate).

In more recent years serotonin reuptake inhibitors (SSRIs) have come on the market and have become a drug of choice for first line treatment of depression. Medications in this class include: fluoxetine (Prozac), citalopram (Celexa), sertraline (Zoloft), fluvoxamine (Luvox), citalopram (Celexa) and escitalopram (Lexapro). In comparison to older antidepressants, this group has the advantage of simple dosing; they are easy to titrate, have fewer side effects, have fewer drug interactions and are low toxicity in overdose.

Different drugs have different side effects and different interactions, but a few common adverse effects include nausea, agitation, weight changes, delayed ejaculation, fatigue, impotence and restlessness. One major concern with SSRIs is that there are reports of increased suicidal thoughts and attempts in children on SSRIs with depression.

Fluoxetine (Prozac) was the first SSRI available in the United States. It is dosed at 20 mg in the morning and may be increased up to 80 mg. Each titration must occur after a few weeks on the medication. It is not indicated for those less than 8 years old and the dose should not be pushed past 20 mg in those between 8 and 17. A weekly formulation is available that is dosed 90 mg once a week. Fluoxetine can increase the levels of warfarin, phenytoin, carbamazepine, TCAs and benzodiazepines. It may lower the therapeutic effect of codeine. It may cause the serotonin syndrome when combined with other SSRIs and other antidepressants. It is pregnancy category C. Pregnancy category C means that there are no adequate animal or human studies that there are adverse fetal effects in animal studies but no human study data available.

Escitalopram (Lexapro) is a newer drug that may work faster than other SSRIs. Depression may lessen after 1-2 weeks instead of the standard 4 to 6 weeks that is common with other antidepressants. Escitalopram is dosed at 10 mg once a day and may be increased to 20 mg after one week. It has few interactions but may interact with other SSRIs, cimetidine and alcohol. It is pregnancy category C.

Serotonin and norepinephrine reuptake inhibitors (SNRIs) are a newer class of medications to treat depression. Drugs in this class include venlafaxine (Effexor), duloxetine (Cymbalta) and desvenlafaxine (Pristiq). This class has similar safety to SSRIs, but occasionally they may be associated with an increase in blood pressure. They can be used as a first line agent to treat depression or in those who do not respond to SSRIs. The SNRIs work on multiple neurotransmitters and do a better job at reducing the pain and other somatic complaints in depression when compared to other antidepressants (Thase, 2003).

Venlafaxine (Effexor) comes as an immediate release form and an extended release form. The extended release form is dosed 37.5 to 75 mg a day and may be titrated up to 225 mg. It is indicated for adults. It may interact with other antidepressants, cimetidine, diuretics and alcohol. It should not be used in those with severe uncontrolled hypertension. It is pregnancy category C.

Desvenlafaxine (Pristiq) is the newest drug in this class and is dosed 50 mg once a day for adults. It may interact with other SSRIs or blood thinners. It is pregnancy category C.

Duloxetine (Cymbalta) is dosed 20 mg twice a day to start and may be increased to 30 mg twice a day or 60 mg once a day in the adult. It may interact with ciprofloxacin, SSRIs, TCAs, antiarrhythmic and anti coagulants. It is pregnancy category C.

Duloxetine has multiple indications. It is approved for the treatment of depression in addition to diabetic peripheral neuropathy, fibromyalgia and generalized anxiety disorder. This drug is often used by those who have depression in addition to one of these co-morbid conditions.

Other antidepressants include bupropion (Wellbutrin), nefazodone (Serzone), mirtazapine (Remeron) and trazodone (Desyrel). Generally, this group has low toxicity in overdose and may have an advantage over the SSRIs by causing less sexual dysfunction and GI distress.

Bupropion is indicated for both major depression and seasonal affective disorder. It is indicated for those 18 year and older. It comes formulated multiple ways including Wellbutrin XL, Wellbutrin SR and Wellbutrin. It increases the risk of seizure at higher doses, particularly in those with a history of seizures.

Mirtazapine (Remeron) is dosed 15 mg at bedtime and may be increased every 1-2 weeks up to 45 mg in adults. It is given at bedtime because one of its major side effects is sedation. Another common side effect is weight gain. It rarely causes neutropenia. None the less, if any sign or symptom of infection is noted the medication should be discontinued.

Trazodone is indicted for those 18 years of age and older. It is not commonly used as an antidepressant because it is very sedating.

Medications need to be continued for at least 6-12 months for them to have lasting effects. If treatment is discontinued early than there is a high risk of relapse. Most antidepressants need to be weaned gradually. Abrupt discontinuation of antidepressants can result in serious side effects known as the discontinuation syndrome. Medications should be discontinued over about 2 months for those on treatment for 6-12 months and up to 6 months for those on long term treatment. Gradually tapering the medication is more critical if the patient is on a high dose.

St. John's wort is an herbal remedy for the treatment of depression and has been around for many years. St. John's wort (Hypericum perforatum) is used as a primary agent for depression in Europe, but in the United States it is an over-the-counter product. Its dosing is inconvenient as it is dosed 300 mg, three times a day. It is associated with nausea and should be taken with food.

Research suggests that it is no more effective than placebo in the treatment of moderate to severe depression. Some evidence suggests that it is helpful in mild to moderate depression. (National Center for Complementary and Alternative Medicine, 2008). Ongoing research is looking at its benefits in other mood disorders.

There is concern with some drug to drug interactions associated with St. John's wort. Case reports have suggested that it may lower cyclosporine levels and could lead to organ rejection (in organ transplant patients). It may also interact with other SSRIs and may lead to serotonin syndrome. Serotonin syndrome most often occurs when two drugs that affect the body's level of serotonin are taken together at the same time. The drugs cause too much serotonin to be released or to remain in the brain area. Symptoms occur within minutes to hours, and may include:

• Agitation or restlessness
• Diarrhea
• Fast heart beat
• Hallucinations
• Increased body temperature
• Loss of coordination
• Nausea
• Overactive reflexes
• Rapid changes in blood pressure
• Vomiting

Other drugs that it may interact with include birth control pills, digoxin, warfarin and indinavir. Side effects of St. John's Wort include fatigue, dry mouth, headache, anxiety, dizziness, nausea and sexual dysfunction.

Electroconvulsive therapy (ECT) can be used in specific cases of resistant or severe depression. This type of therapy involves sending an electrical impulse to an unconscious patient which triggers a small seizure. It is done a few times a week for 2-4 weeks. Benefits may be noticed after a few treatments but a full course is needed for maximal effectiveness. The patient is at high risk for relapse if there is no follow up.

ECT is believed to alter the chemistry of the brain. The benefits of this treatment are that it provides rapid onset of effect as opposed to other methods of treatments. It can be used in those with severe depression who are at high risk to commit suicide, those with catatonia, severe weight loss or those who are not eating. It is useful in those with depression and delusions and bipolar disease (Bhalla & Moraille-Bhalla, 2010).

ECT is associated with side effects. Confusion may occur, but this typically subsides within a few hours No major long-term side effects are noted. Memory loss may occur. Most commonly it is a retrograde amnesia which mean that patient may not recall things from just before the treatment. This typically improves after 1-2 months. Other side effects include headache and muscle aches. ECT is done under anesthesia which is associated with risk. The patient needs to be evaluated prior to the treatment to assure anesthesia is safe.

Light therapy is primarily used in those with seasonal affective disorder. It involves being exposed to a bright light and is thought to change the circadian rhythm. This bright light gives off an intensity that is more than the typical lighting found in the home. This may affect brain chemistry to help reduce depression related to seasonal affective disorder. It can also be used in those with typical depression as an augmentation method to an antidepressant. Side effects are typically mild and usually only transient. Side effects include nausea, vomiting, fatigue, headache, agitation and sleep problems.

Light therapy should be used cautiously in those who have bipolar depression as it may precipitate a manic episode. In addition, those with sensitive skin or taking a medication (retinoids or some antibiotics) that increase sun sensitivity may want to avoid this type of therapy. Light therapy may not be effective as a solo therapy. It is often combined with other treatments for maximal effectiveness. Light therapy may take a few weeks to work, but some notice benefits in a few days.

Pregnancy and depression is a hot medical topic. It is a prevalent problem, but the use of medication has some potential drawbacks. It is particularly problematic because many people are on antidepressants when they get pregnant and abrupt withdrawal of these agents is problematic.

Recently the American Psychiatric Association and the American College of Obstetricians and Gynecologists developed a statement to discuss how depression in pregnancy should be managed (Cowley, 2009). The groups determined that depression increases the risk of preterm birth, miscarriage, fetal growth problems and developmental delay. Antidepressant medications were also problematic. Antidepressants increase the risk of low birth weight, miscarriage and pulmonary hypertension. Each case must be evaluated individually. Ideally, depression should be identified and treated before the female becomes pregnant. Individuals who become mildly to moderately depressed during pregnancy should participate in psychotherapy. Those with severe depression are the most problematic. A few options are available.

• Treat the patient with medications after a complete discussion of the risks and benefits with the patient.
• Referral to a psychiatrist can be considered especially for those who have severe depression, suicidal ideation, psychosis, bipolar disease or those who are considering electro convulsive therapy.

One glaring omission from the statement was the fact there was no recommendation about which medication to use during pregnancy if one is needed. There was a warning against paroxetine as this drug was associated with a higher risk of cardiac malformations. Although this may be a class effect from the SSRIs.

Postpartum depression is also a major issue. It is very common with over 80% of women having a mood disturbance after childbirth (Bhalla & Moraille-Bhalla, 2010). Most cases are mild, but it can be severe and lead to significant morbidity for the mother. The majority of antidepressants are safe for the breastfeeding mother, but there is not enough research to say this definitely. Like in pregnancy, psychotherapy is a safe option.

Bipolar depression is a mental health condition where there is both depression and manic episodes. Undiagnosed bipolar depression can be a common cause of resistant depression. It is critical that providers consider this when faced with resistant depression. Bipolar depression can be picked up if the clinician performs the Mood Disorders Questionnaire. Treatment of bipolar depression often requires the addition or the sole use of a mood stabilizing agent such as lithium, divalproex sodium, olanzapine or quetiapine.

A black box warning has been posted on the use of some antidepressants indicating that antidepressant medications increase the risk of suicidal thoughts and attempts. This warning includes everyone taking antidepressants under the age of 25. There is a higher rate of suicidal thought and suicidal attempts in adolescents taking antidepressants than those taking a placebo (Food and Drug Administration, 2004).

Clinicians need to closely monitor young patients on antidepressants especially in the early phase of treatment with antidepressants. Healthcare providers need to watch out for suicidal thoughts, depression that is becoming worse or behavioral changes such as withdrawal and agitation.

Jenny was given the diagnosis of depression and was started on Sertraline (Zoloft) 25 mg and then the dose was titrated up after 2 weeks to 50 mg. She has a follow up appointment in six weeks after the initial appointment. She reported that she had more energy, but was still feeling a little sad. Her dose was increased to 100 mg once a day. She was encouraged to see a psychotherapist, but did not have time. At this point her PDQ-9 score improved to 10; which while improved still equated to moderate depression.

She had another appointment in 6 weeks. At this time she noticed an improvement in her mood, but did not feel 100%. Her PDQ-9 score was 9, which is classified as the upper range of minimal symptoms. She reported having no side effects from the drug, so at this point the nurse practitioner increased the dose to 150 mg. Even though her symptoms were classified as mild, she still had depression and given the improvement in response with the progressively increased dose and the lack of side effects the decision to increase the dose was carried out. At the follow up appointment in 6 weeks she reported that she had started seeing the psychotherapist that the nurse practitioner recommended and she felt as well as she had in years.

The point of this case study is that sometimes the dose needs to be pushed to achieve an adequate response. When medications improve mood, patients will at times consider getting themselves involved in therapy to enhance treatment.

John did not report depression on exam, but his irritability, social withdrawal and preoccupation with death were suggestive of depression. Depression is common after the loss of many social contacts. Dementia can cloud the depression picture. John reported that he is frustrated with his memory loss which was likely a contributing factor to his depression.

The patient was placed on escitalopram 10 mg and had a follow up appointment in four weeks. This drug is a nice choice in the older adult because it lacks many drug interactions and has a rapid onset of action. At the follow up appointment the son reported that he was much less irritable, but continued with social isolation. The MMSE improved to 22/30 and his Cornell Depression Score increased to 10. At this point, the escitalopram was increased to 20 mg. The son was given the number of the local Alzheimer's Association to help with support. The patient was also given the number of a psychologist to discuss some of his issues.

After another 4 weeks the patient was feeling much better. He was involved with a therapist and in a social group of older adults. At his follow up appointment depression was not clinically evident.